What's new in asthma management?
Author: Kevin M. Casey, DO, Assistant Director, Emergency Department, St. Vincent Mercy Medical Center; Clinical Assistant Professor, Department of Surgery, Medical University of Ohio, School of Medicine, Toledo, OH
Peer Reviewer: Jacob W. Ufberg, MD, Associate Professor of Emergency Medicine, Residency Director, Department of Emergency Medicine, Temple University Hospital, Philadelphia, PA
Asthma is a very common disease in the United States, and it continues to affect substantial numbers of people.1 Inhaled corticosteroids, with the occasional dose of a short-acting rescue beta2-agonist inhaler, is the most effective and appropriate preventative management for mild to moderate asthma.2 Exacerbations of asthma are cause for great concern because they often lead to emergency department visits, hospitalization, and, although infrequent, death.3 Endotracheal intubation of a patient with an acute asthma exacerbation often makes the care of the patient more complicated, has a significant association with adverse effects,4 and a high mortality rate.5
There have been many modalities suggested as a means to decrease the frequency and severity of asthma exacerbations, manage acute exacerbations, and to prevent the need for endotracheal intubation in a patient with a severe exacerbation. This article reviews some of the more recent literature in an attempt to determine which modalities are helpful, which are potentially harmful, and those that are neither.
Salmeterol: A SMART idea?
Source: Nelson HS, et al. The Salmeterol Multicenter Asthma Research Trial (SMART). A comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129:15-26.
The authors undertook this randomized, blinded, placebo-controlled study of patients older than 12 years to compare the safety of salmeterol with placebo when given in addition to the usual asthma therapy. The study was stopped after an interim analysis of 26,355 patients demonstrated a statistically significant increase in the number of respiratory-related deaths and asthma-related deaths among the subjects assigned to the salmeterol group when compared with the placebo group. The difference was most pronounced in the African-American subpopulation. The authors pointed out the lack of statistical significance for respiratory-related deaths in the total population.
A large study in the United Kingdom, comparing salmeterol with salbutamol, demonstrated an increased risk of death (three times) from asthma among the patients using the salmeterol.6 To address these findings, GlaxoSmith-Kline (the manufacturer of salmeterol xinafoate) then undertook the SMART study. The numbers found in the SMART study are very similar to those of the UK study (e.g., 4.4 times the rate of death in the salmeterol group). These numbers alone would suggest that long-acting beta-agonists such as salmeterol present an increased risk in certain patients with a diagnosis of asthma.
There is also evidence to suggest that the negative outcomes with the use of long-acting beta-agonists can be decreased with the concurrent use of an inhaled corticosteroid.7,8 The SMART study did not address the use of inhaled corticosteroids with the long-acting beta2-agonist, nor did it address medical compliance. The African Americans in the SMART trial also tended to have more severe and more poorly controlled asthma. Nonetheless, the findings of these studies have led the U.S. Food and Drug Administration to require a "black box warning" on salmeterol and on the salmeterol-fluticasone combination.
Current studies demonstrate the need for more studies to address the use of long-acting beta-agonists. Currently, long-acting beta-agonists should not be used as monotherapy for the treatment of asthma. For those patients who are not well controlled on inhaled corticosteroids and who need a rescue beta-agonist more than two times a day, then a long-acting beta-agonist may be considered. The patient should be chosen carefully, and should be reliable enough to take all the medications as prescribed. Close monitoring is a must. A combination of the long-acting beta2-agonist with an inhaled corticosteroid in the same inhaler may be an appropriate choice. However, given the required "black box" warning, any physician prescribing a long-acting beta-agonist does so at considerable risk.
Levalbuterol vs albuterol
Source: Qureshi F, et al. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005; 46:29-36.
Levalbuterol has been touted as being superior to racemic albuterol in the treatment of a moderate to severe acute exacerbation of asthma. It also has been claimed that levalbuterol is better tolerated and has fewer side effects than racemic albuterol. The authors of this prospective, double-blind, randomized controlled study of 129 children between the ages of 2 and 14 years attempted to prove that levalbuterol is more efficacious than racemic albuterol.
All were treated according to a standardized ED asthma treatment pathway. All were experiencing an acute, moderate to severe asthma exacerbation. Equivalent doses of levalbuterol or racemic albuterol were given, and measurements were taken after the first, third, and fifth treatments. Measurements were recorded as changes in the following parameters: clinical asthma score, percentage of predicted forced expiratory volume in 1 second, total number of treatments needed, length of ED stay, rate of hospitalization, changes in pulse rate, respiratory rate, and oxygen saturation.
The results demonstrated no statistically significant difference in any of the outcome measures between the levalbuterol group and the racemic albuterol group.
Previous studies of the utility of levalbuterol in the setting of an acute asthma exacerbation have demonstrated a benefit toward decreased hospitalization with levalbuterol when compared with racemic albuterol in children.9 Methodological concerns preclude basing the use of levalbuterol upon that one study. Other studies—most with methodological concerns themselves—have been conflicting in their results.
This study demonstrated no superiority of levalbuterol over racemic albuterol. Although this study does not have the power to demonstrate efficacy of the two treatments, it would have the power to show a clear superiority of one over the other. In a recent study, Schreck and others have suggested that the more expensive levalbuterol is actually cost effective, because it demonstrated a greater number of ED discharges in comparison with the racemic albuterol.10 The problematic design, and the lack of controls in the study by Schreck make that conclusion very suspect. One very interesting aspect of the study by Qureshi is that it is sponsored by a manufacturer of levalbuterol. The lack of significant superiority in the study, coupled with the financial backing, makes the results of this study that much more compelling.
While one has not been conclusively shown to be more effective, or to have fewer side effects than the other, the increased cost of levalbuterol when compared that of racemic albuterol makes it hard to use levalbuterol as the primary beta-agonist in the patient with a moderate to severe acute asthma exacerbation.
Corticosteroids for asthma?
Source: Clark S, et al. Observational study of intravenous versus oral corticosteroids for acute asthma: An example of confounding by severity. Acad Emerg Med 2005;12:439-445.
Corticosteroids are a mainstay of treatment in the patient with a moderate to severe asthma exacerbation. It also has been well established that oral and intravenous corticosteroids are equally efficacious. The results of this study seem to refute the findings of the previous studies.
This was an observational study—not one that was randomized — of 1847 patients. In an attempt to correct for the lack of randomization, multivariate logistic regression and stratification were employed. A number of characteristics and outcomes were measured, with a majority of them finding statistical difference between the two. The most important clinical variables measured were ED length of stay and hospital admission (defined as observation admission, hospital admission, or reoccurrence of the asthma attack within 48 hours). All of the statistically significant differences were in favor of a better outcome with the oral route of corticosteroid administration.
The authors appropriately stated that the results they obtained, in comparison to previous studies, were not due to a true difference resulting from the route of corticosteroid administration. They were a result of the difficulty of providing an accurate study design in the treatment of a disease entity that may dictate certain aspects of the care.
There is little debate that corticosteroids are a very important treatment in patients with acute asthma exacerbations.11 While there is much debate regarding the acute efficacy of the use of inhaled corticosteroids, it is fairly well established that oral and intravenous routes of corticosteroid administration are equally effective.12-14 This study demonstrated that what appears to be convincing results can often be misleading and needs to be interpreted with care.
This study mimics what is most often seen in clinical practice. It is difficult to give oral medications to a patient who is having difficulty breathing. It is not difficult to give oral medications to a patient who is complaining of shortness of breath, but is conversing in full sentences. By the nature of the disease, those who are experiencing a worse exacerbation would be preferentially given corticosteroids through an intravenous route. The factors that skewed the results of this study demonstrated what most of us believe in our everyday practice: Intravenous steroids may be reserved for those asthma exacerbations where the patient is in extremis and cannot safely take oral medications.
Combination therapy reduces admission rate
Source: Rodrigo GJ, et al. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax 2005;60(9):740-746.
The National Heart, Lung, and Blood Institute states, "Ipratropium bromide may provide some additive benefit with inhaled beta2-agonists in severe asthma exacerbations."15 The literature supporting this recommendation, however, has been less than overwhelming. The authors of this study attempted to pool, review, and organize the information from multiple studies to either strengthen or refute the use of nebulized anticholinergics in addition to beta-agonists when compared with the use of beta-agonists alone.
This study is a meta-analysis of more than 3000 subjects from 32 randomized, controlled trials. Heterogeneity of the different protocols and outcomes tested in the various studies make any meta-analysis dealing with asthma exacerbations difficult, but the authors believed that they were able to compensate for this fact.
The authors concluded that children who received both the nebulized beta-agonist and anticholinergics had a significantly lower admission rate (number needed to treat = 13 for all exacerbations, number needed to treat = 7 for severe exacerbations). Similar results were found for adult admissions (number needed to treat = 14). There were also statistically significant improvements with spirometric testing in children with the combination treatment, with greater benefit with a greater number of treatments. There was no significantly greater incidence of side effects with the combined treatment when compared with the beta-agonist alone.
The results of this analysis are quite impressive. They certainly suggest that inhaled anticholinergics show great benefit in the moderate to severe asthma exacerbation, with a greater benefit to those with a more severe exacerbation. The lack of increased side effects noted with the use of the anticholinergics makes this use even more attractive. In looking at some of the studies included in this analysis, the lack of adequate beta-agonist dosing could have affected the results. However, results as stated here are impressive enough to warrant very strong consideration of multiple, fixed-dose inhaled anticholinergics in addition to adequate doses of inhaled beta-agonists for a patient with a moderate to severe asthma exacerbation.
Driving for results with helium/oxygen
Source: Kim IK, et al. Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: A randomized, controlled trial. Pediatrics 2005;116:1127-1133.
The use of a helium/oxygen combination has been studied in a recent Cochrane review as an adjunct treatment for an acute asthma exacerbation in adults.16 The review concluded that the combination is ineffective as a treatment, as measured by pulmonary function tests. What has not been well tested, however, is the use of a helium/oxygen combination as a driver for the nebulized beta-agonist medication. The authors of this study addressed this question in children with acute asthma exacerbations.
In this small (15 subjects per arm), randomized, controlled, single-blinded study, the authors studied the effects of helium/oxygen as a driver for the nebulized beta-agonist on the following factors: pulmonary index (PI) score, discharge to home from the ED, discharge from the ED in less than 3 hours, and numbers admitted to the floor and to the PICU.
All patients were given 5 mg of nebulized albuterol with 100% O2 and a dose of oral corticosteroids. At the administration of the steroid dose, the patients were assigned to 15 mg nebulized albuterol driven with either 100% O2 by facemask or by a helium/oxygen concentration of 70%/30%. Evaluation of the patient was made every 60 minutes, and disposition was made after 240 minutes of treatment. PI scores were significantly different, in favor of the helium/oxygen driven arm after 125 minutes of treatment, and continued to be significant through 240 minutes. Twice as many patients were discharged from the ED in the helium/oxygen group. One from each group was admitted to the PICU, and four from the helium/oxygen group were admitted to the floor, with nine from the oxygen driven group (none statistically different).
Although a small study, results suggested that the use of a helium/oxygen mixture as a driver for beta-agonists is beneficial for children in moderate to severe asthma exacerbations. One of the more clever things in this study was the use of video monitors to help blind one of the scorers from the voice changes associated with the use of helium. It is also interesting to note that this study ensured the use of adequate doses of beta-agonists, which is lacking in many studies addressing asthma exacerbations.
These results are supported in a recent study of adults with severe asthma exacerbation, as measured by peak expiratory flow rate.17 The study found a greater benefit in older patients and in those with worse exacerbations. However, another small blinded, randomized, controlled study involving children demonstrated no statistically significant benefit between the two modalities in modified dyspnea index score or admission rates.18
The results of this study show promise. Further studies are needed, but this is a treatment modality that appears to show more promise than most adjunct treatments currently being touted.
Nebulizers vs aerochambers
Source: Cates CJ. et al. Holding chambers versus nebulizers for inhaled steroids in chronic asthma. The Cochrane Database of Systematic Reviews 2006, Issue 1, Art No: CD001491.pub2.
The authors of this review attempted to collect, review, and analyze literature comparing the efficacy of inhaled corticosteroids delivered through a nebulizer when compared with using an aerochamber.
Three studies were found to be worthy of review. All were randomized, but were of variable quality. Two of the studies involved adult patients, while the third evaluated the effects in 12 children. Different outcome endpoints were measured in the three studies. A clinically relevant outcome of number of doses of a rescue inhaler needed was found. This significant difference was in favor of the nebulizer group, when using 8000 mcg a day, in comparison to using an aerochamber. There was no difference when using 2000 mcg a day in the nebulizer.
In addition to the endpoint outcomes measured, the pediatric study inquired about the parent's preference in method of delivery. The parents preferred the aerochamber to the nebulizer machine.
These results lead us to conclude that there is a lack of convincing evidence to support the use of either the nebulizer machine or an aerochamber as a preferred method of delivery for inhaled corticosteroids. Which method is used would best be dictated by the parent's preference and ease of use. If a family already has a nebulizer machine and is very comfortable in its use, then using it as a delivery method for inhaled corticosteroids might be more appropriate. There were a few questionably clinically relevant outcomes that had better results with the nebulizer. However, if the patient is unfamiliar with the use of a nebulizer machine, if the nebulizer would be cost prohibitive, or the patient/parental investment is suspect, then the use of an aerochamber in an effort to increase compliance would certainly be warranted. Prescribing the appropriate medication in a manner that the patient will actually use it is a very important aspect of good patient care.
BiPAP as alternative to ETI
Source: Soroksky A, et al. A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest 2003;123:1018-1025.
Endotracheal intubation of a patient in respiratory distress often makes the care for the patient more complicated, not less. An intervention that would help improve the patient's condition without the complications associated with endotracheal intubation would be a great addition in the care of the patient with a severe asthma exacerbation. Noninvasive positive pressure ventilation has been shown to be beneficial in a number of respiratory conditions, and the hope that it could be useful in the care of the severe asthma exacerbation has led many to study its use. This is a placebo-controlled, randomized trial comparing standard medical care for asthma (salbutamol, ipratropium, and intravenous corticosteroids at physician discretion) alone with the standard medical care plus the addition of bi-level positive airway pressure (BiPAP). Statistically significant outcome differences between the two groups included hospitalization rate, discharge rate from the emergency department, FEV1, PEFR, and respiratory rate after treatment, all in favor of the bi-level positive airway pressure group. There was no difference in the number of treatment failures, need for endotracheal intubation, or deaths between the two groups.
While the study is small (15 patients per arm), the results initially look promising. Concerns with the methodology include the small inspiratory pressures used with the BiPAP and the lack of standardization of the medical care given to the patients. The BiPAP group received a larger dose of intravenous corticosteroids, received it more often, and received a greater number of nebulized salbutamol and ipratropium doses (none of which were statistically different). Although the researchers were unable to completely blind the participants in the study, the device and method used is quite creative.
The idea of using BiPAP to avoid endotracheal intubation in the severe asthmatic patient is quite attractive. This study provides a good starting point for further research (using a much greater number of subjects) to support its use. While this study does not show a greater number of adverse outcomes with the use of BiPAP, the small numbers used also make the validity of this measurement questionable. However, despite some differences in a few measured outcome variables, this study does not support the use of BiPAP as a measure to prevent endotracheal intubation in the patient with acute, severe asthma exacerbation. It is important to note that the use of BiPAP may not result in patient improvement, nor does its use require less diligence on the part of the physicians and nurses caring for the patient.
Agarwal and others reported a case of failed BiPAP in a severe asthmatic patient who required endotracheal intubation.19 The case they presented only demonstrates the careful monitoring that must take place of the patient with a severe asthma exacerbation, no matter what modalities are used to treat the patient.
Ketamine use in severe asthma
Source: Allen JY, et al. The efficacy of ketamine in pediatric emergency a department patients who present with acute severe asthma. Ann Emerg Med 2005;46:43-50.
Ketamine has been reported in case reports to be an effective treatment for the acute, severe asthma exacerbation.20 In this study, the authors attempted to demonstrate whether ketamine would be shown to be effective in a double-blind, randomized, placebo-controlled study of 53 patients.
Each of the patients was given three treatments of nebulized albuterol, ipratropium bromide, and oral or intravenous corticosteroids. If the patient was deemed to have not improved sufficiently after the initial treatment, the patient was started on either a continuous infusion of ketamine or placebo. Measurements were taken of the patient's pulmonary index, pulse rate, blood pressure, temperature, and continuous pulse oximetry. Disposition of the patient was logged as a secondary outcome. There were no significant differences between the groups that completed treatment in the outcomes measured.
Ketamine is another of the "alternative bronchodilators" that has been discussed in case reports as a useful adjunct in the care of a patient with severe, acute asthma exacerbation. An earlier pilot study by Petrillo and colleagues suggested that ketamine might have just such utility.21
This study by Allen and colleagues would refute that point. It, however, is not without a few points of contention. The patients were enrolled as a convenience sample. There is also some question as to the dose that was given. The dosages used in this study were considerably smaller than the dosages used in the study by Petrillo. The lack of central nervous system effects while the ketamine was infused could suggest that the dosages were insufficient.
This study may not purely represent the results of ketamine use because all the patients were receiving adequate doses of other medications while the ketamine was being infused. This is appropriate, however, as it is difficult to imagine a situation where an emergency medicine physician would withhold nebulized albuterol aerosol treatments while infusing ketamine.
This current study seems to suggest that ketamine is not effective in the treatment of the acute, moderate to severe asthma exacerbation. While not as benign as magnesium sulfate and furosemide, the side effects of the use of an appropriately dosed ketamine infusion may not be enough to prohibit its use in an attempt to avoid endotracheal intubation of the patient in extremis.
Use of nebulized beta-agonist alone?
Source: Yen ZS, et al. Best evidence topic report. Nebulized furosemide in acute adult asthma Emerg Med J 2005; 22:654-655.
The authors reviewed 87 studies evaluating the use of nebulized furosemide in the patient with acute asthma exacerbation. The question asked was: Is nebulized beta-agonist with furosemide more efficacious than nebulized beta-agonist alone in the treatment of an acute asthma exacerbation?
They identified three studies in this shortcut review that presented evidence contributing results to the clinical question. All three studies were prospective, randomized controlled studies and included 86 patients. Other variables made each of the studies suspect in their conclusions. PEFR was measured in two studies, and FEV1 in the third. No clinical differences were measured. The smallest study demonstrated a statistically significant difference in the PEFR in favor of the combined treatment at 30 minutes. None of the other studies demonstrated any significant difference between the two groups.
The authors concluded that there is insufficient evidence to support the use of nebulized furosemide in the patient with an acute asthma exacerbation.
Furosemide and magnesium sulfate are two of the more commonly discussed "alternative bronchodilators" in the a patient with acute asthma exacerbation. Although magnesium has generated more popular support in the treatment of the moderate to severe asthma exacerbation, furosemide remains popular with many. The authors suggested that there is a lack of evidence to support the use of inhaled furosemide in the acute exacerbation. Interestingly, a small study of 39 people suggested that inhaled furosemide is more effective than inhaled magnesium sulfate when both are compared with placebo, although they did not look at outcomes that are directly clinically relevant.22
Another recent pediatric study compared 20 children who received nebulized albuterol, 20 children who received nebulized furosemide, and 19 children who received both nebulized albuterol and furosemide.23 Their results suggested that the combination therapy provides a greater increase in peak flow rate, but not in FEV1, FVC, respiratory rate, pulse oximetry, or any clinically relevant variables.
Although not supported strongly with the current literature, the lack of significant side effects makes nebulized furosemide a potential tool in an effort to prevent endotracheal intubation for the asthmatic children in extremis.
(Editor's note: currently, furosemide aerosol is not FDA approved for this indication.)
Is magnesium a player?
Source: Blitz M, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev. 2005; Issue 4: CD003898.
Many have accepted the use of intraveous magnesium in the treatment of the patient with a moderate to severe asthma exacerbation. Many have championed the use of inhaled magnesium sulfate for the moderate to severe asthma exacerbation as well. In an effort to pool, review, and provide evidence-based conclusions to the use of inhaled magnesium, the researchers have provided a Cochrane review of the relevant literature.
The review found six relevant studies, with a total of 296 patients. Three of the studies were of adults only, two of pediatric patients only, and one involved pediatric and adult patients. The severity of disease, lack of common outcome measures (except pulmonary function tests), the heterogeneity of the patients, and the other treatments provided make the combining of the information difficult.
There appears to be no difference in hospital admission in patients who are given a beta-agonist alone versus those given a beta-agonist with inhaled magnesium sulfate, or those given inhaled magnesium instead of an inhaled beta-agonist. There may be a benefit in pulmonary function test results for those who are given both a beta-agonist and magnesium sulfate, but the clinical relevance of this is unclear.
Despite most ED physicians believing that inhaled magnesium sulfate is beneficial in the patient with an acute asthma exacerbation,24 convincing evidence of this belief is lacking.
In what appears to be an attempt to provide the best evidence-based information on the use of inhaled magnesium sulfate in an asthma exacerbation, the authors were unable to arrive at a strong conclusion. The heterogeneity of studies and of the severity of the asthma exacerbations as complications of of this disease makelarge studies entity very difficult. What most studies have demonstrated is a lack of adverse side effects from the use of inhaled magnesium sulfate—when used in addition to adequate beta-agonists—for cases of moderate to severe asthma exacerbation.
Inhaled magnesium sulfate does not appear to have a great clinical benefit for moderate to severe asthma exacerbations, and it is certainly not ready to be listed as a first-line treatment. However, the possible benefit, with the very low side effect profile, makes the use of inhaled magnesium sulfate another tool that may be used in a concentrated attempt to prevent the need for endotracheal intubation in a patient with a severe asthma exacerbation. Currently, the literature is insufficient to suggest that inhaled magnesium sulfate is more effective or should be used in place of intravenous magnesium sulfate.
(Editor's note: currently, magnesium aerosol is not FDA approved for this indication.)
A moderate to severe asthma exacerbation can be frightening to the patient, the patient's family, and to the health care providers caring for the patient. The care can be very labor and time intensive. With the increasing number of patients reported to have asthma, the number of exacerbations also can be expected to increase.
The first-line treatment for the asthma exacerbation remains aerosolized short-acting beta2-agonists. Adequate doses of the beta2-agonists often are enough to correct the exacerbation. For those with more than a mild exacerbation, corticosteroids also should be given. Although the effects of the corticosteroids will not be appreciated for some hours after they are given, they clearly help the patient to recover and to help prevent another exacerbation in the near future. When the beta2-agonists fail to improve the patient's condition satisfactorily, other adjunctive therapies may be used in an attempt to prevent the need for endotracheal intubation.
The use of nebulized anticholinergics and the use of a helium/oxygen combination as a driver for the nebulized beta2-agonists appear to be somewhat effective, and may be very helpful for the moderate to severe asthma exacerbation. Nebulized magnesium sulfate, furosemide, ketamine infusion, and bi-level positive airway pressure do not seem to be as effective, if effective at all. Given the low incidence of side effects found with these treatments, they still may warrant consideration in the patient with a severe asthma exacerbation in an attempt to prevent the need for endotracheal intubation. There is no difference in the efficacy of corticosteroids if they are given either intravenously or orally, and there is no superiority of levalbuterol over racemic albuterol. Similarly, nebulizers and aerochambers for inhaled corticosteroids appear equally efficacious. The use of long-acting beta2-agonists should not be used as monotherapy, if at all.
More well-designed, large studies still are needed to develop an effective protocol in the treatment of the moderate to severe asthma exacerbation. Until then, the practicing physician will have to continue to give care as is deemed appropriate for the individual patient, with careful weighing of the risks and benefits of each treatment.
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