Inhaled Flunisolide in Acute Severe Asthma

ABSTRACT & COMMENTARY

Synopsis: In this study, high-dose inhaled flunisolide was associated with greater improvement in lung function than placebo over three hours in patients treated for acute asthma, although the magnitude of the difference was small.

Source: Rodrigo G, Rodrigo C. Am J Respir Crit Care Med 1998;157:698-703.

In this prospective, randomized, controlled trial, 94 adult patients presenting to a hospital emergency room with acute severe asthma (forced expiratory volume in the first second [FEV1] approximately 26% of predicted, peak expiratory flow rate [PEFR] about 160 L/min) received inhaled albuterol plus either inhaled flunisolide or placebo over a period of three hours. Both drugs were administered successively through a metered-dose inhaler plus spacer at 10-minute intervals. Both FEV1 and PEFR improved significantly over baseline values in both treatment groups, but both measures were significantly greater in the flunisolide group at 90, 120, 150, and 180 minutes using ANOVA. Two-way ANOVA suggested that the difference between the treatment groups increased over time. The difference for FEV1 between the two patient groups amounted to about 10% of the predicted value at three hours; PEFR was also about 10% of the predicted value.

Further analysis of the data revealed significantly different responses depending on how long the asthma attacks had been going on before the patients presented to the emergency room. Among patients randomized to the placebo group, those whose attacks were of greater than 24 hours duration had significantly lower FEV1 at 120, 150, and 180 minutes than those patients in the three other groups.

For all the patients in the study, there was no significant difference in the rate of hospitalization following emergency room treatment for patients treated with flunisolide vs. placebo. However, when only patients with attacks lasting more than 24 hours were considered, those who received placebo were statistically more likely to be admitted to the hospital than those treated with flunisolide (7/25 vs 1/27; P = 0.005).

COMMENT BY DAVID J. PIERSON, MD

The results of this carefully designed and well-performed study from Uruguay seem to be at variance from those of all previously reported studies on corticosteroid treatment in acute severe asthma. That is, all available in vitro and clinical data tell us that it takes at least 4-6 hours for the intracellular sequence of events to occur, which results in improved airway function associated with the anti-inflammatory effect of corticosteroids. Why, then, was there a greater improvement in airway function in patients who received both albuterol and flunisolide than in patients who received only albuterol?

One possible reason, discussed both by the authors and in an accompanying editorial by McFadden (McFadden ER. Am J Respir Crit Care Med 1998;157:677-678), is that flunisolide at high doses may have airway effects in addition to those usually associated with corticosteroids. To varying degrees, different corticosteroids applied topically produce local vasoconstriction, and flunisolide is some 300 times more potent in this regard than dexamethasone. Patients in the flunisolide group received 18 mg of the drug over the three-hour study period-a high dose. Thus, it is possible that the significant differences in FEV1 and PEFR observed in the steroid-treated patients represent a temporary, nonspecific local vascular effect unrelated to anti-inflammatory action that might have little effect on the overall recovery from the asthma attack. In patients whose attacks had been going on for more than 24 hours prior to being treated, there may have been more airway edema (a known feature of acute severe asthma), explaining the greater effects on airway function and, also conceivably, the different rate of hospitalization in this subset of patients.

In any event, the results of this study are provocative and worthy of further confirmation by other investigators. Should clinicians change the way they manage asthma in the emergency room (and by inference, also in the ICU) on the basis of this study? In my opinion, they should not. The differences shown were statistically significant but modest in magnitude. No other study has shown a detectable effect of corticosteroids (by any route of administration) in the first three hours of treatment, and topical administration in other circumstances has less clinical effect than intravenous administration in the dose range used for acute severe asthma. If the difference observed in this study proves to be the result of temporary local vasoconstriction in the airway mucosa, unrelated to the effects of corticosteroids beginning several hours later, whether it represents a clinically significant effect will also need to be determined.