A Controlled Trial of Long-term Bronchodilator Therapy in Cystic Fibrosis* Peyton A. Eggleston, M.D.; Beryl J Rosenstein, M.D.; Claire M. Stackhouse, M.S.N., C.P.N.P.; E. David Mellits, Sc.D. and Rosemary A Baumgardner, B.A. To evaluate the effect of long-term bronchodilator therapy in CF patients with demonstrated bronchial hyperresponsiveness, we first performed methacholine challenges to determine responsiveness, then entered 27 patients (16 methacholine responders and 11 nonresponders) into a twomonth double-blind crossover trial of albuterol, 90 p.g by inhalation four times a day vs placebo. Among the responders, daily PEFR measures improved significantly more during treatment with albuterol (12±32 Umin) than with placebo (- 0.4 ± 19 Umin; psponses to methacholine were excluded. Patients were not excluded on the basis of their disease severity, except as it influenced their ability to perfi>rm a methacholine challenge test. llowewr, patients who had three or more pulmonary exacerbations in the previous six months and those who felt they muld not disl•mtinue their usual hronchrts; the highest value fi>r each was l•>mpared with predicted norms." " Acute bronch was mnducted on a separ.de day by the meth•KI ofChai and l•>lleagues." Bronchooilators were excluded for at least 12 hs and subjects were not tested within one month of an acutt• respiratory infection (ie, a viral "cold" or an acute t>Xal-erbation treated with antibiotics). Patients whose baseline FEV, was less than 25 percent of predicted were not tested. The patient long-term Bronchodilator Therapy in CF (Eggleston et at)
inhaled five breaths of buffered saline solution and FEY, was measured again at 1'12 min. If this control value did not decrease by 10 percent, increasing concentrations (0.075, 0.15, 0.3, 0.6, 1.25, 2.5, 5, 10, 25 mglml) of methacholine were inhaled until the FEY, decreased by 20 percent or more from the control value. Subjects with PD,..FEY, values less than 60 breath units (one breath unit equals one inhalation of 1 mg/ml) were classified as responders since over 95 percent of patients with asthma respond at this concentration.'" Those with values over 90 breath units were classified as nonresponders. Patients with PD,.,FEY, values between 60 and 90 breath units were not included to allow clearer separation between responders and nonresponders. Medication Trial
Patients first underwent a two-week observation period, followed by a ten-week treatment period. During the treatment period, either albuterol or placebo was administered from metered-dose inhalers four times a day for four weeks. After a two-week washout period, the other treatment medication was administered for the last four weeks. Beginning with the initial observation period, patients and their parents maintained a diary of symptoms and daily PEFR measurements. Every two weeks, they returned to the clinic to review their diary, record a spirogram and re21 ·22 may have ht>en eq11ally important. It is possible that higher doses of inhaled adrenergic agonists or dosing in combination with methylxanthines might have been mort> dlel'tive, hut these possibilities will have to he addresst>d in fitture st11dies. Treatment with prednisone ewry other day has been reported to slow the decline of pulmonary f11nl'tion in CF patients. 23 Chronic corticosteroid therapy diminishes brmtl·hial responsiveness in patients with asthma, 2 t perhaps because of its effect on airway inflanunation2.5 and on the inereased bronchial responsiveness that results from acute airway inflammation. 26 It wo11ld th11s he of partil'11lar interest to evaluatt> chronic curtil'osteroid therapy in CF patients with bronchial hyperresponsiveness, whom we finmd to have benefitted by chronic bronchodilator therapy. ACKNOWLEDGMENTS: The author~ ~ratefully acknowled~e l1t'lp of Dmma Dieterid1 with preparation of the manuscript.
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Di Sant"A~nese PA. Pulmonary manifestations of fihnK·ystic disease of the panL·reas. Dis Chest 1955; 27:6.'>4-67 Lloyd-Still JR. Khaw KT, Shwachman II. Severe respiratory disease in inlimts with cy stil· fihrusis. Pediatrics 1974; 30:389-96 \'an 1\lt'tre TE Jr. Cooke RE, Cihson LE, Winkenwerder \\'L. Evidt'nt•e of all .. ..,.,') in patients w;th t:ystit• llhrusis of the lliiiKTeas. J Aller,_'). 1000; :31:141-.'50 Zaplt•tal A. 1\lotoyama EK. Gihson LE. Boulmys A. Pulnumary nll'dmnit·s in asthma and cystil· fihrusis. Pediatrics 1971; 41!:6472 Chan~ N. Levison II. Tht• eRect of nehulized hrunchodilator administered with ami without iutermittent posith·e pressure hreathin~
inhaled five breaths of buffered saline solution and FEY, was measured again at 1'12 min. If this control value did not decrease by 10 percent, increasing concentrations (0.075, 0.15, 0.3, 0.6, 1.25, 2.5, 5, 10, 25 mglml) of methacholine were inhaled until the FEY, decreased by 20 percent or more from the control value. Subjects with PD,..FEY, values less than 60 breath units (one breath unit equals one inhalation of 1 mg/ml) were classified as responders since over 95 percent of patients with asthma respond at this concentration.'" Those with values over 90 breath units were classified as nonresponders. Patients with PD,.,FEY, values between 60 and 90 breath units were not included to allow clearer separation between responders and nonresponders. Medication Trial
Patients first underwent a two-week observation period, followed by a ten-week treatment period. During the treatment period, either albuterol or placebo was administered from metered-dose inhalers four times a day for four weeks. After a two-week washout period, the other treatment medication was administered for the last four weeks. Beginning with the initial observation period, patients and their parents maintained a diary of symptoms and daily PEFR measurements. Every two weeks, they returned to the clinic to review their diary, record a spirogram and re21 ·22 may have ht>en eq11ally important. It is possible that higher doses of inhaled adrenergic agonists or dosing in combination with methylxanthines might have been mort> dlel'tive, hut these possibilities will have to he addresst>d in fitture st11dies. Treatment with prednisone ewry other day has been reported to slow the decline of pulmonary f11nl'tion in CF patients. 23 Chronic corticosteroid therapy diminishes brmtl·hial responsiveness in patients with asthma, 2 t perhaps because of its effect on airway inflanunation2.5 and on the inereased bronchial responsiveness that results from acute airway inflammation. 26 It wo11ld th11s he of partil'11lar interest to evaluatt> chronic curtil'osteroid therapy in CF patients with bronchial hyperresponsiveness, whom we finmd to have benefitted by chronic bronchodilator therapy. ACKNOWLEDGMENTS: The author~ ~ratefully acknowled~e l1t'lp of Dmma Dieterid1 with preparation of the manuscript.
the
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16 17 II!
2 3
4
.'5
6
7
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Di Sant"A~nese PA. Pulmonary manifestations of fihnK·ystic disease of the panL·reas. Dis Chest 1955; 27:6.'>4-67 Lloyd-Still JR. Khaw KT, Shwachman II. Severe respiratory disease in inlimts with cy stil· fihrusis. Pediatrics 1974; 30:389-96 \'an 1\lt'tre TE Jr. Cooke RE, Cihson LE, Winkenwerder \\'L. Evidt'nt•e of all .. ..,.,') in patients w;th t:ystit• llhrusis of the lliiiKTeas. J Aller,_'). 1000; :31:141-.'50 Zaplt•tal A. 1\lotoyama EK. Gihson LE. Boulmys A. Pulnumary nll'dmnit·s in asthma and cystil· fihrusis. Pediatrics 1971; 41!:6472 Chan~ N. Levison II. Tht• eRect of nehulized hrunchodilator administered with ami without iutermittent posith·e pressure hreathin~
