Corticosteroids have proven to be valuable in the treatment of asthma, but their use is limited because of the undesirable and often serious side effects from their prolonged administration. Al-temate-day administration has reduced, but not eliminated, these difficulties. As another means of reducing systemic side effects, administration of aerosol hydrocortisone, prednisolone, and dexa-methasone has been evaluated. These steroids were effective only at doses which suppressed adrenal function. Fluorinated steroid esters that are highly active topically show promise of controlling asthma at doses that do not produce systemic effects.
Triamcinolone acetonide, a nonpolar water-insoluble fluorinated corticosteroid, had been prepared in a metered-dose aerosol device propelled by dichlorodifluoromethane (Freon 12 J.” In a one-month double-blind controlled study involving 25 steroid-dependent severely asthmatic patients, triamcinolone acetonide aerosol proved superior to a placebo in reducing the oral requirement for corticosteroids. Herein we present the results of treatment of these severely asthmatic patients with triamcinolone acetonide aerosol for 12 months, emphasizing the long-term efficacy, side effects, and adrenal recovery. Hopefully, our experience will guide physicians in the management of asthmatic patients who will soon be making the transition from oral steroid therapy to aerosol steroid therapy.
Materials and Methods
The group under study consisted of 12 men and 11 women (with ages ranging from 20 to 67 years) who required maintenance therapy with steroids for at least a year and had required, for the previous three months or more, at least 15 mg of prednisone daily or 30 mg of prednisone on alternate days (or an equivalent dosage of another corticosteroid). The patients were selected from among the most steroid-dependent and most disabled of a clinic population of about 5,000 patients with asthma. In order to exclude complicating chronic irreversible obstructive pulmonary disease, no patient was included who, within five years of entry into the study, failed to register on at least one occasion a one-second forced expiratory volume (FEVj) of at least 85 percent of the predicted normal. Also, at the time of admission to the study, the patients were required to demonstrate at least a 20 percent increase in their FEV1 after aerosol administration of isoproterenol. Excluded were patients with heart disease or a history of sudden respiratory failure.
Population of Patients
During the three months prior to entry into the study, 15 patients required an average daily dose of 23 mg of prednisone, and eight patients required an average altemate-day dose of 41 mg of prednisone to control the symptoms of asthma (Table 1). Eleven patients had rhinitis, seven had nasal polyps, five had atopic eczema, and five had a history of hypersensitivity to aspirin. The duration of asthma for the patients varied from 2 to 50 years, with an average of 19 years. The number of years of dependence on oral therapy with steroids prior to the study varied from 1 to 15 years, with an average of seven years. Eleven patients had a past history of smoking; only one patient (patient 22) continued to smoke during the study. All patients manifested at least one symptom which they related to long-term oral use of corticosteroids. The most frequent side effects attributed I о steroid therapy were a tendency toward increased bruising, obesity, hypertension, edema of the lower extremities, blurred vision, and acne (Table 2).
Micronized triamcinolone acetonide was supplied with dichlorodifluoromethane (Freon 12) as the propellant and alcohol as the solvent (1 percent weight/volume) in a pressurized canister attached to an adapter designed to provide slower-moving, drier, monodispersed particles. Ninety percent of the particles are less than 5/a in diameter; one actuation of the device delivers about 50^g of triamcinolone acetonide to the patient. The patients were instructed to operate the device in the following way. The canister was vigorously shaken before each use. After a complete exhalation, with the neck extended, the tongue fully protruded, and the mouth maximally open, the device was actuated at the beginning of a deep inspiration, with the opening of the adapter inserted into the oral cavity. After holding their breath for several seconds at full inspiration, the patients expired slowly through the nose. After delivery of the desired dose, the patients were instructed to rinse their mouths and gargle thoroughly with tap water.
Conduct of Trial
All patients continued to take their usual bronchodilator drugs. A measurement of FEV1 was obtained initially using a spirometer (Vitalograph 122000), and the measurement was repeated at least every two months and whenever indicated by a change in clinical status. The forced vital capacity (FVC) and the mean forced expiratory flow between 25 and 75 percent of the FVC (FEF25-75%) were measured on a 9-L spirometer (Collins) initially and every six months. The forced expiratory flow at 50 percent of the FVC (FEF-50%) and the forced expiratory flow at 75 percent of the FVC (FEF75X) were determined initially and every six months with a wedge spirometer (Med-Science 570), were displayed on an XY recorder (Esterline-Angus XY 1117), and were calculated as die average of three reproducible curves of maximum expiratory flow vs volume. Predicted values for FEVi, FVC, and FEF25-75% were obtained from data published by Morris et al and Kory et al. Predicted values for FEF503? and FEF75% were obtained from Bass. A 9 am fasting cortisol level (measured by competitive protein-binding radioimmunoassay) was determined every two months at least 24 hours after the patient’s last dose of prednisone. Every six months, all patients had measurements of complete blood cell’ count, automated studies of blood chemistry (SMA-12), urinalysis, electrolyte studies, and oropharyngeal and indirect laryngoscopic examinations by an otolaryngologist. Oropharyngeal cultures for Candida and other organisms were obtained whenever the patients complained of a sore throat and lesions were visible. Patients were checked for precipitins to Candida albicans during the baseline period and at the end of the one-year trial. A chest x-ray film and an electrocardiogram were obtained at the end of one year. Informed consent allowed the patients to withdraw from the study at any time at their own request
Patients kept careful diaries of the daily dosages of all medications. Every two months, each patient’s oral and aerosol intake of steroids was tabulated. Side effects and symptoms of steroid withdrawal were recorded, and the patient was asked his opinion about the aerosol.
The initial dose of triamcinolone acetonide aerosol was 300^ (six puffs) four times daily. This dose was adjusted appropriately (maximum dose of 2,000^g/day) to maintain an optimal FEV1 with minimal oral therapy with corticosteroids. Ten days after beginning aerosol steroid therapy, patients receiving daily oral therapy with steroids were instructed to double their dosage of prednisone and administer it on alternate mornings. The dose was then reduced by 5 mg every seven to ten days or by 2.5 mg if the altemate-day dose was less than or equal to 10 mg. An altemate-day schedule for reduction of the oral dosage of steroids was chosen to minimize adrenal suppression. When necessary to control exacerbations of asthma, patients were given prednisone orally in divided doses for several days.
Table 1—Population of Patients
|Patient,||Duration||Prestudy Therapy with PrednisoneA|
|Sex, i||Df Asthma,||Provocative||Duration,||Dose,||Other|
|1, M, 30||30||C,U,D,S,0||3||qd||15||E|
|2, M, 47||16||5||qd||30||E|
|3, F, 45||13||C,E,U,D,S,0||8||ad||30||R,P|
|4, F, 58||4||C,E,U,D,S,0||4||qd||20||R,P,A,E|
|5, M, 67||30||D||14||qd||15||R|
|6, M, 55||10||C,E||6||ad||30||R,P,A|
|7, M, 47||30||C,E,U,D||4||qd||15|
|8, F, 61||13||C,E,U||12||qd||20|
|9, M, 63||25||E,U,S||2||qd||30||E|
|10, M, 20||11||C,E,U,A||10||ad||55||R,P|
|11, F, 51||10||C,E,U,S,0||8||ad||40||R,P,A|
|12, M, 52||43||C,E,U,S,0||10||qd||20|
|13, F, 37||10||C,U,S,0||10||qd||20||R|
|14, M, 56||9||C,E,U,D,S,0||2||ad||50||R,E|
|15, M, 38||37||10||qd||35||. *.|
|16, F, 40||12||C,E,U,S||5||qd||15|
|17, F, 45||16||C,E,U,S,0||8||ad||30||R,P,E,A|
|18, F, 21||9||E,U,S,0||8||ad||40||R,P,A|
|19, F, 36||27||C,E,U,D,S,0,A||4||qd||30|
|20, M, 61||15||U,D,S,0||15||qd||15|
|21, F, 57||38||u,s||2||qd||30|
|22, F, 33||2||E,D,S,0||2||ad||55|
|23, M, 53||50||C,E,U,0||1||qd||40||R|
Table 2—Side Effects of Steroid Therapy At Time of Admission to Study
|1||2||3 4||5||6||7||8||9 10||11||12||13||14||15 16||17||18||19||20||21||22||23|