Evidence Of Adrenal Suppression Research Articles

Inhalational Steroids and Iatrogenic Cushing's Syndrome.

Bronchial asthma (BA) and Allergic rhinitis (AR) are common clinical problems encountered in day to day practice, where inhalational corticosteroids (ICS) or intranasal steroids (INS) are the mainstay of treatment. Iatrogenic Cushing syndrome (CS) is a well known complication of systemic steroid administration. ICS /INS were earlier thought to be safe, but now more and more number of case reports of Iatrogenic Cushing syndrome have been reported, especially in those who are taking cytochrome P450 (CYP 450) inhibitors. Comparing to the classical clinical features of spontaneous Cushing syndrome, iatrogenic Cushing syndrome is more commonly associated with osteoporosis, increase in intra-ocular pressure, benign intracranial hypertension, aseptic necrosis of femoral head and pancreatitis, where as hypertension, hirsuitisum and menstrual irregularities are less common. Endocrine work up shows low serum cortisol level with evidence of HPA (hypothalamo-pituitary-adrenal) axis suppression. In all patients with features of Cushing syndrome with evidence of adrenal suppression always suspect iatrogenic CS. Since concomitant administration of cytochrome P450 inhibitors in patients on ICS/INS can precipitate iatrogenic CS, avoidance of CYP450 inhibitors, its dose reduction or substitution of ICS are the available options. Along with those, measures to prevent the precipitation of adrenal crisis has to be taken. An update on ICS-/INS- associated iatrogenic CS and its management is presented here.

Striae atrophicans: A mimic to Cushing′s cutaneous striae

Sir, A 30-year-old male patient was referred for evaluation of Cushing's syndrome when he presented with purple striae over both the thighs [Figure 1] for 1 month. He did not have any systemic symptoms. There was no history of any drug intake including oral or parenteral steroids. He was applying steroid ointment (halobetasol propionate 0.05%) for fungal infection locally for 3 months prior to this. These striae were violaceous, with the largest one measuring 10 cm in length and 1.8 cm in width, which is classical for Cushing's syndrome. His body mass index was 26.0 kg/m2. He did not have any systemic effects of steroid, though human and animal studies indicate that less than 6% of the applied dose of halobetasol propionate enters the circulation within 96 hours following topical administration of the cream.[1] His morning and evening cortisol levels were 10.65 μg/dL and 5.28 μg/dL, respectively. Overnight dexamethasone test revealed suppressible serum cortisol (0.55 μg/dL). Halobetasol propionate cream produced hypothalamic-pituitary-adrenal (HPA) axis suppression when used in divided doses at 7 g/day for 1 week.[2] His serum cortisol level following adrenocorticotropic hormone (ACTH) stimulation test was 25.6 μg/dL. He was diagnosed as a case of striae atrophicans, which is a known complication of chronic application of topical steroid preparations. Halobetasol is grouped under ultra high potency topical steroid and has more propensity to cause side effects. The glucocorticoids affect the epidermis by preventing the fibroblasts from forming collagen and elastin fibers, necessary to keep the rapidly growing skin taut. This creates a lack of supportive material, as the skin is stretched and leads to dermal and epidermal tearing.[3] Topical application of steroids is known to cause systemic effects of hypercortisolism and suppression of HPA axis, but this is very rarely manifested clinically and is easily reversible. This patient has neither any systemic manifestation nor any evidence of adrenal suppression. Figure 1 Multiple cutaneous striae at thigh

Fluocinolone Acetonide 0.01% in Peanut Oil: Safety and Efficacy Data in the Treatment of Childhood Atopic Dermatitis in Infants as Young as 3 Months of Age

Fluocinolone acetonide 0.01% in a blend of refined peanut and mineral oils has been established as effective and safe treatment for atopic dermatitis in patients 2 years and older, including those with peanut sensitivity, for several years. We sought to study the safety of fluocinolone acetonide 0.01% oil and its potential for adrenal axis suppression in infants as young as 3 months of age. A controlled, open-label study was performed in children aged 3 months to 2 years with moderate to severe atopic dermatitis at two academic pediatric dermatology centers. Patients received topical fluocinolone acetonide 0.01% oil twice daily to affected areas involving a minimum of 20% body surface ratio for 4 weeks. Cortisol stimulation testing was performed at baseline and at the end of the treatment phase. Patients were monitored for medication use and adverse events. Efficacy was assessed using the Investigator Global Severity and Response scales. Thirty-two patients with moderate to severe atopic dermatitis were recruited into the study and 30 were evaluated with the Physician's Global Improvement Assessment tool. The mean body surface ratio treated for all age groups was 48%. Eighty-three percent of patients had marked or better improvement scores by week 2 and 96% by week 4, with 40% completely cleared. No adrenal suppression occurred in the 24 patients that met inclusion criteria for hypothalamus-pituitary axis (HPA) axis analysis. No relevant adverse events occurred. Results of this study support the safety and efficacy of fluocinolone acetonide 0.01% in refined peanut oil vehicle, for infants as young as 3 months of age with atopic dermatitis. No evidence of adrenal suppression or adverse local effects was demonstrated after 4 weeks of twice daily treatment.

A284 Cytarabine-Based Regimens for Mobilization of Peripheral Blood Stem Cells in Multiple Myeloma

this difference in outcomes may reflect differences in adrenal suppression, we studied patients from our myeloma database. Early morning serum cortisol levels at baseline and again at 3 months were determined to compare adrenal function in patients with MM receiving either lowor high-dose dexamethasone. At baseline, 8 AM serum cortisol levels were not different between the groups. At 3 months, 72.7% of the high-dose group had a decline in their 8 AM cortisol levels compared to 32.4% of the low-dose group (P = .03). The proportion of patients with a 3-month 8 AM serum cortisol level below 3 mcg/dL, a level considered to be presumptive evidence of adrenal suppression, was also increased in the high dose group (45.5% vs. 8.8%; P = .01). Overall, the high-dose dexamethasone group experienced a mean decline of 6.4 mcg/dL in their 8 AM serum cortisol levels after 3 months (95% CI, –10.7 to –2.1), while the low-dose group demonstrated no significant change (95% CI, –0.2 to 4.3). Additional studies are needed to determine the impact of corticosteroid-induced adrenal insufficiency on important treatment outcomes such as symptom relief and prognosis.

Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids

The present study identified three patients with bronchiectasis receiving inhaled corticosteroids (ICSs) who had symptomatic adrenal suppression secondary to ICS. The prevalence of adrenal suppression is unknown in bronchiectasis. The frequency of adrenal suppression and the impact of ICS use in bronchiectasis patients were examined. In total, 50 outpatients (33 receiving ICSs) underwent a short Synacthen test and completed a St George's Respiratory Questionnaire (SGRQ). Symptoms of adrenal suppression, steroid use and lung function were compared between subjects who were suppressed and those who were not. Adrenal suppression was evident in 23.5% of subjects who did not receive ICSs and 48.5% of those who did. Basal cortisol and the increments by which cortisol increased 30 min after Synacthen were lower in suppressed than in nonsuppressed subjects. The incremental cortisol rise was negatively correlated with SGRQ impacts and total score, suggesting a worse quality of life in those who had an impaired adrenal response. The greatest frequency of generalised symptoms was seen in the suppressed group. A significant proportion of subjects with bronchiectasis have evidence of adrenal suppression, and this is increased when inhaled corticosteroids are also used. Impairment of the cortisol response to stimulation is associated with poorer health status.

Assessment of Adrenal Suppression in Children With Asthma Treated With Inhaled Corticosteroids: Use of Dehydroepiandrosterone Sulfate as a Screening Test

Dorsey MJ, Cohen LE, Phipatanakul W, Denufrio D, Schneider LC. Ann Allergy Asthma Immunol. 2006;97:182–186 PURPOSE OF THE STUDY. To evaluate dehydroepiandrosterone sulfate (DHEA-S), a corticotropin-dependent adrenal androgen precursor, as a possible marker for adrenal function and hypothalamic-pituitary-adrenal axis suppression in children treated with inhaled corticosteroids (ICSs) compared with low-dose (0.5 μg/m2 up to 1.0 μg) and standard-dose (250 μg) cosyntropin-stimulation testing. STUDY POPULATION. Twenty-two patients with moderate-to-severe–persistent asthma receiving a medium-to-high dose of ICSs for at least 6 months were enrolled (definition of median-to-high dose of ICS: budesonide >400 μg/day or fluticasone >176 μg/day for children <6 years old or >200 μg/day for those ≥6 years). Patients had received no more than 2 courses of systemic corticosteroid exposure of <10 days’ duration in the previous 6 months and no systemic corticosteroid in the 1 month before enrollment. The average age of the patients was 8.6 years (range: 2–12 years). METHODS. After a 12-hour fast, morning cortisol, corticotropin, DHEA-S, and fasting blood sugar levels were measured. Cortisol was measured after the stimulation tests. A cortisol level of ≤18 μg/dL was considered abnormal (adrenal suppression). RESULTS. Of 22 patients, 13 (59%) had an abnormal response to low-dose cosyntropin. One patient had an abnormal standard-dose cosyntropin test result. The normal and abnormal low-dose cosyntropin responders did not differ in age, height, BMI, predicted forced expiratory volume in 1 second, or morning cortisol, corticotropin, or fasting blood sugar levels. There was no difference between normal and abnormal low-dose cosyntropin responders in relation to type of ICS (fluticasone, fluticasone-salmeterol, or budesonide) or dose. DHEA-S levels were significantly lower in abnormal low-dose cosyntropin responders compared with normal responders (31 vs 91 μg/dL; P = .004). Age- and gender-specific mean DHEA-S z scores were significantly lower in abnormal low-dose cosyntropin responders. Receiver-operating-characteristic (ROC) curves for DHEA-S z scores were calculated to obtain optimal cutoff values for DHEA-S. The ROC curve for DHEA-S z scores reached 100% sensitivity with a DHEA-S z score of less than −1.5966 and 100% specificity with a DHEA-S z score >0.0225. CONCLUSIONS. Fifty-nine percent of the children on a medium-to-high dose of ICS had biochemical evidence of adrenal suppression according to the low-dose cosyntropin-stimulation test. Low DHEA-S levels can be used as a screening test to identify children who need more formal testing of the hypothalamic-pituitary-adrenal axis. The half-life of DHEA-S (10–20 hours) is substantially longer than that of cortisol (<2 hour) and, therefore, has less diurnal variation or fluctuating concentration depending on exogenous stress and time of day. REVIEWER COMMENTS. The cosyntropin-stimulation test is cumbersome, labor intensive, and not practical as a screening test, so the DHEA-S test may be more useful. The number of patients on a moderate dose of ICS found to have biochemical adrenal suppression by low-dose cosyntropin tests (59%) is higher than seen in most other studies. The authors speculated that the higher rates of adrenal suppression may be associated with “real-world” ICS use versus study-protocol use. The clinical significance of this biochemical suppression is not clear.

Iatrogenic Cushing’s Syndrome with Osteoporosis and Secondary Adrenal Failure in Human Immunodeficiency Virus-Infected Patients Receiving Inhaled Corticosteroids and Ritonavir-Boosted Protease Inhibitors: Six Cases

Ritonavir, a protease inhibitor (PI), is a potent inhibitor of cytochrome P450 3A4. This pharmacological effect, even at low doses (</=200 mg/d), is used to "boost" levels of other PIs in the treatment of HIV infection and facilitate once or twice daily dosing with reduced pill burden. Six patients with preexisting HIV-lipodystrophy developed symptomatic Cushing's syndrome when treated with inhaled fluticasone at varying doses for asthma while concurrently treated with low-dose ritonavir-boosted PI antiretroviral therapy (ART) regimens for HIV infection. There was evidence of adrenal suppression in all patients on stimulation studies. After the withdrawal of inhaled fluticasone, four patients became symptomatic of hypocortisolism, and three required oral corticosteroid support for several months. Other complications included evidence of osteoporosis (n = 3), crush fractures (n = 1), and exacerbation of preexisting type 2 diabetes mellitus (n = 1). In part, the diagnosis of fluticasone-induced Cushing's syndrome was delayed because all patients had preexisting body composition changes of ART-associated lipodystrophy, masking the Cushing's features. Practitioners should be aware of the impact on the adrenal axis of coadministration of PI-based ART regimens with inhaled corticosteroids and the potential for exacerbating or even inducing other metabolic conditions, such as osteoporosis or diabetes.

Use and safety of budesonide aerosol in infants with asthma

Inhaled corticosteroids have become a standard first-line therapy for mild to severe persistent asthma in children of all ages. Budesonide inhalation suspension is a nebulized steroid approved for children as young as 12 months. In a study by Berger et al. in this issue of The Journal, the safety of budesonide inhalation suspension was studied in infants aged six to twelve months. The safety profile was excellent, and not significantly different to that of placebo, with no evidence of adrenal suppression. Safety of budesonide inhalation suspension in infants aged six to twelve months with mild to moderate persistent asthma or recurrent wheezeThe Journal of PediatricsVol. 146Issue 1PreviewTo compare the safety of budesonide inhalation suspension (BIS) with placebo in infants 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze. Full-Text PDF

Decreased cortisol response to insulin induced hypoglycaemia in asthmatics treated with inhaled fluticasone propionate

Aims: To assess adrenal function in asthmatic children treated with inhaled fluticasone propionate for up to 16 weeks. Methods: Children with asthma and bronchial hyperresponsiveness to inhaled methacholine were treated...

Systematic review of the dose-response relation of inhaled fluticasone propionate

Aims: To examine the dose-response relation of inhaled fluticasone for both efficacy and adrenal function in children with asthma. Methods: Systematic review of double blind randomised dose-response studies of fluticasone...

Safety of fluticasone propionate HFA in treating children 4-11 years of age with asthma

Rationale To evaluate the safety of fluticasone propionate HFA 88μg BID (FP) vs placebo HFA (PLA) for 12 weeks in children aged 4 to 11 years with asthma. Methods A randomized, double-blind, parallel-group, placebo-controlled trial in 241outpatients (160 FP: 81 PLA), with a ≥6 month history of asthma requiring pharmacotherapy. Patients receiving systemic steroids ≥10 weeks prior to randomization were excluded; inhaled corticosteroids were discontinued at randomization. Safety measures included assessment of adverse events (AEs), 12-hour overnight urinary cortisol excretion, clinical labs, oropharyngeal examinations, and vital signs. Results No deaths or treatment-related serious AEs were reported. Following 12 weeks of treatment, the percentage and types of AEs as well as clinical laboratory results and vital signs were comparable between the active and placebo groups. There were no shifts from normal to abnormal in oropharyngeal pathology from baseline to endpoint, with all patients having negative results and no evidence of oropharyngeal candidiasis in either group at endpoint. The median 12-hour overnight urine cortisol excretion was similar for both treatment groups at baseline (FP 88=3.5ug; PLA=3.1ug). At the end of the treatment period, there was little change from baseline in 12-hour overnight urine cortisol excretion (medians: FP 88=−0.1ug; PLA=0.1ug). Conclusions FP 88μg BID for 12 weeks was well tolerated in 4-11 year old children with asthma. The safety profile was similar to PLA with no evidence of adrenal suppression.

Fluocinolone acetonide 0.01% in peanut oil: Therapy for childhood atopic dermatitis, even in patients who are peanut sensitive

Background: Fluocinolone acetonide 0.01% in a blend of refined peanut and mineral oils has been used as treatment for scalp psoriasis for several years, but only more recently for atopic dermatitis. Objective: We sought to study the effectiveness for atopic dermatitis, potential for adrenal axis suppression, and safety of the fluocinolone acetonide 0.01% in oil in children with atopic dermatitis, including children with atopic dermatitis and peanut allergic sensitivity. Methods: Three separate studies were performed in children aged 2 to 12 years with atopic dermatitis: multicenter double-blind, randomized, and vehicle-controlled trial; cortisol stimulation testing; and prick testing, patch testing, and monitored medication use in children with peanut allergic sensitivity. Results: Improvement of ≥50% was demonstrated within 2 weeks in 81% to 87% of 81 patients treated with active medication versus 39% of 45 children treated with vehicle oil alone. No adrenal suppression occurred after 4 weeks of therapy in 32 patients. None of 9 patients who were peanut sensitive reacted to either the full formulation or vehicle in prick or patch testing; 20 children who were peanut sensitive showed no allergic reactions after application of the medication. Conclusion: Fluocinolone 0.01% in peanut oil is an effective alternative to the use of topical corticosteroid agents in ointment, cream, and lotion forms in children. No evidence of adrenal suppression or adverse local effects were demonstrated in these studies. The medication was well tolerated in patients with peanut allergic sensitivity. (J Am Acad Dermatol 2003;48:569-77.)

Safety of inhaled and intranasal corticosteroids: lessons for the new millennium.

Although inhaled and intranasal corticosteroids are first-line therapy for asthma and allergic rhinitis, there has recently been an increasing awareness of their propensity to produce systemic adverse effects. The availability of more potent and lipophilic corticosteroids and new chlorofluorocarbon (CFC)-free formulations has focused attention on these safety issues. The main determinant of systemic bioavailability of these drugs is direct absorption from the lung or nose, where there is no first-pass inactivation. Consequently, the systemic bioavailability of inhaled corticosteroids is greatly influenced by the efficiency of the inhaler device. Thus, when comparing different inhaled corticosteroids it is imperative to consider the unique drug/device interaction. The pharmacokinetic profile is important in determining the systemic bioactivity of inhaled and intranasal corticosteroids. For highly lipophilic drugs, such as fluticasone propionate or mometasone furoate, there is preferential partitioning into the systemic tissue compartment, and consequently a large volume of distribution at steady state. In contrast, drugs with lower lipophilicity, such as triamcinolone acetonide or budesonide, have a smaller volume of distribution. The systemic tissue compartment may act as a slow release reservoir, resulting in a long elimination half-life for the lipophilic drugs. For intranasal corticosteroids, a high degree of lipophilicity diminishes water solubility in mucosa and therefore increases the amount of drug swept away by mucociliary clearance before it can gain access to tissue receptor sites. This may reduce the anti-inflammatory efficacy in the nose, but might also reduce the propensity for direct systemic absorption from the nasal cavity. The hydrofluoroalkane (HFA) formulations of beclomethasone dipropionate are solutions and exhibit a much higher respirable fine particle dose than do the CFC formulations. Dose-response studies with one of the HFA formulations have shown therapeutic equivalence at half the dosage, with little evidence of adrenal suppression at dosages up to 800 microg/day. A lack of similar studies for another of the available HFA formulations has led to a discrepancy in the recommendations for equivalence. Although in vitro studies have pointed to a similar fine particle distribution for the HFA and CFC formulations of fluticasone propionate, this is not supported by in vivo data for lung bioavailability, suggesting that care will be required when switching these formulations. Prescribers of inhaled and intranasal corticosteroids should be aware of the potential for long term systemic effects. The safest way to use these drugs is to 'step-down' to achieve the lowest possible effective maintenance dosage.

Adrenal function in premature infants during inhaled beclomethasone therapy

Objective: We tested the hypothesis that inhaled beclomethasone therapy for prevention of bronchopulmonary dysplasia does not cause adrenal suppression. Study design: Infants receiving ventilatory support with birth weights ≤1250 g and born at <33 weeks’ gestation, age 3 to 14 days, were enrolled in a multicenter randomized trial to study the efficacy and safety of beclomethasone therapy versus placebo for prevention of bronchopulmonary dysplasia. Adrenal function was assessed on study day 21 (± 2 days) by determination of basal and stimulated plasma cortisol levels. Initially, cortisol response was assessed with insulin-induced hypoglycemia test (IIHT) (n = 63) until an interim analysis revealed insignificant cortisol response in both study groups. Thereafter, cosyntropin stimulation was used (n = 85). Results: Beclomethasone therapy was associated with lower median basal cortisol levels (5 μg/dL beclomethasone, 6 μg/dL placebo, P = .04). IIHT revealed insignificant change in cortisol response within each group. Cortisol response to cosyntropin stimulation was similar for each group (17 μg/dL beclomethasone, 18 μg/dL placebo, P = .86). Conclusion: Beclomethasone therapy was associated with a small decrease in basal cortisol levels. There was no evidence of adrenal suppression in response to cosyntropin stimulation during beclomethasone therapy. Lack of cortisol response to hypoglycemia may reflect missed timing and/or decreased response of the premature infants’ hypothalamic-pituitary-adrenal axis to hypoglycemia. (J Pediatr 1999;135:65-70)

Once-daily inhaled corticosteroids in mild to moderate asthma: improving acceptance of treatment.

Despite the established efficacy of inhaled corticosteroids in improving lung function in asthma, there has not been a corresponding improvement in morbidity and mortality associated with the disease, which, in part, may result from non-compliance with the prescribed regimen. The reasons for this are many and varied, but an important measure in improving the level of compliance in asthma patients is simplification of the treatment regimen, which may be achieved by reducing the dose frequency and improving the ease of administration. In clinical trials designed to determine whether a reduction in dose frequency to once daily is associated with similar efficacy to that with more frequent administration, a number of studies have shown that once-daily administration of inhaled corticosteroids in both adults and children is as effective in controlling asthma as twice-daily administration of the same dosage, both when given as initial therapy in corticosteroid-naïve patients and in patients already receiving an inhaled corticosteroid. The drug for which most evidence to support a dosage change from twice-daily to once-daily therapy currently exists is budesonide, though limited evidence with other inhaled corticosteroids such as beclomethasone dipropionate, fluticasone propionate and flunisolide also supports once-daily use. Despite the larger single dosage with once-daily budesonide therapy, there has been no evidence in clinical trials of a greater incidence of local adverse effects such as hoarseness, throat irritation or oropharyngeal candidosis, and no evidence of adrenal suppression or growth retardation. Since compliance is an important factor that can affect the success or failure of asthma therapy, a reduction in the frequency of administration to once daily offers the potential advantage of improved compliance with treatment and hence better control of asthma. In the short term clinical trials conducted to date, patient preferences have favoured the once-daily regimen over twice-daily administration. When combined with other (e.g. educational) measures to improve patient compliance, a switch from twice-daily (or more frequent) administration to once-daily inhaled corticosteroid therapy seems likely to be beneficial in improving the long term outcome of treatment.

A Pilot Study of Steroid Therapy After Emergency Department Treatment of Acute Asthma: Is a Taper Needed?

The purpose of this study was to determine if there is a difference in early relapse rates between patients receiving an 8-day course of 40 mg/day prednisone and those receiving an 8-day tapering course of prednisone. Furthermore, we wished to determine if one regimen is superior to the other for minimizing adrenal suppression. This was a prospective, randomized, double blind clinical trial conducted in an urban, university-affiliated Level 1 trauma center. All asthmatic patients with exacerbation who were judged well enough for discharge home from the emergency department (ED) were eligible for participation. Patients with a history of chronic obstructive pulmonary disease, congestive heart failure, pneumonia, pneumothorax, or other pulmonary process, and asthmatics already using inhaled or oral steroids within 2 weeks of admission to the ED were excluded. Before treatment, a cosyntropin stimulation test was administered to all asthmatics admitted to the ED. All patients treated in the ED then received three doses of aerosolized albuterol, 60 mg of i.v. methylprednisolone, and oxygen. FEV1 was measured before treatment, after each treatment, and 1 h after the third aerosol administration. Patients were then sent home with either an 8-day course of 40 mg/day prednisone or an 8-day tapering course of prednisone (tapering from 40 mg to 0 mg). Patients were asked to return on day 12 for another cosyntropin stimulation test and pulmonary function testing and on day 21 for pulmonary function testing only. Fifteen patients participated: seven received a nontapering dose of prednisone and eight received a tapering dose of prednisone. There were no differences in the FEV1 percent predicted, the incidence of relapse, or the incidence of adrenal suppression between the two groups. In our small study, we found no difference in relapse rate between asthmatics receiving an 8-day tapering dose of prednisone and those receiving 40 mg/day prednisone upon discharge from the ED. Furthermore, no patients had evidence of adrenal suppression from either dosing regimen.

Unexpected side-effects of inhaled steroids: A case report

An asthmatic child is presented who developed a cushingoid appearance with evidence of adrenal suppression and growth impairment while on low dose inhaled topical steroids. When the inhaled steroids were replaced by inhaled sodium cromoglycate his adrenal function recovered while his appearance and growth returned to normal. This report indicates that there are some children who are at risk of developing side-effects on doses of inhaled topical steroids normally considered to be entirely safe.

Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children.

Oral methylprednisolone combined with troleandomycin has been reported to be successful in treating poorly controlled, severe asthma in adults. We found this drug combination to be effective in treating 11 steroid-dependent children with poorly controlled asthma who were aged 7 to 13 years, for 12 to 28 months. Improvement of clinical and pulmonary functions was achieved within seven days, with the forced expiratory volume in 1 s increasing by 38% and the maximal midexpiratory flow rate increasing by 55% over the baseline value. By one year, the former improved to 98% of predicted value and the latter, to 79% of predicted value. Compared with the prior 12 months, patients at this time required fewer emergency visits, missed fewer days of school, and had fewer hospitalizations. Side effects included transient-increased cushingoid features, abdominal pain, and liver enzyme level elevation. Patients showed less evidence of adrenal suppression.

Effects of long term inhaled high dose beclomethasone dipropionate on adrenal function.

Studies of adrenal function were performed on 54 asthmatic patients who were taking long term high doses of inhaled beclomethasone dipropionate ranging from 500 to 2000 micrograms/day for between six and 60 months. Of the 43 patients taking up to 1500 micrograms/day, 39 (91%) had normal basal plasma cortisol concentrations and normal short tetracosactrin responses and 24 hour urinary free cortisol excretion was within the normal range in eight of nine patients tested. Some evidence of adrenal suppression was found in patients taking 2000 micrograms/day, with basal plasma cortisol below the normal range in four out of 11 patients and 24 hour urinary free cortisol excretion below the normal range in five out of six patients tested. Only one of the 11 patients taking 2000 micrograms/day had a short tetracosactrin response below the normal range: the mean rise in plasma cortisol was, however, significantly lower in this group than in those taking 1000 micrograms/day (328 (SE 30) and 506 (34) nmol/l respectively) (p less than 0.01). Patients taking more than 1500 micrograms/day of inhaled beclomethasone may require systemic corticosteroids during prolonged stress.

Flunisolide Aerosol for Treatment of Severe, Chronic Asthma in Steroid-Independent Children

The efficacy and safety of flunisolide aerosol were studied in 46 steroid-independent children with asthma inadequately controlled by nonsteroid drugs. This was a double-blind, placebo-controlled, parallel study lasting eight weeks. Patients were randomly assigned either flunisolide by inhalation, 0.5 mg twice a day, or placebo. Effectiveness was evaluated daily by symptom scores, by Wright peak flow measurements twice daily, and weekly by spirometry and physical examination. Adrenal function and throat cultures for Candida were evaluated before and after the test-drug treatment period. Flunisolide was administered to 25 patients and 21 received placebo. Most symptom scores were statistically significantly better in flunisolide-treated than in placebo-treated patients; these included severity of wheezing (P = .01), chest tightness (P = .01) and shortness of breath (P = .02), and frequency (P = .001) and severity of asthma attacks (P = .03). In addition, placebo-treated patients used significantly more bronchodilators than flunisolide-treated patients. In the final therapeutic effectiveness evaluation, 72% of flunisolide-treated patients received very good or good ratings, whereas only 29% of placebo-treated patients received these ratings (P = .005). No patient developed thrush, evidence of adrenal suppression, or other severe adverse reaction. Flunisolide aerosol was shown to be effective and safe in controlling asthma in children who were candidates for oral steroid therapy.