A COMPARISON OF EFFICACY AND SAFETY OF A SINGLE DOSE OF INTRAMUSCULAR DEXAMETHASONE ACETATE WITH ORAL PREDNISOLONE IN THE MANAGEMENT OF ASTHMA EXACERBATIONS IN CHILDREN

Objective: To determine whether a single intramuscular dexamethasone acetate injection is as effective as 5 days of oral prednisolone in improving symptoms and preventing relapse in children with acute asthma.

Methods: This is a prospective, quasi, randomized, and non-blinded trial. We enrolled 30 children, aged 9 months to 14 years with known history of asthma who presented to the emergency department with moderate exacerbation. Patients were randomized to receive either a single intramuscular dexamethasone acetate injection or 5 days of oral prednisolone. The primary out-come was to measure the rate of relapse, persistence, worsening, recurrence of symptoms and hospitalization in 5 and 21 days after discharge from emergency department.

Results: All patients completed the study. More patients in the prednisolone group continued to use bronchodilator than patients in the dexamethasone group (three patients in the former compared to one patient in the second group). No patient in both groups had severe relapse or needed hospitalization. Patients in the prednisolone group experienced difficulty in administration of the tablets and 3 of them missed 50-75% of the total dose. There were no significant local or systemic adverse effects in both groups. All patients in dexamethasone group were satisfied with the treatment while most parents in the prednisolone group preferred an alternative form of treatment.

Conclusion: We found that IM dexamethasone acetate is more clinically effective than a 5-day course of oral prednisolone tablets in treatment of moderate asthma exacerbations. It was well tolerated, and preferred by most parents. We recommend it, as an alternative option especially in those who are not compliant to oral prednisolone.

Key words: Intramuscular, Dexamethasone, Oral, Prednisolone, Asthma, Acute.

JRMS June 2006; 13(1): 15-18


Introduction

Asthma accounts for > 1.8 million emergency department visits annually, and children account for approximately half of these visits (1). Acute asthma relapse after treatment and discharge from the emergency department remains a substantial problem (2). Suppression and reversal of inflammation is the cornerstone for managing acute symptoms and preventing relapse (3). A common practice is to prescribe 4-5 day course of prednisolone to children with asthma exacerbation (4). Despite receiving prescription for corticosteroid 5 % to 25 % of patients discharged from the Emergency department (ED) will have relapse within 3 weeks (1).  Even with short-term medication regimens, 7% to 28% of patients never fill their prescriptions.

Poor palatability of the medications and treatment period for several days may further reduce patient compliance (2).  Researchers reported that children with prior episodes of asthma who present to ED could be treated effectively with a single dose of intramuscular (IM) dexamethasone acetate, potentially replacing a five-day course of oral steroids (3). Dexamethasone is a long acting corticosteroid that is well absorbed and has been used safely in children with croup.  Side effects of burst dosing increase in appetite, mild cushingoid effects, no or only mild hypothalamic-pituitary-adrenal (HPA) axis suppression except in patients with > 4-bursts / year (4).

We compared the safety and efficacy of single IM injection of dexamethasone acetate, which is a long acting depot preparation, to a five-day course of oral prednisolone in 30 children presenting with acute asthma exacerbation.


Methods

The study is prospective randomized and non-blinded. It consisted of children 9 months to 14 years old with moderate exacerbation of asthma in emergency department (ED) at King Hussein Medical Center (KHMC) between May to July 2004. A locally modified scoring system based on GINA guidelines in management of asthma for evaluation of clinical response at presentation, and 5 days after treatment was used (Table I) (3).

  Each parameter in mild, moderate, and severe asthma exacerbation was given the score of 1, 2, and 3 respectively. Age related modification was considered. Moderate exacerbation was defined as a clinical asthma score of > 6 and ≤ 12 (Table I). This subjective scoring system was used because we could not use objective measures of clinical improvement.

Children were eligible for the study if they were above 6 months of age, had an attack of moderate asthma exacerbation. Patients, who required hospitalization, had varicella exposure, had systemic steroids within 2 weeks of the start of the study and those with fever were excluded. Patients were randomized to receive either a single Intramuscular (IM) dose of dexamethasone acetate (1.7mg /kg )or prednisolone taken orally each day for 5 days (2 mg /kg/day) (Table II) (3).  The end points were change in clinical asthma score from day one through day 5 of treatment, assessment of those patients who maintained remission after 21 days, and their salbutamol use and tolerance of corticosteroid medication. On study day 5, clinic visits included a physical examination, review of clinical score, evaluation of blood pressure and muscular atrophy at site of IM injection. Clearing of an asthma exacerbation was resolving of asthma symptoms and signs, the use of salbutamol less than 2 puffs per day and an additional course of systemic steroids were not considered necessary (2).

 The number of patients who had relapsed, family satisfaction with the treatment received was evaluated at study day 21. Relapse was defined as if patient returns to have symptoms and signs requiring treatment with corticosteroids after initial clearance within 21 days of treatment (3).  Patients were advised to keep on their maintenance treatment when returning  home.

The statistical package for social science (SPSS) version 10 for windows was used for statistical analysis. Chi square test was used to compare between medians. P value less than 0.05 was taken as significant.


Results

We enrolled 30 patients from May to July 2004 (age range, 9 months to 14 years). Sixteen children received IM dexamethasone acetate and 14 received oral prednisolone randomly.

None of the patients was withdrawn from the study.  Males out-numbered females in both groups (13:4 in the dexamethasone group, and 7:5 in the second group). Patients in dexamethasone acetate group were older than those in prednisolone group (p value <0.007), which can be probably, explained the small-sized sample and the random assignment of patients to either group. Clinical severity before treatment was similar in both groups, where no patient in either group was diagnosed to have severe exacerbation.

There is only one patient in the dexamethasone group who continued to use bronchodilator frequently compared with 3 patients in the prednisolone group. There were 3 patients in the prednisolone group who required subsequent treatment with corticosteroids within the 3 weeks of the follow-up as extension of initial therapy compared to one patient in the dexamethasone group. No patient in the both groups required hospitalization or emergency department visit during the 3 weeks of follow-up (Table IV).

Reluctance to accept the tablets is the main problem reported by the family but no patient in either group reported significant personality changes. Parents of 8 patients reported that they found it difficult to give the tablets to their children without force and 3 and 1 patient missed 50 % and 75 % of their doses respectively. There were no local and systemic complications from IM injections. All parents in dexamethasone acetate group found that this treatment is effective, practical, and safe while most of patients in oral prednisolone group prefer syrup instead of tablets and some inquired about an alternative injectable treatment.    


Discussion

Because corticosteroid improves pulmonary function, reduces the rate of hospitalization, and decreases the relapse rates in patients with acute asthma exacerbation, it is recommended for outpatient use after asthma exacerbation (1,9). Prednisolone is a relatively short-acting steroid, having a biologic half-life of 12-36 hours, necessitating daily dosing of the drug, usually for 4- 5 days (1,10). Intramuscular dexamethasone acetate is a potent, long acting glucocorticosteroid with duration of action of 1-3 weeks. It has approximately 6 times the anti-inflammatory potency of prednisolone (11). This study showed a significant difference in clinical efficacy between patients who were treated with a single IM dexamethasone acetate and those who were treated with 5 days oral prednisolone for moderate asthma exacerbation in  the first 5 days of treatment (p<0.01).

This clinical trial found that the relapse rate and hospitalization in both groups were similar but more patients in the oral prednisolone were not able to clear symptoms and required continuation of steroid course.

These patients were found non-compliant to treatment. Parents reported that they missed 50-70% of their doses because oral prednisolone was poorly tolerated. We found that patients who completed their treatment in oral prednisolone group had responded significantly similar to IM dexamethasone acetate group. None of the patients in both groups was found to have relapsed especially when the missed doses had been compensated. The only one patient who needed subsequent steroid treatment in dexamethasone acetate group was found to stop his inhalation corticosteroid, because parents thought that this injection is an enough alternative treatment.

These results keep with other investigators who found that a single dose of IM methylprednisolone acetate (80) mg, which is also a repository preparation, decreased rates of relapse from 20% to 0% compared with a 10-day tapering dose of oral methylprednisolone in 17 patients (1,12). A larger trial revealed a decrease in relapse rate from 31% to 7 % in 56 patients given single dose of 240 mg compared with placebo (1,13).

 The prolonged duration of action of dexamethasone acetate (1-3) weeks has given rise to the concern of adrenal suppression, but studies have shown that this is to be more considered in prolonged courses or multiple doses over short time (14). We could not demonstrate any local or systemic complications of IM dexamethasone acetate in our study especially when sometimes we had to use large volume of the injection.

When compliance is ensured, oral prednisolone is an effective treatment for acute exacerbation of asthma. Poor tolerance of oral steroids by children mandates looking for an alternative treatment form; so intramuscular dexamethasone acetate was tried and found to be effective and safe (15).

Other forms as intravenous corticosteroids are not suitable for outpatient, short-course use, and inhaled steroids are not easily accessible and not as effective as oral prednisolone in treating asthma exacerbation (3,13).

Our study showed comparable results to other studies but we had some limitations (16). It was not a double-blinded study because our ethical committee considered it unethical to use bad tasting or IM injections placebo and we were not able to use objective methods to assess hypothalamic-pituitary-adrenal axis function due to financial restrictions.
 

Conclusion

We found that IM dexamethasone acetate is more effective clinically than a 5-day course of oral prednisolone in treatment of moderate asthma exacerbation especially in the first five days of treatment. It was well tolerated, and preferred by most parents. Although we recommend it as an alternative option especially in those who are not compliant to treatment with oral prednisolone, still there is a need for multi-center larger studies to determine the most effective form of corticosteroids for the treatment of acute asthma exacerbations after discharge from the ED.
 
Table I: Clinical scoring of severity of asthma attacks.

Parameter	Mild	Moderate	Severe
Breathless*	Walking can lie down	Moderate movement	Sitting or lying down
Talks in distress*	Sentences may be agitated	Phrases usually agitated	Words usually agitated
Respiratory rate	Increased	Increased	Often >30/min
Accessory muscle use	Usually not	Usually	Usually
Pulse/min	<100	100-120	>120
Wheezes	Moderate, often only end expiratory	Loud	Usually loud

* Age-related modifications were taken into-consideration.

Table II: Doses of dexamethasone acetate and prednisolone used in treatment.

Age	DEXA	PRED
6-12 months	16 mg IM	10 mg BD for 5 days
13-35	24 mg	15 mg BD for 5 days
> 36 months	36 mg	20 mg BD for 5 days

Table III: Group characteristics at initial presentation

Variable index	IM dexamethasone (n=16 )	Oral Prednisolone (n=14 )	P value
Age (month)	79.7٭	45.4٭	0.007
Sex (Male : Female)	13:4	7:5	0.016
Steroids dosage (mg)	24.0٭	19.2٭

٭ mean value

Table IV: Analysis of clinical response in both groups.

Outcome variable (Number of patients)	IM dexamethasone (%)	Oral prednisolone (%)	P value
Symptoms clearance first 5 days	81.2%	50.1%	0.01
Patient who required continuation steroid course	6.25%	14.3%	0.008
Number of bronchodilator administrations on day 5	6%	21%	0.95

# Both groups of patients continued to receive salbutamol 100-microgram puff every 4-6 hours as needed.
 

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