Dexamethasone Versus Prednisone for Asthma Treatment in the Pediatric Inpatient Population; a Feasibility Study
Dexamethasone Versus Prednisone for Asthma Treatment in the Pediatric Inpatient Population; a Feasibility Study
Current corticosteroid regimens for children hospitalized with asthma typically include a
 5-day course of prednisone or prednisolone. However, these medications taste poorly and are
 associated with vomiting and poor compliance. Outpatient evidence suggests that a 2-day
 course of dexamethasone is as effective as a longer course of prednisone and prednisolone,
 and better tolerated. Studies in hospitalized patients are lacking.

 The investigators' primary objective is to determine the feasibility of a non-inferiority
 trial, comparing 2 days of dexamethasone to 4 days of inpatient prednisone/prednisolone for
 inpatient asthma treatment. The investigators also wish to determine the feasibility of 1)
 enrolling patients upon admission to hospital, 2) asking patients and/or caregivers to
 complete a symptom weekly for 4 weeks, 3) reassessing patients post hospital discharge, 4)
 successfully completing phone follow up 4 weeks post hospital discharge, and 5) collecting
 health utilization data post hospital discharge.

 This study will inform a future multi-site trial comparing prednisone/prednisolone to
 dexamethasone in inpatient asthma treatment. It has the potential of improving the delivery
 of care in asthma, by improving compliance with a mainstay of treatment. It will also enhance
 collaboration within Ontario pediatric hospitals, facilitating knowledge translation and
 standardization of care across institutions.
1. BACKGROUND AND RATIONALE 1.1 Background Information Summary of the problem Asthma is the
 most common childhood chronic disease, affecting over 15% of children between the ages
 of 4 and 11 years. In 2004, asthma contributed to 10% and 8% of all Canadian hospital
 admissions for children aged 0 to 4 years and 5 to 14 years, respectively. In Ontario,
 the burden of illness caused by asthma is enormous, accounting for one third of
 government expenditures for the general population.

 A key element for treating children with acute asthma exacerbations is the
 administration of corticosteroids. Corticosteroids (CS) reduce the need for
 hospitalization and the risk of relapse after initial treatment, and may also facilitate
 an earlier discharge from the hospital.

 While some hospitals already use a short course of dexamethasone for the inpatient
 asthma treatment, there is no evidence to support this practice in the inpatient
 population. Most current CS treatment regimens for the treatment of children
 hospitalized with an asthma exacerbation consist of a 5-day course of prednisone or
 prednisolone. However, prednisone and prednisolone are associated with poor taste and
 significant vomiting, as well as poor compliance with the treatment course. The lifetime
 prevalence of asthma in Canadian children has been estimated at 11% to 16% and asthma
 exacerbations are the leading cause of hospitalization in children. At the Children's
 Hospital of Eastern Ontario (CHEO), 215 children were admitted to the inpatient units
 for asthma in 2015, representing 5.4% of the yearly medical admissions.

 Current corticosteroid standard of care for inpatient treatment of asthma CS are one of
 the cornerstones of therapy for acute asthma. They should be administered as early as
 possible in the Emergency Department (ED). Treatment with CS reduces the need for
 hospitalization, decreases the risk of relapse post treatment, and leads to a shorter
 length of stay. Current corticosteroid treatment regimens for the treatment of children
 hospitalized with an asthma exacerbation typically consist of a 4-day course of
 prednisone or prednisolone in addition to the dose of oral CS received in the ED.

 Dexamethasone vs prednisone/prednisolone treatment A recent meta-analysis has shown that
 2 days of once daily dexamethasone is a least as effective as 5 days of prednisone for
 preventing relapse in outpatient pediatric asthma. In addition, patients receiving
 dexamethasone were significantly less likely to experience vomiting in the ED and even
 after returning home. Preliminary cost-estimates suggest that dexamethasone may result
 in at least a $3500 cost savings per 100 patients compared to traditional treatment with
 prednisone or prednisolone. At CHEO, this would result in over $7000 in savings per
 year.

 Compliance with corticosteroid treatment Prednisone is only available in Canada as a
 tablet or compounded suspension, which limits use due to swallowing ability and
 accessibility. When compared to dexamethasone, prednisolone is associated with poor
 palatability, significant vomiting and poor compliance. Prednisone and prednisolone are
 compounded with similar recipes, and therefore have a similar taste. Compliance with 5
 days of prednisone has been estimated in one study to be as low as 64% for pediatric
 asthma. As mentioned above, outpatient evidence shows that a 2-day course of
 dexamethasone is as effective as a longer course of prednisone and prednisolone, and
 better tolerated. However, as determined by a systematic review conducted by the
 principal investigator of this current proposal (PROSPERO 2016:CRD42016041766), studies
 in hospitalized patients are lacking. Promisingly, a retrospective cohort study in
 pediatric inpatients hospitalized with asthma has suggested that dexamethasone, when
 compared to prednisone/prednisolone, may result in a shorter length of hospital stay and
 reduced costs with no difference in number of transfers to intensive care or
 readmissions.

 Safety of dexamethasone Dexamethasone is a potent glucocorticoid with a long half-life,
 therefore concerns have been raised regarding its potential for adrenal suppression.
 However, a study of high-dose (~1.7 mg/kg) IM dexamethasone in acute asthma found no
 significant difference in adrenal function at day 14 between single-dose dexamethasone
 and 5 days of oral prednisone. The degree of adrenal suppression induced by
 dexamethasone is likely comparable to that observed with intravenous methylprednisolone
 or moderate to high doses of inhaled corticosteroids. Children in our proposed study
 will receive a cumulative dexamethasone dose of 1.2 mg/kg orally, significantly less
 than used in the aforementioned study.

 1.2 Rationale Given the importance of CS in the treatment of asthma, the significant
 decrease in relapse associated with their use, and the high prevalence of childhood
 asthma, there is a need to determine whether a better tolerated and more palatable CS
 can be used as first line therapy. Although outpatient data on this issue exists,
 extrapolating treatment regimens from the outpatient population may not be appropriate
 as hospitalized children represent a sicker group of patients than those discharged from
 the emergency department.

 In order to determine whether dexamethasone is at least as effective of
 prednisone/prednisolone in the treatment of inpatient asthma, the investigators propose
 a feasibility study, as a first step in the development of a future multi-site trial.

 2. STUDY OBJECTIVES

 The investigators plan to determine the feasibility of a non-inferiority trial, comparing 2
 days of dexamethasone to 4 days of inpatient prednisone/prednisolone for inpatient asthma
 treatment. Specifically, The investigators we will determine the feasibility of:

 1. Enrolling patients upon admission to hospital, after they receive their first dose of
 corticosteroid (CS) in the ED

 2. Asking patients and/or caregivers to complete a symptom diary weekly for 4 weeks

 3. Reassessing patients 7 days after hospital admission day

 4. Successfully completing phone follow up 4 weeks post hospital discharge

 5. Collecting health utilization data post hospital discharge.

 3 METHODOLOGY 3.1 Trial design A pragmatic randomized trial is proposed. Children presenting
 to the Children's Hospital of Eastern Ontario (CHEO) Emergency Department (ED) will receive
 CS (typically prednisone/prednisolone 2mg/kg) as per standard of care outlined in the ED
 pre-printed order and Nursing Medical Directive. . This practice differs from most other
 pediatric EDs across the country where children typically receive dexamethasone 0.3 mg/kg on
 presentation to the ED. As there is significant outpatient evidence showing that
 dexamethasone is non-inferior to prednisone for outpatient asthma treatment, it is possible
 that the CHEO ED will have switched over to administering dexamethasone 0.3 mg/kg to children
 presenting with acute asthma exacerbation by the time this study is implemented. Blinding of
 the participants and members of the health care team will not be feasible. Given that the
 investigators are aiming to test the effectiveness of their intervention across routine
 clinical practice, they elected to conduct a pragmatic trial. Since the palatability of the
 CS is likely to affect compliance, masking the taste of the CS to ensure blinding would
 decrease the ability to detect a difference in compliance due to taste. Moreover, given the
 length of therapy for prednisone/prednisolone is longer than that of dexamethasone,
 introducing placebo doses to ensure similar length of treatment would also potentially impact
 compliance and undermine the investigators' ability to detect a difference between groups.
 Investigators, data analysts, and research assistant completing patient assessment at the
 follow-up visit will be blinded to group assignment.

 A research assistant will review the list of admissions for the previous 12 hours, on a twice
 daily basis, from Monday to Friday. The research assistant will then ask a member of the
 patient's health care team (bedside nurse, charge nurse, resident, staff physician) to ask
 the family members for permission to approach them about the study. The research assistant
 will then complete an eligibility screen, and maintain a phone follow-up ledger for consented
 patients. If the patient is eligible and the family gives their informed consent, they will
 be allocated to one of the study groups. Once written, informed consent has been obtained,
 the research assistant will communicate with the health care team to ensure the patient
 continues on the CS initiated in the ED, for the appropriate number of doses as determined by
 CS group assignment. A record will be kept of all screened patients, patient eligibility,
 allocation, and follow up to allow reporting according to CONSORT guidelines. Additional
 consent will be requested to access patients' health utilization data (readmissions, ED
 visits, visits to family physicians) through linkage with ICES data.

 After enrollment, the patients will be randomly allocated to one of the two treatment groups.
 The randomization schedule will have been previously generated using a computer.
 Randomization will be blocked with randomly chosen block lengths of 4 or 6. Treatment
 assignments will be written on a piece of paper and concealed in sequentially numbered opaque
 envelopes kept in a secure locked location in the study research office. The PI and analyst
 will be blinded to the treatment intervention, but the research coordinator in charge of
 assessing eligibility and allocation and the patient's treating team (physicians and nurses)
 will not because of the nature of the pragmatic nature of the trial.

 4. ANALYSIS 4.1 Sample size The investigators sought a sample size that would allow them to
 estimate their feasibility outcomes with reasonable precision. As such, they have set out to
 achieve a 15% margin of error (i.e. half-width of 95% confidence interval=0.15) for any
 proportions to be estimated (e.g. allocation success, retention success). At a hypothesized
 proportion of 50%, they determined that 43 patients will be needed to achieve this level of
 precision. This provides a most conservative estimate since any proportions other than 50%
 will require fewer patients. Factoring in an additional 15% of patients as allowance for
 attrition or incomplete data they have set a recruitment target of n=51 in total. With
 approximately 18 asthma admissions per month, assuming 70% are eligible and 50% of eligible
 patients consent, the investigators expect to meet this sample size requirement in 9 months.

 4.2 Quantitative Data Analysis For all relevant feasibility outcomes, binary proportions
 (e.g. % success) and the associated 95% confidence interval will be estimated using the
 Wilson method. To help inform the design of main trial (i.e. expected effect sizes), the
 investigators will apply intention-to-treat principles and estimate the treatment effect (and
 95% CI) by comparing outcomes (proposed for the main trial) between intervention groups using
 statistical techniques appropriate to the type and distribution of the various outcomes (e.g.
 continuous, binary, count data).

 4.3 Qualitative Data Analysis Semi-structured interview at week 4 will be audio taped and
 transcribed verbatim. Analyses will be conducted using NVivo 9 software. Inductive analysis
 will be used to identify categories, patterns and themes.
Inclusion Criteria:

 1. Children admitted during the study period with a diagnosis of asthma exacerbation,

 2. Children aged 18 months to 17 years of age

 3. Children who received oral Corticosteroids in the Emergency Department prior to
 admission under our hospital Emergency Department Nursing Medical Directive and/or
 Pre-Printed Order Form

 Exclusion Criteria:

 1. Children who received IV Corticosteroid (CS) in the Emergency Department (ED)

 2. Children who received oral CS in the ED prescribed in any other way than through the
 Children's Hospital of Eastern Ontario ED Nursing Medical Directive and/or Pre-Printed
 Order Form as doses may not be standardized

 3. Children who have received more than one dose of oral CS prior to enrolment

 4. Children who have received their first dose of oral CS greater than 12 hours prior to
 enrolment

 5. Children who received oral or IV CS in the previous 4 weeks

 6. Children with any of the following: unrepaired congenital heart disease, chronic lung
 diseases other than asthma, severe neurological impairment and other significant
 co-morbid disorders as they are not typically treated on our hospital's asthma pathway

 7. Children whose caregivers do not understand English or French