RCT of IV Dexamethasone to Prevent Relapse in the Treatment of Migraine in a Paediatric ED
RCT of IV Dexamethasone to Prevent Relapse in the Treatment of Migraine in a Paediatric ED
Background: Headaches is one of the most common complaints of children in the ED and the
 treatment of pediatric migraine is largely based on extrapolation data from adult studies,
 limited pediatric trials, clinical experience and expert consensus. Despite the fact that
 dexamethasone has already been proven effective to reduce recurrence and is currently used in
 treating adults with migraine, no studies have looked at its use in the treatment of
 childhood migraine where relapse rate of about 50% are described in the 48h following
 successful treatment in the ED.

 Objective: To examine the effectiveness of parenteral dexamethasone at preventing migraine
 recurrence in children and to study the risk factors for migraine relapse after discharge
 from the ED.

 Methods: This a randomised, double-blind, placebo-controlled clinical trial among all
 children 8 to 17 years of age with a presumptive diagnosis of acute migraine and treated with
 a standardized protocol in the ED of the CHU Ste-Justine, a tertiary care pediatric hospital.
 After the parenteral administration of prochlorperazine or metoclopramide and
 diphenhydramine, the patients were randomised to receive either dexamethasone or a placebo.
 They were excluded from the intervention if they had a known allergy or absolute
 contraindications to receiving parenteral corticosteroids, if they were already on a
 corticosteroid regimen or if they did not respond to the initial abortive migraine therapy.
 All included patients were discharged on a 48-hour course of naproxen and with a headache
 diary to fill out and return. The primary outcome was the incidence of relapse in the 24-48h
 following discharge from ED. The secondary outcomes evaluated were the mean level of pain,
 the use of rescue medication after ED discharge, the return rate to the ED or the visit to a
 health care professional within 7 days including hospitalisation. The associated symptoms,
 the adverse events after parenteral corticosteroids and the risk factors for migraine relapse
 were also evaluated. A telephone follow-up was made to ensure the headache diary was
 completed and returned.
Study design This was a randomised, double-blind, placebo-controlled clinical trial among
 children with a presumptive diagnosis of acute migraine in the ED. The study was approved by
 the institutional IRB and written informed assent and consent were obtained by the patient
 and a parent respectively, prior to enrolment.

 Study setting All patients were treated in the ED of the CHU Ste-Justine, a tertiary care
 pediatric hospital with approximately 70 000 visits annually. For over 10 years, the members
 of this ED have been using a standardized protocol for the treatment of migraine. (7) This
 protocol suggests the administration of prochlorperazine and diphenhydramine, to decrease the
 rate of akathisia, if the patient is 8 years of age or more and presents with severe migraine
 (unable to perform normal activities) or status migrainosus (migraine that last more than 72
 hours) to be followed by a few day-course of naproxen. Unfortunately, there was a shortage of
 prochlorperazine at the moment of the study, so a decision was made to use metoclopramide
 instead, another dopamine (D2) receptor antagonist known to be effective in the treatment of
 migraine in adults. (15) To minimize the impact of this research on the clinical management
 of patients, it was decided that migraine would be treated according to the standardized
 local protocol depending on the availability or not of prochlorperazine. This means that the
 treating physician did use the prochlorperazine protocol when possible and metoclopramide if
 not. This was accounted for in the randomization to insure balance distribution between
 groups. While using dual intervention decreased the homogeneity of the participants, it
 improved drastically our external validity.

 Participants Inclusion criteria Patients were eligible if they were between 8 and 17 years of
 age and if they were presenting a diagnosis of acute migraine requiring treatment with an
 intravenous rescue therapy (either metoclopramide or prochlorperazine) because of the
 severity of the migraine according to the treating physician. In a prior study, the same
 group of pediatric emergency physicians had their migraine diagnosis confirmed by a pediatric
 neurologist in 64 of 68 patients.(16) Exclusion criteria Patients were excluded if they had a
 known allergy to any study drugs or a component or absolute contraindication to receiving
 corticosteroids such as: active untreated infections, systemic fungal infections, cerebral
 malaria, respiratory tuberculosis, hypertension, heart failure, renal or hepatic impairment,
 GI diseases, myasthenia gravis, diabetes, cataracts, glaucoma, seizure disorder, thyroid
 dysfunction, and thromboembolic tendencies. Also, patients who were already on
 corticosteroids were not eligible. Finally, patients who were initially recruited but who did
 not respond to the abortive migraine therapy (no modification in the pain level) were not
 randomized to receive the intervention or placebo. Information about these patients was kept
 but it was not included in the primary analysis.

 Intervention/procedure As mentioned, all participants received a standardized treatment
 consisting of metoclopramide (0.5 mg/kg IV, maximum 10 mg, q 1h prn, maximum of 3 doses) or
 prochlorperazine (0.15 mg/kg IV over 2-3 minutes, maximum 10 mg) and diphenhydramine (0.5
 mg/kg IV, maximum 25 mg). The intervention of interest was the administration of
 dexamethasone 0.6 mg/kg IV (max 24 mg) before departure from the ED. The control group
 received a similar looking placebo (NaCl 0,9% IV) with the same volume. All patients received
 a perfusion of D5% NaCl 0.9% at basal requirements during their stay in the ED and were
 discharged on a 48-hour course of naproxen (Naprosyn® 5 mg/kg/dose BID, max 500 mg) provided
 by our pharmacy.

 Primary Outcome The primary outcome was the incidence of relapse following discharge from the
 ED and up to 48 hours after metoclopramide or prochlorperazine initial administration.
 Relapse was defined as either occurrence of any headache pain, regardless of its severity,
 after a pain free status, or any increase in the pain intensity in participants who left the
 ED with residual pain.

 Secondary outcome The secondary outcomes was the mean level of pain using the VAS at 24 and
 48 hours following the initial administration of metoclopramide or prochlorperazine, the use
 of any rescue medication after ED discharge, the return rate to the ED, or the visit to a
 health care professional within 7 days including hospitalization. Also, the associated
 symptoms (i.e. nausea, vomiting, photophobia and sonophobia), the adverse events after
 parenteral corticosteroids (heartburns, constipation, personality changes such as
 irritability, and sleeping problem) and the following risk factors for migraine relapse were
 evaluated: headache duration, past history of headache, presence of familial history of
 migraine, age, sex, rescue medication at home prior to ED visit, prophylaxis at home prior to
 ED visit, past history of neurology consultation, past history of CT scan, maximal pain
 intensity, pain intensity on arrival to ED and at discharge, duration of sleep in ED, quality
 of sleep in ED, treatment in ED, treatment at discharge, compliance with medication after
 discharge, time to return to school, time to return to normal activities, number of hour of
 sleep after discharge of ED, and quality of sleep at home after ED discharge.

 Study protocol All eligible children for whom the treating physician prescribed the migraine
 protocol in the study setting were invited to participate in the study before administration
 of the first medication (either metoclopramide or prochlorperazine). Baseline demographic
 data, vital signs, characteristics and duration of the headache were recorded on a standard
 data form. Patients were asked to complete a standardized questionnaire during the ED stay
 with the help of their parents if needed. At time 0, prior to any treatment, patients rated
 their headache severity on a 100 mm visual analogue scale (VAS), on a 0 to 10 verbal numeric
 scale (VNS) and on a 4-point verbal numeric scale (VNS) as 0=no headache, 1=mild headache,
 2=moderate headache or 3=severe headache. The participants were also asked to rate their
 headache on a 4-point functional disability scale as 0=no disability (i.e. able to function
 normally); 1=mild disability (i.e. able to perform all activities of daily living but with
 some difficulty); 2= moderate disability (i.e. unable to perform certain activities of daily
 living); 3= severe disability (i.e. unable to perform most to all activities of daily living,
 or requiring bed rest). The participants then received the standard abortive migraine therapy
 previously detailed. Patients rated their headache severity on the three scales previously
 mentioned 2 hours after the abortive medication was given or as soon as they woke up (if they
 fell asleep) and they were asked to report any associated symptoms (i.e. nausea, vomiting,
 photophobia and sonophobia) and adverse effects (severity, seriousness, time of onset and
 resolution). The same assessment was repeated at discharge. Patients were discharged
 according to the clinical decision of the ED physician. In the uncommon situation where a
 participant was hospitalized because he did not respond adequately to the abortive
 intervention, this patient was excluded from the study and was not offered the intervention.
 The rationale behind this procedure was that dexamethasone was given to decrease migraine
 recurrence but it could not be effective if the migraine did not regressed. Just before
 discharge and the removal of the intravenous access, the research nurse took the next
 available study package according to the status of the patient (absence or presence of
 residual pain at discharge and abortive medication used) and administered the intervention,
 either the study drug or the placebo. All patients were discharged on a 48-hour course of
 naproxen provided by our pharmacy to facilitate compliance at a dosage of 5 mg/kg twice a day
 for 48 hours. The participants were also given a headache diary to fill out and a stamped
 envelop with the standardized questionnaire used by the research assistant for follow up in
 case the phone interview would not happen. The participants were instructed to answer the
 questions of the diary once a day for the first 48 hours after discharge and then on day 4
 and 7 and to then return the diary in the stamped envelop. To facilitate compliance with the
 headache diary, patients were contacted by telephone at 24-48 hours and one week later to
 remind them to complete and return the diary and they were also asked the same questions by
 the research assistant on the phone.

 Randomization and blinding The hospital pharmacist created the randomization table using
 computer generated sequence using block randomization of variable sizes. Stratification was
 performed according to the absence or presence of pain at discharge and also depending on the
 abortive medication used (prochlorperazine or metochlopramide). The pharmacist coded the
 study medications in advance. Either dexamethasone (10 mg/mL) or normal saline (placebo) was
 placed into each respective syringe and labeled with a code number. Once consent for study
 enrolment was obtained, the next consecutive study package was used. Blinding was assured by
 dexamethasone and placebo having the same appearance and being administered in the same
 volume.

 Compliance and quality control Because the intervention was limited to a single dose of
 intravenous medication, compliance was almost perfect. However, we did ensure that the dose
 was effectively given to the participants according to their charts. Several precautions were
 taken in order to minimize potential biases. A screening log was maintained to record the
 number of patients screened, excluded, missed, or not randomized for any other reason. The
 diagnosis and reason for exclusion (ineligible or refused patients) was recorded in order to
 help us in detecting any selection bias. We also implemented a number of study manoeuvres
 aimed at minimizing measurement biases, including (a) designation of a research pharmacist
 (not a team member) to prepare the medications according to the randomization list, and (b)
 documenting the use of any major co-intervention, such as the use of other analgesia.

 Statistical analysis All data were entered in an Excel database (Microsoft Inc., Richmond,
 WA) and analyzed with SPSS v17 software (SPSS Inc., Chicago, Illinois). To assess balance
 across arms, baseline demographic (i.e. gender, age) and clinical data of patients were
 compared between arms. In the very unlikely event that a substantial imbalance is found,
 additional analyses, in addition to the one proposed below, were carried out to assess the
 potential confounding effects of this imbalance. The primary analysis was performed among all
 study participants who received the study medication using an intention-to-treat principle.
 This was the comparison of the proportion of relapse in the 48 hours following intervention
 between the 2 groups using chi-square analysis. A secondary analysis compared relapse
 proportion at one week. Another secondary analysis used a student t-test to compare mean VAS
 for pain at 24 hours, 48 hours and 7 days following intervention. Finally, use of rescue
 medication, unplanned visit to a healthcare setting and side effects were compared using a
 chi-square statistics.

 Sample size requirement A previous study done in a pediatric emergency department had
 reported that approximately 50% of children successfully treated for migraine in our study
 setting had a relapse in the following 48 hours.(7) Based on this, the minimal clinically
 significant difference was defined a-priori by our group of pediatric emergency physicians to
 be a decrease of that relapse rate to 25%. Assuming these numbers, a total of 58 patients
 were required in each group for a power of 0.80 with an alpha of 0.05.
Inclusion Criteria:

 -  presenting a diagnosis of acute migraine

 -  requiring treatment with an intravenous rescue therapy (either metoclopramide or
 prochlorperazine) because of the severity of the migraine according to the treating
 physician.

 Exclusion Criteria:

 -  known allergy to any study drugs or a component

 -  absolute contraindication to receiving corticosteroids such as: active untreated
 infections, systemic fungal infections, cerebral malaria, respiratory tuberculosis,
 hypertension, heart failure, renal or hepatic impairment, GI diseases, myasthenia
 gravis, diabetes, cataracts, glaucoma, seizure disorder, thyroid dysfunction, and
 thromboembolic tendencies

 -  patients who were already on corticosteroids

 -  patients who were initially recruited but who did not respond to the abortive migraine
 therapy (no modification in the pain level) were not randomized to receive the
 intervention or placebo.