Critically Appraised Topic (CAT)

For the CCFP-EM year, residents typically present and write-up a “Critically Appraised Topic”. This is a systematic review of the literature in attempts to best answer a clinical question chosen by the resident. Other types of academic/research projects are possible if desired, but residents are cautioned that the CCFP-EM training is only one-year in duration and is very busy. Residents should know that initiating and completing an original research study during this year would be quite challenging. An example of a Critically Appraised Topic is below:

Critically Appraised Topic
 
Dr. Allan Bell
2008 - 2009

 
Clinical Question
 
Does parenteral dexamethasone diminish headache
recurrence when included in emergency department
treatment of migraine?

Critically Appraised Topic
 
Clinical Question: Does parenteral dexamethasone diminish headache recurrence when included in emergency department treatment of migraine?
 
Articles Chosen:
 
  1. Baden EY, Hunter CJ. Intravenous dexamethasone to prevent the recurrence of benign headache after discharge from the emergency department: a randomized, double-blind, placebo-controlled clinical trial. Can J Emerg Med. 2006;8:393-400.
  2. Donaldson, D, Sundermann R, Jackson R, et al. Intravenous dexamethasone vs placebo as adjunctive therapy to reduce the recurrence rate of acute migraine headaches: a multicenter, double-blinded, placebo-controlled randomized clinical trial. Am J Emerg Med. 2008;26:124-30.
  3. Fiesseler FW, Shih R, Silverman ME, et al. Dexamethasone for migraine headaches: an emergency department randomized double-blind placebo-controlled trial (abstract). Acad Emerg Med. 2006;13:S137.
  4. Friedman BW, Greenwald P, Bania TC, et al. Randomized trial of IV dexamethasone for acute migraine in the emergency department. Neurology. 2007;69:2038-44.
  5. Innes GD, Macphail I, Dillon EC, et al. Dexamethasone prevents relapse after emergency department treatment of acute migraine: a randomized clinical trial. Can J Emerg Med. 1999;1:26-33.
  6. Jones JS, Brown MD, Bermingham M, et al. Efficacy of parenteral dexamethasone to prevent relapse after emergency department treatment of acute migraine (abstract). Acad Emerg Med. 2003;10:542.
  7. Rowe BH, Colman I, Edmonds ML, et al. Randomized controlled trial of intravenous dexamethasone to prevent relapse in acute migraine headache. Headache. 2008;48:333-40.
 
Clinical Bottom Line:
 
People with severe migraine represent approximately 5% of all emergency department presentations, and while many agents are moderately effective in relieving acute migraine, recurrences are common within 24-72 hours.1 The pathophysiology of migraine is multimodal, but it appears to involve a significant inflammatory component, which in theory may respond to corticosteroids. This review corroborated that theory, as the addition of parenteral dexamethasone to standard emergency department abortive migraine treatment produced a 26% relative reduction in headache recurrence within 72 hours (NNT=9).
 
The Search:
 
Using MEDLINE (1996-November 2008) and EMBASE (1996-2008 Week 48), search “dexamethasone” and “intravenous or parenteral” and “migraine disorders” limited to humans. In addition, using the Cochrane Central Register of Controlled Trials, search “dexamethasone” and “migraine or migraine disorders.” 
 
The search strategy produced 50 articles for consideration. Articles written in languages other than English were excluded, as were non-randomized trials, case reports, and review articles. Any study investigating the non-parenteral administration of dexamethasone or the use of dexamethasone in a setting outside of the emergency department was excluded. Lastly, all articles solely researching the utility of dexamethasone for abortive migraine treatment were excluded, given that the scope of this analysis was instead to examine the role of dexamethasone in preventing migraine recurrence following initial emergency department treatment.
 
Ultimately five articles satisfied the inclusion and exclusion criteria. The references of these articles were examined, and an additional two publications were identified as satisfactory for inclusion, thereby generating seven articles in total for review. Five of the seven articles were published, and two were in abstract form.
 
Design
 
Population:
 
All studies were prospective, randomized, double-blinded, placebo-controlled trials conducted on emergency department patients greater than 18 years of age at enrollment. Six studies required patients to satisfy diagnostic criteria for migraine headaches, as defined by the International Headache Society classification. The remaining study by Baden and Hunter 2006 included all patients who satisfied the International Headache Society classification for benign idiopathic headache, as the authors felt the distinction between migraine and tension-type headaches is blurred and of limited clinical importance. All investigators excluded pregnant patients, and those known to be allergic to the study medication. Additional exclusion criteria applied variably amongst the investigations included: findings inconsistent with a benign headache (e.g. fever, meningismus, focal neurologic findings), active peptic ulcer disease, gastrointestinal bleeding within the past year, type I and II diabetes, previous steroid use within 7-30 days, immunosuppression, suspicion for narcotic-seeking behaviour, and lumbar puncture given its independent association with 24-hour headache.
 
Intervention:
 
All investigations permitted the treating physician to administer standard abortive medical treatment for migraine headache in the emergency department, including but not limited to antiemetics, non-steroid anti-inflammatory medications, and opioids. In addition, those patients randomized to the treatment group received parenteral dexamethasone prior to discharge from the emergency department, while the control group received a placebo of similar appearance and volume to the active medication. The investigations varied regarding how the active medication and placebo were administered, utilizing either a bolus or infusion. Refer to Table 1 for a description of the dexamethasone and placebo doses utilized in the included articles.
 
 
Table 1. Characteristics of included articles examining the utility of dexamethasone vs placebo in reducing headache recurrence following standard abortive treatment of migraine in the emergency department.
Reference
Enrollment
Setting
Treatment
Control
Initial ED Measurement
Baden 2006
55
EDs of two military hospitals
10 mg IV Dexamethasone
IV Saline
10 cm VAS before ED intervention and ED discharge
Donaldson 2008
99
EDs of trauma centre and community hospital
24 mg IV Dexamethasone
5 ml IV
“indistinguishable solution”
None
Fiesseler 2006
85
ED of community hospital
10 mg IV Dexamethasone
IV Saline
None
Friedman 2007
205
EDs of four academic hospitals
10 mg IV Dexamethasone
IV Saline
Four-point descriptive scale of migraine severity q30 min in ED; four-point functional disability scale prior to ED discharge
Innes 1999
98
EDs of tertiary care centre and community hospital
24 mg IV Dexamethasone
IV “Placebo”
10 cm VAS before ED intervention and ED discharge
Jones 2003
70
ED of community hospital
20 mg IV/IM Dexamethasone
IV “Placebo”
None
Rowe 2008
126
EDs of four urban hospitals
15 mg IV Dexamethasone
IV “Placebo”
10 cm VAS before ED intervention and ED discharge
NB: All studies allowed the treating emergency physician to utilize standard abortive treatments for migraine headache in addition to the treatment and control protocols previously listed.
 
 
Outcomes Measured:
 
The primary outcome of interest was recurrence of headache within 24-72 hours following initial emergency department treatment and discharge. This inherently required resolution of the presenting migraine; however, in some instances patients were not completely pain-free at discharge, but had nonetheless shown substantial improvement. Thus, some patients had headaches that worsened after partial relief in the emergency department (persistent) whereas others had headaches that initially resolved but recurred during the follow-up period (recurrent). For the purposes of this investigation, both of these conditions were considered “recurrences.” The secondary outcome of interest was adverse events associated with treatment. The details of how and when the primary and secondary outcomes of interest were attained for each included investigation are demonstrated in Table 2.
 
 

Table 2. Primary and secondary outcome assessments and the follow-up period at which they were attained for included articles.

 

Reference
Follow-Up Period
Primary Outcome Assessment
Secondary Outcome Assessment
Baden 2006
48-72 hours following ED discharge
Patients pain-free at discharge who had a return of a headache and those with pain at discharge who were “worse” or “unchanged” were both considered to have had a recurrence.
Patients were asked if they experienced adverse effects potentially attributed to their treatment.
Donaldson 2008
72 hours following ED discharge
Patients pain-free at discharge that had a return of a headache and those with pain at discharge who had any degree of ongoing headache were considered to have had a recurrence.
Patients were asked if they experienced adverse effects potentially attributed to their treatment.
Fiesseler 2006
24-48 hours following ED discharge
Patients pain-free at discharge that had a return of a headache and those with pain at discharge who had any degree of ongoing headache were considered to have had a recurrence
Not assessed.
Friedman 2007
24 hours following ED discharge
A disability scale was administered to patients, and regardless of condition at discharge, those with a headache at follow-up resulting in mild, moderate, or severe impairment of daily activities were considered to have had a recurrence.
Patients were asked if they experienced “any other symptoms” since receiving the study medication.
Innes 1999
48-72 hours following ED discharge
Patients who had recurrent headaches provoking another physician visit or interfering with daily activities were considered to have had a recurrence.
Patients were asked if they experienced adverse effects potentially attributed to their treatment.
Jones 2003
48 hours following ED discharge
Patients who had recurrent headaches provoking another physician visit or interfering with daily activities were considered to have had a recurrence.
Not assessed.
Rowe 2008
48-72 hours following ED discharge
Patients who had recurrent headaches provoking another physician visit or interfering with daily activities were considered to have had a recurrence.
Patients were asked if they experienced adverse effects potentially attributed to their treatment.

Results:

 
Only Innes et al (1999) demonstrated a statistically significant reduction in headache recurrence when parenteral dexamethasone was added to standard emergency department treatment of migraine. However, the remaining investigations all found a non-significant trend favouring the use of dexamethasone for this purpose. Given that the individual trials had limited enrollment, a meta-analysis of the seven trials listed and described above was undertaken by Colman et al (2008) to further elucidate the role of parenteral dexamethasone in limiting migraine headache recurrence. The pooled results revealed a significant reduction in recurrence rates among patients treated with parenteral dexamethasone in addition to standard abortive care (relative risk 0.74, CI 0.60-0.90), as shown in Table 3. The estimated number needed to treat to prevent one recurrent headache was 9 (CI 6-25).
 
 
 
Table 3. Relative risk of headache recurrence with the addition of dexamethasone to standard abortive
                 migraine therapy in the emergency department, as per Colman et al (2008).
Number with recurrent headache / Number in group
 
Reference
Dexamethasone Group
Placebo Group
Weight (%)
Relative Risk (95% CI)
Baden 2006
4/31
8/24
7.45
0.39 (0.13 – 1.13)
Donaldson 2008
21/57
18/42
13.41
0.86 (0.53-1.40)
Fiesseler 2006
19/44
20/41
11.52
0.89 (0.56-1.40)
Friedman 2007
39/106
43/99
27.78
0.85 (0.61-1.19)
Innes 1999
9/49
22/49
13.28
0.41 (0.21-0.80)
Jones 2003
8/34
10/36
9.49
0.85 (0.38 – 1.89)
Rowe 2008
14/64
20/62
17.07
0.68 (0.38 – 1.22)
Total
385
353
100
         0.74 (0.60-0.90)
 
 
The pooled data for adverse events found no significant differences between the treatment and control groups for patient described sensations of drowsiness, numbness, tingling, nausea, restlessness, swelling, or “other adverse events”. There was a trend for patients treated with dexamethasone to have an increased likelihood of dizziness (RR 2.15, 0.98-4.74), although neither the duration nor severity of this effect were quantified. A summary of the adverse event data from the meta-analysis of Colman et al (2008) is included in Table 4.
 
Table 4. Relative risk of specified adverse events with the addition of dexamethasone to standard abortive
                 migraine therapy in the emergency department, as per Colman et al (2008).
Adverse Event
Relative Risk of Pooled Data (95% CI)
Restlessness
0.97 (0.64-1.48)
Drowsiness
0.84 (0.57-1.23)
Nausea
0.70 (0.48 – 1.02)
Dizziness
2.15 (0.98-4.74)
Tingling, Numbness, or Swelling
1.84 (0.69-4.90)
Other Adverse Events
0.50 (0.30-0.82)
 
 
Comments:
 
Research indicates that 6% of men and 15-17% of women experience migraine headaches, and that these headaches are directly responsible for approximately 5% of emergency department visits.1 Furthermore, although acute migraine headaches often initially respond to standard abortive treatments, these headaches frequently recur shortly following discharge.2, 3, 4 In fact, headache within 24 hours of discharge occurred in 23-87% of subjects in emergency department based migraine clinical trials.5 Consequently, migraine headaches have a substantial impact on health-care costs, but perhaps more impressive is their impact on lost productivity costs, estimated to range from 5-17 billion dollars annually in the U.S.6 
 
The pathophysiology of acute migraine remains the subject of intense investigation, but there is accumulating evidence that neurogenic inflammation perpetuated by vasoactive neuropeptides may contribute to the development, maintenance, and recurrence of migraine headache.7 Given that dexamethasone has been used to treat a variety of CNS inflammatory diseases - including bacterial meningitis and vasogenic edema – it may have similar utility limiting the sterile inflammatory response of migraines. Moreover, considering its superior potency, prolonged duration of action, and improved CNS penetration compared to other corticosteroids, there has indeed been increasing focus on the potential of dexamethasone to limit migraine recurrence.7,8
 
This review utilized a comprehensive search strategy to identify seven double-blind, placebo-controlled randomized controlled trials examining the utility of parenteral dexamethasone in conjunction with standard abortive therapies to reduce headache recurrence within 72 hours of emergency department migraine treatment. The data was analyzed at depth in a recently published meta-analysis, which found single dose parenteral dexamethasone was associated with a 26% relative reduction in recurrent headache, and that only nine patients need to be treated to prevent one recurrent headache.6 Furthermore, there were no significant differences between the dexamethasone and placebo group pertaining to adverse effects, although there was a trend towards an increased propensity for dizziness in the treatment arm, the duration and severity of which was not quantified.
 
Although the results are suggestive of a beneficial effect when parenteral dexamethasone is added to standard emergency department abortive migraine treatments, there are some important limitations to consider.   Firstly, the trials included in this review were all conducted in emergency departments, and thus the results may not be applicable to treatment in alternative settings, such as primary care clinics. Secondly, none of the included studies followed patients beyond 72 hours, and thus the potential exists for delayed side effects secondary to dexamethasone to have been undetected. Thirdly, the small number of studies reviewed and limited sample sizes therein may not have provided a significant number of patients to document and examine some of the rare side effects of dexamethasone.   Nonetheless, there has been only one reported death following a single-dose of dexamethasone, secondary to disseminated strongyloidiasis.9 Lastly, the dose of dexamethasone dispensed varied considerably amongst the included articles. Considering that Innes et al (1999) used a large dose of dexamethasone relative to its comparators, and that it was the only investigation to show a statistically significant treatment effect, further research should attempt to elucidate the optimal dexamethasone dose. This research should also focus on the long-term safety of repeated dexamethasone doses, since patients with migraine may present to the emergency department on numerous occasions for treatment.
 

 

References:
 
  1. Rowe BH, Colman I, Edmonds ML, et al. Randomized controlled trial of intravenous dexamethasone to prevent relapse in acute migraine headache. Headache. 2008;48:333-40.
  2. Innes GD, Macphail I, Dillon EC, et al. Dexamethasone prevents relapse after emergency department treatment of acute migraine: a randomized clinical trial. Can J Emerg Med. 1999;1:26-33.
  3. Jones JS, Brown MD, Bermingham M, et al. Efficacy of parenteral dexamethasone to prevent relapse after emergency department treatment of acute migraine (abstract). Acad Emerg Med. 2003;10:542.
  4. Fiesseler FW, Shih R, Silverman ME, et al. Dexamethasone for migraine headaches: an emergency department randomized double-blind placebo-controlled trial (abstract). Acad Emerg Med. 2006;13:S137.
  5. Friedman BW, Greenwald P, Bania TC, et al. Randomized trial of IV dexamethasone for acute migraine in the emergency department. Neurology. 2007;69:2038-44.
  6. Colman I, Friedman BW, Brown MD, et al. Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomized controlled trials for preventing recurrence. BMJ. 2008;336:1359-1361.
  7. Singh A, Alter HJ, Zaia B. Does the addition of dexamethasone to standard therapy for acute migraine headache decrease the incidence of recurrent headache for patients treated in the emergency department? A meta-analysis and systematic review of the literature. Acad Emerg Med. 2008;15:1223:33.
  8. Donaldson, D, Sundermann R, Jackson R, et al. Intravenous dexamethasone vs. placebo as adjunctive therapy to reduce the recurrence rate of acute migraine headaches: a multicenter, double-blinded, placebo-controlled randomized clinical trial. Am J Emerg Med. 2008;26:124-30.
  9. Baden EY, Hunter CJ. Intravenous dexamethasone to prevent the recurrence of benign headache after discharge from the emergency department: a randomized, double-blind, placebo-controlled clinical trial. Can J Emerg Med. 2006;8:393-400.