Critical appraisal SAQ – July 2012 RTD
Intramuscular vs intravenous Therapy for Prehospital Status Epilepticus
N Engl J Med 2012;366:591-600
Que 1 – Write a 200 word abstract for this paper. Bullet points can be used. (8 marks)
Introduction
-To determine if intramuscular midazolam is as effective and safe as intravenous lorazepam in terminating status epilepticus in the pre-hospital environment.
Methods
-Randomised, double-blinded, non-inferiority trial
-Simple randomisation used
-Subjects were adults and children with an estimated weight more than 13kg who were in status epilepticus
-Double dummy strategy was used to administer drugs
-Primary outcome was termination of seizures before arrival in the emergency department without the need for rescue therapy
-Secondary outcome measures were length of hospital and ITU stay, time to termination of seizures, time to administration of trial drug, rates of endotracheal intubation and seizure recurrence within 12 hours.
Results
-An intention to treat analysis was performed
-893 patients were randomised into the study, 448 in the midazolam and 445 in the lorazepam group
-10% more patients had stopped convulsing on arrival in the emergency department in the midazolam group compared to the lorazepam group (95% CI 4-16.1, p <0.001)
-Secondary outcome measures did not differ significantly between the two groups
-Overall time to seizure cessation did not differ between the two groups
Conclusion
-Pre-hospital treatment with intramuscular midazolam was as effective as intravenous lorazepam in the treatment of status epilepticus.
Que 2 – What do you understand by the term ‘double dummy strategy’ and why is it used?(1 mark)
A double dummy strategy is a method of retaining blinding when the interventions under study cannot be made identical eg nebuliser versus intravenous therapy.
All study participants would appear to receive both interventions but they could be either placebo or study intervention in any combination as per the randomisation process.
Que 3 – The following quote is from the ‘primary outcome’ section of the paper (page 597):
‘Seizures were absent without rescue therapy...active treatment with intramuscular midazolam (73.4%) and...intravenous lorazepam (63.4%) (difference, 10 percentage points; 95% confidence interval (CI), 4.0 to 16.1; P<0.001 for noninferiority...)’
What does ‘95% confidence interval 4.0 to 16.1’ mean? (2 marks)
Confidence intervals provide a range of values around an estimate that have a certain probability of encompassing the true value.
95% confidence interval of 4-16.1 in this statement means that the true difference between intramuscular midazolam and intravenous lorazepam in stopping seizures is between 4-16.1% in favour of midazolam, with a 95% probability that the true value lies between this range.
What does P<0.001 for noninferiority mean in relation to the primary outcome in this paper? (2 marks)
P values represent the statistical probability that the result has arisen by chance and that the null hypothesis is therefore true.
P<0.001 for noninferiority means that the chance that no difference exists between midazolam and lorazepam is less than 1 in 1000 (<0.001). Therefore the null hypothesis that midazolam is inferior to lorazepam can be rejected ie intramuscular midazolam is non-inferior to intravenous lorazepam.
Que 4 –This trial has a good study design, give 4 reasons why this is so.(4 marks)
- Sample size and power calculation done, patient recruitment achieved these numbers
- Randomisation was pragmatic and although simple, worked (table 1 of paper)
- Double dummy technique used to blind clinicians and conceal allocation to study groups.
- Multicentre trial, therefore increases external validity
- Very few losses to follow up in the secondary analysis. No losses to follow up in the primary analysis.
Que 5 – Define the terms mean and median. (2 marks)
Mean – It is the value obtained by adding all values in a data set and dividing it by the total number of values.
Median –It is the middle value of an ordered (either ascending or descending) set of values.
Que 6 – Your local ambulance officer has read this paper and asks you if you would recommend IM midazolam over IV lorazepam. Based on this paper alone, what would your reply be and state 3 reasons for your decision. (6 marks)
3 reasons to recommend im midazolam
- Good trial with robust methodology showed non inferiority to iv lorazepam.
- Time to cessation of convulsions was favourable to midazolam
- Im midazolam in the autoinjector may be easier to use prehospital than iv medication, may reduce on scene times and quicker hospital transfer.
3 reasons not to recommend im midazolam
- Trial compared autoinjector of midazolam, this may not be available in the UK. Drawing up midazolam may not have the time benefit shown in this study.
- No cost analysis of autoinjector shown
- Iv lorazepam, when given, terminated seizures quicker than midazolam so lorazepam can still be used as 1st line if iv access can be achieved quickly.