Total marks: 23
Time allowed: 90 mins
You might wish to download the paper. Do it in 90 minutes and then compare with the answers provided here.
Paper: A Randomized Trial of Nebulized 3% Hypertonic Saline With Epinephrine in the Treatment of Acute Bronchiolitis in the Emergency Department
1. Provide a summary / abstract for the paper. (Up to 5 marks)
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This should include all or some of the following points:
Objective: To determine whether nebulised 3% hypertonic saline with epinephrine is more effective than nebulised 0.9% saline with epinephrine in the treatment of bronchiolitis in the emergency department.
Design: Randomised double blind controlled trial Setting: Single centre urban paediatric emergency department in Canada. Participants: Infants younger than 12 months with mild to moderate bronchiolitis.
Interventions: Patients were randomised to receive epinephrine in either hypertonic or normal saline.
Outcome measures: The primary outcome measure was the change in respiratory distress, as measured by the Respiratory Assessment Change Score (RACS) from baseline to 120 minutes. Change in oxygen saturation was also determined. Secondary outcome measures included rates of hospital admission and unbooked return to the ED following discharge.
Results: 46 patients were enrolled. The two groups had similar baseline characteristics. RACS from baseline to 120 minutes demonstrated no improvement in respiratory distress in the hypertonic saline group when compared to the normal saline group. The change in oxygen saturations in the hypertonic group was also no different to that of the normal saline group. Rates of admission and unplanned return to the ED were similar between the two groups.
Conclusion: In this study hypertonic saline with epinephrine did not improve clinical outcome in acute bronchiolitis when compared to normal saline with epinephrine.
2. Give 3 strengths and 3 weaknesses of the study design? (Up to 3 marks)
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Strengths:
- Done in a paediatric ED
- Patients defined quite tightly in terms of clinical features and RDAI Score. Patients are thus likely to have bronchiolitis
- Demographic and clinical data collected by research assistants using standard data collection form.
- Excellent allocation concealment. Pharmacy made up identical looking syringes and retained the randomisation list until the end of the study.
- Blinding also good. Neither staff nor patients were aware of their treatment
- Outcomes are clearly defined and seem relevant and important.
Weaknesses:
- Limited hours of enrolment (4pm to 2 am). ? selection bias
- Only conducted if research assistant was available
- Whilst scoring system well defined it seems quite complex and open to interobserver variability (although the authors state not)
- It’s unclear who is assigning the RDAI score.
There are some things you can put into either column! These basically relate to whether you like pragmatic trials (most ED ones should be I think) or explanatory trials. Examples here include:
- Physicians being able to give any other treatment as they see fit during the study period including a further dose of the trial medication. This is very “real world” (pragmatic) and I think is a strength. You may feel that to be of any value all the patients should have had the same treatment except the trial medication (the explanatory approach) and thus see this as a weakness
- Similar argument for the use of trained and educated research assistants in collecting the data and looking after the patients. Could be seen as a weakness as it’s not very “real world” (when stressed out busy people would be trying to look after several patients at a time!). On the other hand, the data you get will be more accurate.
3. What is block randomisation? What are the benefits and pitfalls of this method? (Up to 3 marks)
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Block randomisation is a technique used to ensure that at any particular time in a study, the number of patients in each group is roughly similar.
In this study the authors used blocks of 4. Each block will have 2 of each of the treatments (although their position within the block of 4 will be randomly allocated). The blocks themselves are then randomised. In this way one group can never have more than 2 patients more than any of the others at any time.
The biggest pitfall with this method is that it might be possible for researchers or the ED medical or nursing staff to guess what the next treatment is going to be. E.g. if the research assistant is on patient 7, and knows that the last 2 patients had got better more quickly than usual (if she had a pre conceived idea than hypertonic saline was marvellous!), she might assume that the next patient was going to get normal saline. This might affect decisions about whether to include the patient in the trial in the first place.
In this particular example this doesn’t seem to have been a problem because the treatments look the same and their effects were similar. However it can be a problem when the person initiating the trial treatment is not blinded (eg NIV versus standard facemask) or the treatments can be distinguished in other ways (e.g. a trial of iv Pabrinex versus iv “brown” saline for alcoholics when the smell might give it away!)
4. What alternative methods of treatment allocation are there? (Up to 1 mark)
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Single patient randomisation
Quasi randomisation – e.g. days of the week, hour of the day etc..
5. What do you understand by the term “intention-to-treat”? What are the advantages of this? What is the opposite approach and what advantages does this have? (Up to 4 marks)
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Intention to treat includes all randomised patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol.
Once again this is very “real world”. It’s no good if a treatment is excellent for those who actually take it but a lot of people can’t tolerate it and so withdraw from a trial. Intention to treat analysis will ensure that the real world effects of a treatment are reported by ensuring that the results from “drop outs” are included in the analysis.
The alternative approach is sometimes referred to as “per protocol” or “explanatory” and means that the analysis is done only for those patients who actually took the allocated treatments. This might result in a better understanding of the actual biological effects of the treatment but isn’t so “real world”.
6. The authors used Fishers Exact Test for analysis of some of their data. What type of data can be analysed in this way and when is this used (Up to 2 marks)
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The data is categorical data and usually dichotomous. That is, there are two treatment groups and the outcome measure is binary (i.e a 2 x 2 table can be generated).
Fishers test is used when the “expected” number in any one of the 4 quadrants is low (typically less than 5). Chi squared tests should only be used when all the expected numbers are higher than this.
7. The authors state that a change in RACS Score of anything less than 3 would not be clinically important. Why is it important to decide on the minimally clinically important effect and how does this effect power and sample size. (Up to 3 marks)
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There is no point in designing a study to detect a difference in effect which isn’t clinically important.
Decisions on what is considered clinically important can be made using “hunch”, previous published studies, expert opinion or patient expectations but should be justified in the paper.
Detecting a smaller difference will require a larger sample size or a reduction in the power of the study. Most studies use 80% power as the minimum acceptable.
8. The following table is taken from the paper.
What do you understand by the figure 0.74 (-1.45 to 2.93) in the top right section of the table? (Up to 3 marks)
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The mean difference between the changes in RACS Score over 120 minutes is 0.74 in favour of normal saline (normal saline improving the score by 5.13 points on average compared to hypertonic saline improving the score by 4.39 on average).
However, the 95% confidence intervals for this figure cross zero with a range of -1.45 to 2.93 indicating that the range of “plausible results” lies between hypertonic saline being better and normal saline being best. i.e there is no difference between the two statistically.
9. What are your conclusions overall? Is this paper going to influence your practice? (Up to 2 Marks)
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This is well constructed and described study nebulised hypertonic saline in children attending the ED with bronchiolitis.
A bigger study with across the day patient selection might be useful
It won’t change my practice regarding hypertonic saline but I may have to read about nebulised adrenaline in this condition!
Critical Appraisal Practice Paper 3 (Therapeutic)
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