We have looked at therapeutic hypothermia not once, not twice, but three times already here at St Emlyn’s; most of our ED consultants also work, at least some of the time, down the long corridor in our paediatric ED – so our interest in how we can best look after our post-cardiac arrest patients extends to children as well.
By the wonder that is twitter, it was a matter of moments after the publication of this particular paper that it was tweeted to me as something I might be interested in reading (thank you so much, James Tooley!)
— James Tooley (@jamestooley) April 25, 2015
Of course, Cliff Reid was first off the starting blocks with his appraisal over at Resus.me while Salim Rezaie has written a review at Academic Life in EM which I have peer-reviewed.
That said, before I had a look at either of their appraisals I did read the paper myself (something I’d recommend to all FOAM colleagues) and we plan to look at the paper in the real life journal club as well as here in the virtual one; my thoughts are below and also over at PEMLit.org.
Kudos to NEJM for making the paper open access – please go and read through it yourself before reading reviews here or on any other sites. Click the abstract above which will take you to the NEJM site and the full paper.
What kind of study was this?
This was a single-blinded, multicentre randomised controlled trial of therapeutic hypothermia versus therapeutic normothermia for paediatric out-of-hospital cardiac arrest. Patients who presented after requiring at least 2mins of chest compressions and with an ongoing requirement for mechanical ventilation after return of circulation were randomised in a ratio of 1:1 by permuted blocks stratified by age into either hypothermia (targeted temperature of 33deg for 48h, then targeted temperature of 36.8deg for another 72h) or normothermia (targeted temperature of 36.8deg for 120h).
It’s important to note that this was therapeutic normothermia, so even in the control group there was an active intervention to tightly control the temperature between 36.0-37.5 degrees rather than just allowing the temperature to react spontaneously.
Who was studied?
The subjects were recruited over just more than three years from 36 sites (there were 38 sites involved but two did not recruit any patients). The patients were aged between 48 hours and 18 years and the trial itself was conductive in the Paediatric Intensive Care Unit.
Patients were included if they had received two minutes or more of chest compressions with a subsequent return of circulation but ongoing need for mechanical ventilation. They were then excluded if they could not be randomised within 6 hours of return of circulation, if they scored 5 or 6 for the motor component of the Glasgow Coma Score (implying rapid return to normal conscious level and presumably short anticipated need for mechanical ventilation), a decision by the treating team to withhold aggressive therapy or major trauma as the cause for the cardiac arrest (this seems reasonable as traumatic cardiac arrest has different aetiology).
The primary outcome of interest was survival at 12 months with a “good functional outcome” and the authors were looking for an absolute effect size of 15-20%.
Patients were also excluded if their baseline performance score (VABS-II) was <70 since this was determined to be the marker of good neurological function used as the primary outcome measure at 12 months.
There were 1355 patients meeting the inclusion criteria but after initial exclusions 295 were randomised, 155 to therapeutic hypothermia and 140 to therapeutic normothermia. Results were analysed using an intention-to-treat protocol; this means that patients were analysed according to the group to which they were initially randomised, irrespective of whether they received the intended intervention, the alternative intervention or withdrew from the study altogether after randomisation.
However, 25 patients were found after randomisation to have a baseline performance score <70 so these patients were not included in the analysis of the primary outcome, leaving 138 in the hypothermia group and 122 in the normothermia group for analysis.
The study also explored some secondary outcomes; survival at 12 months and change in neurobehavioural function (defined as the difference in VABS-II score at 12 months from pre-cardiac arrest baseline).
What did they find?
For the primary outcome there was no significant difference between the two groups in survivors with VABS-II score at 12 months;
27/138 in the hypothermia group had a VABS-II score >70 at 12 months
15/122 in the normothermia group had a VABS-II score >70 at 12 months.
The authors calculated a risk difference of 7.3 percentage points (95% confidence interval -1.5 to 16.1) and a relative likelihood of 1.54 (95% confidence interval 0.86 to 2.76).
Although that sounds like a significant difference, the confidence intervals are really important here.
For the risk difference, the 95% confidence interval crosses zero; this means that the “true” value could be 0% difference between the groups. For the relative likelihood, although the confidence interval doesn’t cross zero, remember this is a likelihood: a ratio, where we equivalence occurs at 1 rather than at zero, so it is the fact that the confidence interval crosses 1 which indicates no significant difference between the groups.
In the secondary outcomes (table 2) there was a similar result of no difference in survival at 12 months between the groups, irrespective of neurological function. The authors note that survival over time was significantly longer within the therapeutic hypothermia group (mean survival for hypothermia group 149±14 days compared with 119±14 days) and there is a Kaplan-Meier curve on page 22 of the supplementary material which demonstrates this nicely. This rather leads us to question what we are trying to achieve; survival without the functional score criteria implies survival with poor quality of life. It is not my place to argue here what constitutes meaningful quality of life and I would be interested to hear the thoughts of the parents of these children surviving with poor functional scores, especially if they ultimately die later. There are some big moral and ethical questions here but if anything they do not encourage me to pursue hypothermia in these patients.
Interestingly, the Kaplan-Meier curve shows for both groups the majority of deaths occurred within the first 28 days; the authors tell us this was 87/153 (57%) in the hypothermia group and 93/139 (67%) in the normothermia group with no statistically significant difference between them (P=0.08).
Anything else interesting about this study?
There’s loads of other really interesting data in this study. Aside from the outcome measures, it’s useful to know more about the aetiology and prognosis of paediatric out-of-hospital cardiac arrest. Firstly we can see from table 1 that the majority of cardiac arrests occured due to respiratory causes – it’s good to know that what we teach on APLS is based on evidence! The rates were 111/75 (72%) in the hypothermia group and 102/140 (73%) in the normothermia group.
I was surprised that the rhythm was VF or VT in as many as 23 patients (14 in the hypothermia group, 9 in the normothermia group). Although the paper doesn’t give p values for the baseline characteristics in table 1 the authors have flagged those baseline characteristics with a P<0.05 (number of pre-hospital adrenaline doses and in-hospital adrenaline doses), suggesting this was not a significant difference between the groups even if it does seem higher than I would expect.
I was equally surprised to see that the median time to CPR from cardiac arrest was so low; 3 mins for the hypothermia group and 2 mins for the normothermia group. It’s not clear whether this represents rapid EMS response times or bystander CPR (which occured in 68% of the hypothermia group and 63% of the normothermia group) but I can’t help but wonder whether how well we could achieve that in the UK.
The median time to ROSC is interesting too, 23 mins in the hypothermia group and 28 mins in the normothermia group. We tend to spend longer in our resuscitation attempts for children in cardiac arrest than we do in adults and previous studies have looked at outcomes with resuscitation attempts over 20 minutes in children, showing that good neurological outcomes can occur even after prolonged resuscitation.
Problems with the paper and areas for future work
There are a few sticking points here; there was no reasonable way to use blinding to prevent bias in the intervention groups and although the authors have sensibly used an independent observer to collect the outcome data without knowing which group each subject was randomised to, the data was collected by telephone interview and there is nothing to stop a parent asking whether the researcher thought that their child being cooled had made a difference, for example.
The authors themselves acknowledge that children in the hypothermia group might have been alive longer due to the confounding effect of the hypothermia on the clinical team’s ability to determine futility.
We must also remember that these were out-of-hospital arrests; what should we do with those patients who have a cardiac arrest in-hospital? Is there a benefit from hypothermia for that group of patients?
What does it mean for us in practice?
Remembering that in this study the null hypothesis was no difference between the groups, this study doesn’t prove that hypothermia is harmful or not beneficial; there is simply insufficient evidence to reject the null hypothesis of no difference, based on this study.
So: should we cool our paediatric out-of-hospital cardiac arrest patients? At present, there is no evidence of benefit from this paper – but that doesn’t mean that the benefit doesn’t exist. For now I think we have to follow local protocols and hope for more evidence from larger trials, difficult as that might be to collect. That said, it’s still an important trial because it gives clinicians greater freedom to deviate from protocols when necessary if the evidence of benefit is difficult to prove.
- What is a likelihood ratio?
- What is meant by the sensitivity analysis mentioned in the first paragraph of the Outcomes section and why is it performed? (If you need help, there’s a nice open access article here)
- Why is Intention-To-Treat analysis important in a study like this one?
See also this FCEM style review over at PEMLit.