We need to talk about TTM…. Again

Several months have passed since the results of the Targeted Temperature Management after Cardiac Arrest study (aka the TTM trial) were published in the New England Journal of Medicine (Neilsen et al, 2013). This study has brought about widespread (although not universal) practice change in Australia.Whilst the conclusions of the trial were well received, there have been concerns from those involved in the trial that the study has been misinterpreted as evidence against actively cooling patients following out of hospital cardiac arrest. It is worth noting that many international bodies that set guidelines for the management of cardiac arrest have not endorsed the recommendations of the TTM trial. Currently this includes the Australian Resuscitation Council (ARC).

As has been well documented, social media played a large role in the dissemination of the findings of this study. Now that we are several months down the track I think it is worth (1) asking why these bodies have not endorsed the a target temperature of 36°C, (2) reassessing the conclusions of the TTM trial and (3) to use social media to discuss how centers have been implementing this change and what the initial experiences have been.

Why didn’t the ARC endorse a change following the TTM trial?

In December of 2013 the ARC produced a statement in response to the TTM trial. In this statement they made several observations regarding the study that are worth considering in more detail:

  1. Both groups were undergoing active target temperature management, which prevented fever, and was part of intensive post-resuscitation care.
  2. This study did not show a difference in mortality between the two target temperature groups.
  3. No differences in complications between the two groups were observed.

Both groups were undergoing active target temperature management, which prevented fever, and was part of intensive post-resuscitation care.

The temperature of patients in both treatment groups was very tightly controlled as is represented below.

From Neilsen et al, 2013

From Neilsen et al, 2013

The description of how this was achieved is slightly ambiguous in the methods section of the TTM trial:

“The goal was to achieve the assigned temperature as rapidly as possible with the use of ice-cold fluids, ice packs, and intravascular or surface temperature-management devices at the discretion of the sites.”

More specific details of the interventions were outlined in the protocol, which was linked to the online publication. In the protocol it clearly explains:

“Target temperature 36°C (TTM36): Patients will be managed at 36°C with either intravascular heat-exchange catheters or external temperature management systems. If a patient has a temperature between 30 and 33°C, the patient will be actively rewarmed to 33°C with 0.5°C/h. If a patient has an initial temperature 33-36°C, the temperature will be followed and the patient will be allowed to spontaneously rewarm and temperature management will be instituted when the core temperature is 36°C.”

The fact that these patients were treated with active cooling devices seems to have been missed by many people. One of the criticisms of the TTM trial is that the authors did not report on the interventions used to control temperature in the two groups. This makes it difficult to appreciate how challenging patients in each group were to care for, and hard to adapt the study recommendations to your own practice.

Whilst it was widely reported that the TTM trial supports actively targeting normothermia, I’m concerned that there is a lack of awareness of the level of intervention that is required to achieve this in the post arrest period. Attempting to target 36C without the use of an active cooling system is not supported by the findings of the TTM trial.

This study did not show a difference in mortality between the two target temperature groups.

Prior to the TTM trial, standard practice in Australian ICUs was to target mild hypothermia of 32-34C in the post arrest period. I would argue that using cooling devices to target a temperature of 36C constitutes a novel intervention, and as such a survival benefit needed to be proved for a compelling argument to switch from standard practice. This was not the case.

In a standard superiority trial we compare a novel intervention to placebo or standard therapy. When we frame the research question we set a hypothesis (there is a difference) and a null hypothesis (there is no difference). If we cannot disprove the null-hypothesis of no difference we continue with standard therapy and do not institute the novel intervention.

The TTM trial was unusual in that the control group consisted of patients randomized to an intervention that was neither standard practice nor a placebo. As they were not able to demonstrate superiority of one group over the other, they have advocated using their control intervention.

Their justification for managing the 36C group so aggressively was a concern that allowing patients to become febrile is harmful, and thus unethical. Whilst I agree with this view, I am concerned that we are supporting use of an intervention that has (until now) only been applied to 466 patients and no study has demonstrated superiority or non-inferiority to standard practice of cooling to 32-34C.

At the time of the initial publication of the TTM trial, Simon Carley wrote a detailed analysis here on the St Emlyns blog and discussed the difference between failing to prove superiority and proving equivalence. More recently Sandra Ware wrote about a similar issue with the LINC trial of the LUCAS device, as posted here on Resus.ME.

(If you’re getting the ‘glazed over stats look’ already then skip this bit and go onto ‘No differences in complications between the two groups were observed’… Just take my word for it that they didn’t prove non-inferiority but my feeling is they probably would have done if they had designed the study to do so.)

Non-inferiority trials have been designed for situations where two treatments are likely to be very similar, but one may have other benefits over the other suh as cost, side effect profile, dosing regimen, etc. An example is the work conducted comparing dabigatran with warfarin by Connolly et al, 2009. They randomised 6,000 patients to each intervention arm and were unable to prove superiority of low dose dabigatran in stroke reduction (although the trends suggested this was probably the case) but were able to demonstrate non-inferiority.

In a standard superiority trial we compare the incidence of an outcome such as mortality in the two groups and try to determine whether they are meaningfully different populations. When there is a large difference between the two groups it is relatively easy to demonstrate superiority by increasing the precision of your estimate of the population incidence with a modest increase in sample size.

TTM again 2

When a difference between two groups is small it is difficult to prove superiority without an unrealistically large sample size resulting in a very precise estimate and narrow confidence interval (CI).

TTM again 3

This is clear from the impact the estimated treatment effect has on sample size calculation. The problem is that unless you conduct the larger trial you cannot be certain your results are not a statistical anomaly.

Non-inferiority trials often require large sample sizes, but they are still smaller than adequately powered superiority trials of interventions with similar treatment effect or rare outcomes. In the dabigatran vs warfarin trial the incidence of CVA was 1.5% per year on warfarin. This meant that even with 6000 patients in each treatment group, superiority of dabigatran could not be proved.

In a non-inferiority trial we estimate the treatment effect (the risk ratio is commonly used for a binary outcome such as mortality) and calculate the one sided 95% CI. A non-inferiority limit is set a priori. This is the point that a detrimental effect of the new treatment over standard practice would be considered clinically significant. Factors that affect this limit include the baseline incidence of the outcome with standard intervention and the seriousness of the outcome assessed. If the 95% CI for treatment effect does not breech this limit then non-inferiority is supported.

TTM again 4

In the TTM trial we are looking at a primary outcome of mortality and a baseline incidence of 50% in standard therapy. The TTM data shows a risk ratio for mortality of 1.01 (favoring 36 C) with a 95% CI of 0.91 to 1.13. This means that the CI includes the possibility of an absolute risk increase for mortality of up to 5% in the 36 C group.

This result may, in fact, have been considered sufficient to prove non-inferiority, if the study had been designed to do this. However, this was not the case as a stringent non-inferiority limit with sound justification was not set a priori.

No differences in complications between the two groups were observed

One of the proposed reasons that 36 C was likely to be advantageous was the suggestion that there would be less major complications. Particular concerns regarding the use of hypothermia have been an increased risk of bleeding, incidence of dysrhythmias and the need for vasopressors and temporary pacing.

Whilst TTM was not powered to conclusively detect any minor differences, it failed to demonstrate any significant reduction in major complications. Particularly surprising was the lack of an increase in bradycardia in the T33 C group.

TTM again 5

From the supplement to Nielsen et al, 2013

One of the other proposed benefits was that these patients could be cared for without the use of active cooling devices. As already mentioned, this cannot be supported by the TTM trial as both the intervention and the control arms involved active cooling.

I have heard clinicians involved in recruiting patients for TTM say that caring for patients at 36 C was actually more labour intensive than the 33 C group. There was certainly a higher incidence of shivering at 36 C (141 pts vs 156). This is not unexpected as the reason we cool to 32-34 C is that this is meant to be below the shivering threshold.

The data provided in the TTM trial only describes the number of participants who experienced shivering, but not how long, how frequent or what was required to stop it. Again this highlights the limitations of published data relating to the interventions used to maintain the target temperatures.

So why is this practice changing?

There are a lot of excellent components of TTM but I think any suggestion that this paper dictates a change in practice is an over statement. There is also the risk that confused interpretations of this paper could lead to detrimental care.

The biggest concern is the misunderstanding of the treatment the patients in the 36 C group were receiving. It is very possible that patients are receiving care that is not in concordance with the TTM protocol.

Many clinicians, including investigators involved in the TTM trial, have expressed that they believe active cooling to 33 or 36 C is now justified, and the chosen target depends on which temperature is considered easiest to manage at your centre. This is most likely correct, but the TTM trial in its published form does not conclusively prove that.

I am concerned that no secondary benefit was shown in the 36 C group and that some investigators involved in the study felt that patients are more difficult to manage at this temperature. In that case, if there is no harm in cooling to 32-34 C, why should we stop?

It is worth reading the statement made by the Australian Resuscitation Council. Their conclusion is that they still recommended 32-34C, they also state that anyone choosing to target 36C should avoid fever. I think this should include mandatory use of active cooling devices as per the TTM protocol.

The need for strong guidelines and rigorous adherence to departmental standards of care are vital during periods of practice change. Junior doctors may find themselves exposed if they decide not to initiate standard cooling without departmental agreement, and should continue to follow approved protocols for out of hospital cardiac arrest (OHCA) management.

I am interesting in hearing who is targeting 36 C, how different centers have been achieving this and what the experiences have been so far. Are active cooling devices being used routinely? How easy it has been to keep patients within their targeted parameters?

Please share your views by leaving a comment below.

References and Links

LITFL

Journal articles

  • Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877. PubMed PMID: 19717844.
  • Nielsen N, Friberg H, Gluud C, Herlitz J, Wetterslev J. Hypothermia after cardiac arrest should be further evaluated–a systematic review of randomised trials with meta-analysis and trial sequential analysis. Int J Cardiol. 2011 Sep 15;151(3):333-41. doi: 10.1016/j.ijcard.2010.06.008. Epub 2010 Jul 1. Review. PubMed PMID: 20591514.

FOAM and web resources

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Comments

  1. Gav says

    This is entirely unscientific, but in recent months I have found patients who I have actively cooled have been perfectly stable (haemodynamically) until they are cooled and become very unstable, reductions in CCP in these patients may be just as harmful. Does any of the current evidence suggest that patients that have to be rewarmed due to instability do worse and are they one the final stats in these studies?

    • David Denman says

      I’m guessing you meant CPP. I’m not sure how these patients perform as a sub group in terms of neurological outcome but (probably not great) but the surprising thing is that there weren’t more of them in the 33C group.

      This probably supports the view that these patients have a primary cardiac problem that needs treatment beyond re-warming. The improvement in intra and post arrest care over recent years has meant that patients with much sicker hearts are being resuscitated successfully but they are likely need aggressive supportive therapy if they are to achieve a good outcome

  2. none says

    I didn’t mention this, but, a couple tertiary centres around Vancouver are not cooling because, if if 36 is not inferior to 33, & the evidence was questionable for 33, then just avoid fever.

  3. caseyparker207 says

    Great stuff!
    I work in a remote centre where aggressive cooling is logistically impossible and we do post-resus care infrequently enough to be bad at it if everything goes perfectly!
    For years I have felt a twinge of guilt / inferiority for not cooling as it was just too hard.
    But for me the TTM trial absolves this guilt to some extent.

    Targeting 36 degrees and rigid fever avoidance is a realistic goal for small, remote and under-resourced units. I will never possess a cooling device other than a cold pack and a fan, cold fluids …

    -- so I think this is a great trial. It shows that we are at least non-inferior in our efforts. We can strive to do “the best” and makes the logistics of transferring cold patients in tropical climates do-able

    Casey

    • David Denman says

      Thanks Casey. Trying to translate research to the remote Australian population must be pretty challenging. Would you say TTM has given you the impetus to use the best of your resources to aim for a temperature of 36? If that’s the case I’d say that’s a good interpretation of the trial.

      In terms of the trial overall I’d question the conclusion that it supports using simple measures to treat these patients if you have cooling devices at your disposal because that’s not what they were doing to the 36C group.

      It’s very difficult to extrapolate TTM to a departmental protocol as there is so little information regarding temperature management provided. What temperature do you start intervening at? What’s your first line therapy? As far as I’m concerned it’s 36C and it’s an active cooling device if you have it (if you decide to change your practice at all).

      It’s interesting to note that they were targeting such a precise temperature rather than a range. My guess (and this is really reading between the lines) is that the temperature was dialed into the active cooling device and supplemental management was added as per the treating clinician.

      If anyone was involved in the trial and can explain what was happening to the patients that they were treating it would be really interesting to hear from you

  4. says

    it does sound like they used external cooling with simple devices such as icepakcs which would be easy to deliver in any setting. However it would be good to know how many of the 36 degree patients they ended up having to escalate beyond this to invasive devices.
    I do wonder if you are placing too high a bar for the TTM to prove that the control group is non-inferior to the standard care group when the standard care therapy is not a proven therapy. If the initial positive hypothermia trials had controlled temperature in their controlled group then it would be a standard of care with a more solid evidence base, albeit with small trials. Then it would be reasonable to hold any “novel” therapy to a high standard.
    Since the initial positive trials were so flawed in this manner, it is an unproven standard of care which to me affects the standard to which we must hold up the 36 degree control group to.
    I think we are now left in a position of clinical equipoise between 2 temperature targets. Given clinical equipoise, it is reasonable to choose a target based on other practical matters eg if it is less invasive an less resource intensive to manage a 36 degree target then it should be chosen on those grounds alone. However it is interesting to hear the anecdotes you’ve mentioned from some folks not finding this to be the case.

    • David Denman says

      Thanks Anand,

      I know the method section of the article makes it sound as if they were using simple methods first and additional devices if required but the protocol makes it clear this wasn’t the case.

      Initially I thought the article was confusing because of a grammatical error but actually the way it’s written is correct, just not very clear.

      It’s more obvious if we apply a little Boolean logic to this sentence

      “The goal was to achieve the assigned temperature as rapidly as possible with the use of ice-cold fluids, ice packs, and intravascular or surface temperature-management devices at the discretion of the sites.”

      “With the use of ice-cold fluids, ice packs AND (intravascular OR surface temperature management devices)”

      I also confirmed this with some of the consultants involved in the study before writing this article.

      I’d really like to know how many patients had intravascular cooling catheters as this device is the gold standard for maintaing a target temperature and trying to achieve the same degree of temperature control with ice-packs and cold fluids is not possible, your patients will breech 38C.

      I think the way the methods are written has caused a huge amount of confusion but probably increased the impact factor of the study (not in a good way).

      HACA has issues with external validity as it’s inclusion and exclusion criteria meant that only a small number of OHCA patients were eligible but the study was robust. The fact that clinicians started applying hypothermia to other patient groups without further research was debatable but it was a proven benefit for those patients that met inclusion criteria. The Bernard study was more fundamentally flawed.

      I’d agree that there is definite equipoise but TTM is not enough to support practice change and if anyone is trying to do this without following the TTM protocol they are at risk of their patients becoming febrile and possibly having worse outcomes.

      This is being discussed further on academic life in emergency medicine later today

      David

  5. says

    had a listen to the ALIEM videocast. It sounds like they either had intravascular OR surface temperature management devices in both groups. It seems entirely feasible and believable that then the 36 group may have largely had ice packs +/- cold fluids + simple surface temperature monitoring. In fact at the 20 minute mark the author comments on how targeting 36 degrees was practically easier, noting the lack of need to “force in cold fluids” and that patients usually come in around 36.

    • David Denman says

      The only difference between the treatment received by the two groups was the temperature set on the active cooling device, as was stated at the start of the video. I saw a comment on twitter that roughly 25% had been treated with intravascular cooling devices and 75% with dynamic surface temperature devices but i’m not sure where they had gotten their numbers from.

      Until they publish the data regarding the use of sedation, muscle relaxants, additional cold fluid, shivering etc any comment on the ease of maintaining this temperature will remain anecdotal.

      It’s certainly true that most patients come in around 35.5 and this early phase will generally be much easier when targeting 36C. After this, targeting normothermia can still be very challenging, as most will have seen when managing neuro cases. Simply keeping a patient below 38C can require significant use of sedation to drop their thermoregulatory threshold and muscle relaxant to stop them shivering. I’m really interested to see the follow up publication to TTM as I genuinely don’t know what the differences between the two groups are likely to be.

      Maintaining 36C with the methods you describe would be possible, but it’s likely to be challenging for the nursing staff and the risk of overheating would be a concern. It’s also difficult to write a protocol for as we are targeting a specific temperature. In this study from Critical Care in 2007 they showed that simple techniques can be as good as a dynamic surface cooling device (although not as good as an intravascular device and slower to achieve target temperatures) but I would be surprised if this could be replicated in non study conditions on a busy unit:

      http://ccforum.com/content/11/4/r91

      As it stands we can really only talk about caring for patients using the TTM protocol, if you want to change practice at all. This is a protocol developed by the Queen Alexandra Hospital in the UK. It’s an excellent example of how practice change should be implemented in general as well as specifically TTM:

      http://www.portsmouthicu.com/resources/TTM2014.pdf

  6. dave barounis says

    Hi David,
    Thanks for the excellent review and I apologize for dropping in this late. One thing I did not see you mentioning about the benefit of normothermia versus hypothermia was the neurologic prognostication after cardiac arrest. Prognostication in the ICU is generally delayed with deeper hypothermia than at “relative” normothermia. There hasn’t been an RCT on this, and prognostication was the same in the Nielsen study to prevent potential confounders, but if a patient has been at 36 degrees drug metabolism and clearance (both renally and hepatically) appear to be greater than at 32-34 degrees.
    Sessler DI. Complications and treatment of mild hypothermia. Anesthesiology. 2001;95:531-43.
    Arpino PA, Greer DM. Practical pharmacologic aspects of therapeutic hypothermia after cardiac arrest. Pharmacotherapy. 2008;28:102–111.
    Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med. 2007;35:2196–2204.
    Therefore I feel more comfortable giving family the grave prognosis earlier in a patient with a poor neurologic examination when they have not been cooled to 32 degrees versus 36 degrees. At 32-34 degrees most societies agree on waiting 72 hours before looking at traditional markers of poor prognosis. This to me is a huge benefit for patients, and the expensive US health system.
    -Dave

    • David Denman says

      Thanks for your input Dave. Sorry for the late reply.

      There are many great components about the TTM trial but I really wanted to concentrate on what I felt was a misunderstanding of what the interventions and comparators were.

      I still don’t see anything in this trial that dictates a change of practice and I’ve been dismayed by the widespread belief that any centre that continues to target 32-34 in VF arrest is being unscientific.

      We are unlikely to get any better data than TTM for many years so if a centre feels that they have a good reason for using 36C then there is reasonable support for them to do this, so long as they follow the TTM protocol.

      I’ve given up trying to pick who is going to be able to make a reasonable recovery having been wrong on a number of occasions. Trying to study a protocolised prognostication model is very difficult as it becomes a self fulfilling prophesy. I’d like to know what happened if a patient met criteria for early withdrawal but the family did not consent to this.

      I don’t envy the position you’re in of having to balance the hopes/expectations of a family, the possibility of an unexpected recovery and the significant financial burden you’re placing on that family. It must be emotionally draining

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