March 17th 2016: Fever Control Management Is Preferable to Mild Therapeutic Hypothermia in Traumatic Brain Injury Patients with Abbreviated Injury Scale 3–4

Presented by Dr Evangelos Papadomichelakis

There is a rather long background favouring the neuroprotective role of therapeutic hypothermia (TH) across a range of clinical applications. As we have discussed before at journal club the evidence has fluctuated over the years across a variety of diseases but within the context of traumatic brain injury the most clinically obvious manifestation of TH is the reduction in ICP. The mechanism is multifactorial but the effect seems to be exerted mainly by a reduction in cerebral blood flow.

There have been at least 22 studies reported on TH treatment of TBI. What have we learnt from them?

Unfortunately, the majority are of low methodological quality, mainly because of problems in randomisation and allocation concealment. When viewed overall, there seems to be some evidence in favour of TH. However, when the methodologically less robust studies are taken out of the picture, there is a trend for more harm in the TH groups.

There are several key factors that need to be controlled during the implementation of TH. Induction of TH should be quick – animal studies have shown better results with rapid cooling – and should be maintained, the consensus seems to be for at least 48 hours. Finally, the speed of rewarming should be slow to prevent any secondary injury, as a rapid increase in temperature can cause vasodilation and spikes of rebound ICP plateau waves.

Almost as important is the proper management and prevention of TH-related complications: Shivering, hypovolaemia through a ‘cold diuresis’ effect, low K, Mg and PO4, respiratory alkalosis, hypotension and arrhythmias, increased insulin resistance and hyperglycaemia, coagulopathy and bleeding are well established side-effects that contribute to morbidity and mortality. Last but not least, altered drug pharmacokinetics, mainly due to slowed hepatic metabolism, should be taken into account.

During the last year, two big studies have been published on the subject. The Eurotherm 3235 (editorial) study randomised 387 TBI patients with ICP>20 to either TH (32°C -35°C) vs standard care (osmotherapy and fever control) – we will be discussing this at a later journal club – the study was stopped early because of a consistent trend towards increased mortality in the TH group (34.9% vs 26.6%). Very briefly, this was a large and well-conducted, pragmatic study, and it perhaps seems to be a game changer for the use of TH in TBI patients.

The study we will discuss this week, the B-HYPO study was a multicentre RCT in Japan that tried to compare early (72hrs duration) TH (32°C – 34°C) followed by slow rewarming (< 1 °C/day) versus fever control (35.5°C – 37°C), in respect of neurological outcome and mortality in severe TBI patients. Unfortunately, the study was interrupted early because of difficulty in patient recruitment and evidence of futility in the interim analysis. In total, only 150 patients were randomised instead of 300 that were deemed necessary at the beginning.

Overall, the authors report non-statistically significant results. However, there was a rather impressive trend of increased mortality in this study, like in EuroTherm, from TH – worryingly with a more impressive effect in the higher GCS (6-8) subgroup (33% vs 16%), with a NNH of 7. Furthermore, an increased incidence of complications was reported in the experimental group: 17% (mainly thrombocytopenia-coagulopathy and sepsis or pneumonia, arrhythmia) vs 2% in the fever control group (pneumonia).

This paper discusses a subgroup analysis of the B-HYPO cohort. The authors use the Abbreviated Injury Score (AIS) to define their subgroups with the idea being that the true effect of hypothermia cannot be shown in an underpowered study; it might, however, be unveiled if a subgroup with better prognosis (AIS 3-4) is chosen. The authors claim that TBI patients with less severe head trauma (AIS 3-4) fared less well in the TH group than in the fever control group (mortality 34% vs 9.7% and unfavourable neurological outcome 48.9% vs 35.5%, respectively).

Unfortunately, the paper is plagued by the methodological problems of its mother study (underpowering and considerable unbalancing of the two groups) and this was an unplanned subgroup analysis with the inherent problems. A significant percentage of participants is unaccounted for (up to 16%) and a statistical analysis that was done per protocol (and not as intention-to-treat).

How much can we deduce from the study?

It is difficult to derive many practice changing conclusions; the results of both B-HYPO and its subgroup analysis cannot be clearly attributed to TH itself, rather than simply more severely injured patients being allocated in the experimental group from the beginning. Furthermore, the control group was never actually a fever control group, but more of a ‘mild’ hypothermia group: mean temperature was around 35.5 °C, which is not routine care for most of our patients.

How then do the above apply to our practice?

The results of the study are difficult to change our current practice. TH, in our protocol,  is mainly used as a late intervention to lower uncontrolled ICP when other measures (positioning, sedation & paralysis, CSF drainage, hypertonic solutions and fever control) have failed, and when few alternatives exist. The message from the above studies, however, is that even then TH implementation could be harmful.

To discuss:

1. What is the explanation for the negative results of TH in most recent studies? Should we abandon TH in our practice?
2. When we do deliver TH, is our implementation – induction, maintenance and rewarming phases – well controlled? Do the studies suggest that 35 °C is the temperature to go for? Are we good at recognising and managing complications?
3. Are barbiturates or surgical decompression to be preferred when ICP cannot be controlled? Is our ICP threshold of 25 cm H2O correct?
4. Do you think there is still a place for another big TH trial, or has the medical community said its final word on the issue? How should we proceed with research on the subject?

Some links:

Hypothermia for acute brain injury—mechanisms and practical aspects.
A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury.
Reconsidering the role of hypothermia in management of severe traumatic brain injury.

Peter Andrews presenting the Eurotherm Study.

Podcast from ICS-SOA London 2015.