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Presented by Dr Luke Terrett


Study Question:

In adults with TBI and ICP > 20 mmHg, despite “stage 1 treatments,” does hypothermia (32°C – 35°C) improve outcome compared with standard care?

How does this relate to our practice on NCCU?

Traumatic Brain Injury is almost the raison d’être of NCCU.

Elevated ICP is a frequent finding that requires prompt management in order to prevent further brain injury.

Therapeutic hypothermia (TH) has been shown to lower ICP and is a central part of our protocolised management of patients with TBI and elevated ICP.

TH has been shown to improve neurologic outcomes in comatose survivors of out-of-hospital cardiac arrest. The original 2 studies (HACA and Bernard) from 2002 targeted 32-34°C but in a more recent study (TTM trial), 36°C has been shown to be as good as 33°C. Different population and different indication.

Frankly, removing TH would go against our almost religious approach to the management of TBI – perhaps that is the reason why this study sits so uncomfortably. But, in our business, our thoughts should always be discordant and our actions should always make us uncomfortable. For this reason it is one of the most important studies in the context of how manage patients in Cambridge.

What do we currently know about this area?

TH may have a range synergistic neuroprotective effects:

  • It lowers the cerebral metabolic rate
  • Decreases excitotoxic neurotransmitter release
  • Decreases free radical formation
  • Decreases sustained electrical depolarisations
  • Inhibits proinflammatory and apoptotic pathways

TH lowers ICP perhaps through the following mechanisms, but we really don’t know:

  • Decreased inflammation
  • Decreased vasogenic edema
  • Decreased cerebral blood volume

However, TH is not without risks:

  • Coagulopathy/platelet dysfunction
  • Immunosuppression
  • Cardiac dysrhythmias
  • Hypotension
  • Pneumonia
  • Insulin resistance
  • Cold diuresis and electrolyte depletion
  • Decreased catecholamine responsiveness

Have a look at  Nature Reviews Neurology this blog.

Why was this study needed?

In the setting of TBI, multiple older studies showed mixed results. A 2014 systematic review and meta-analysis found possible benefit for therapeutic hypothermia in TBI. A well-designed RCT was needed to definitively answer the question.

At journal club we should discuss the following:

  • Hypothermia was applied quite early (after 5 min of sustained ICP > 20), seems a bit quick, see our letter.
  • Initial interventions were modest, yet safe, where does the risk of TH sit with this?
  • The study did not use other stage 2 treatments in hypothermia group unless persistent ICP elevation
  • What about how TH was achieved, it was quickly down to the target range 32-35°C, why not use an incremental, stepwise approach and achieve the minimum temp decrease required to control ICP?
  • What about all that fluid?
  • Sadly the trial stopped early after 387/600 patients enrolled, is this a problem?


Should we change practice on NCCU

Not based on the results of this study. They applied therapeutic hypothermia very differently than we do in the NCCU at Cambridge: They used it very early and prior to basic interventions, such as osmotherapy. Although basic is a word we use when we don’t know the harm a treatment really casues.

A trial that more closely mirrors our pattern of practice is needed prior to considering a change.

The next big RCT on TH in TBI, POLAR, has just finished enrolling patients, will this help us? Let’s see at journal club.


Further Reading

BTF guidelines

The Bottom Line 

Nature Reviews Neurology – Hypothermia for acute brain injury

SNACC Review

Intensive versus standard lowering of blood pressure in the acute phase of intracranial haemorrhage

Intensive versus standard lowering of blood pressure in the acute phase of intracranial haemorrhage: a systematic review and meta-analysis.

Adriana Cordier

Study Question: Is intensive BP lowering (systolic BP goal < 140mmHg) better compared to standard BP lowering (systolic BP goal < 180mmHg) in the acute phase management of Intracranial Haemorrhage (ICH)?

How does this relate to our practice on NCCU?

Spontaneous ICH is a common presentation seen on NCCU. We generally aim to achieve a systolic range of 140 – 160mmHg, however target values for the systolic BP sometimes varies depending on clinician and patient.

What do we currently know about this field?

Blood Pressure targets for the acute phase management of ICH are controversial. Traditionally the BP was only treated once it exceeded 180mmHg systolic with a target reduction of 160/90 mmHg.

The INTERACT II trail published in 2013, looked at intensive BP lowering to < 140mmHg compared to standard BP lowering to < 180mmHg. No difference in death or major disability were found, but better functional outcomes were reported in the intensive treatment group. The ATACH II trail published in 2016 also looked at intensive vs standard BP management in acute phase management of ICH and found no difference in death, disability or haematoma size between the two treatment groups, they did however report an increase incidence of adverse renal events (9% vs 4%, p=0.002) in the intensive treatment group.

Based on the results of the INTERACT II trail, current guidelines (2015), recommend that the systolic BP should be lowered to < 140mmHg in patients presenting with spontaneous ICH and systolic BP between 150mmHg – 200mmHg, provided there are no contra-indications. The optimum BP target in patients presenting with systolic BP > 220mmHg is less clear, but is still felt that aggressive BP lowering is reasonable.

Why is this meta-analysis needed?

The controversy in the treatment of the acute phase BP lies between decreasing the BP enough to prevent exacerbation of the bleed whilst still maintaining sufficient cerebral blood flow to prevent secondary ischaemic injury in patients who may be chronically hypertensive.

Stroke is currently the leading cause of disability in the UK. ICH is the most common cause of stroke in young adults and the second most common cause of stroke in general.

It is therefore important to try and identify the treatment that is associated with the best outcome.

Background reading

Wikijournal gives a quick summary of the INTERACT II and ATACH II ( trials which are by far the 2 largest studies included in this meta-analysis.

The Bottom Line also gives a good review of the ATTACH II trail.

Reviews on the CHIPPS trail and other issues in this field: Medscape, LITFL, EMCritJournal of Vascular and Interventional Neurology, and EMJClub.

Points for consideration

Population: In both the INTERACT II and the ATTACH II trails, the majority of the study population were Asian, which may not reflect our local population.

Onset as well as period of treatment varied significantly between different studies.

Better functional outcomes were reported in the intensive treatment group during the INTERACT II trail, but this was a secondary outcome measure for which the study was not powered. Also, the improvement in functional outcome seen was based on an ordinal analysis of the modified Rankin scale scores, without which it would not have been statistically significant. Furthermore, this analysis was considered only after the trial had commenced.

Meta-analysis may be at risk of publication bias. (No funnel plot included)

They used risk ratios as outcome measure, which may have been influenced by varying baseline event rates in the different studies used in this meta-analysis.

Should we change practice on NCCU?

I don’t think so. At present we usually aim to lower the systolic BP in the acute phase to below 160mmHg, but tend to decide the target systolic based on individual presentation. Looking at the evidence, there is certainly no convincing proof that aggressively lowering blood pressure offers any benefit to patients compared to standard reduction in BP. I think we should be mindful that the increase in BP after an intracranial event may be a protective mechanism and that some patients may be used to a having a much higher average BP, so by lowering the BP to aggressively in the acute phase, we may actually be causing the exact opposite from what we are trying to achieve.

Further reading

Current NICE guidelines are based on the AHA/ASA Guidelines for the management of Spontaneous Intra-cerebral Haemorrhage

Review on the current management of spontaneous intra=cerebral haemorrhage.

Approaches to appraising a meta-analysis here and here.

UK Stroke Statistics