Extended indications for therapeutic hypothermia

Beyond its uses in cardiac arrest, therapeutic hypothermia has a million and one uses. It has been used to decrease raised intracranial pressure in traumatic brain injury and hepatic encephalopathy; it is being investigated in the management of stroke, and it has known decades of effective use in the operating theatre, allowing safe circulatory arrest to take place in people who are having their aortic root repaired.

This has appeared in the exam twice:

• Question 9 from the first paper of 2015
• Question 20 from the second paper of 2006

In their comments regarding Question 9 from the first paper of 2015, the examiners lamented their trainees'  unfamiliarity with the more outré  applications of therapeutic hypothermia. This chapter is a summary of all such uses, and some of the evidence behind them. If one digs deep enough, one is able to unearth many more indications than the college could have possibly included in their model answer. Of course, this also means that the exam candidate will probably not benefit from knowing very much about the more bizarre indications. Beyond the first four or five subheadings lies an evidence-free territory.

The more traditional uses of TH are discussed in separate chapters:

• Mild therapeutic hypothermia for survivors of cardiac arrest
• Therapeutic hypothermia for traumatic brain injury

The resources used to construct this list of indications were many and varied. An early article by Kees Polderman (2004) is twelve years out of date now, but is still interesting because it lists the suggested indications in exactly the same order as the college model answer to Question 9. It's always nice to read the same material as the examiners.

Therapeutic hypothermia in cooling of a hyperthermic patient

• Hyperthermia is associated with substantial harm, particularly if the temperature increases beyod 41°C
• Causes of such hyperthermia may be numerous, including sepsis, malignant hyperthermia, anticholinergic drug poisoning, heat stroke, and so on and so forth.
• In brief, these causes all have specific management strategies which may take time to work.
• In the interim, the temperature must be managed, so that organ damage does not occur
• Induction of hypothermia (or maintenance of controlle dnormothermia) by cooling the patient can be viewed as one of the indications.

Therapeutic hypothermia for subarachnoid haemorrhage

• Theoretically, TH may be protective in SAH in the same way that it is supposed to be protective in traumatic brain injury. Areas affected by ischaemia in the context of vasospasm may benefit from having a lower metabolic rate.
• TH certainly  seems to decrease the flow velocity in the MCA of subarachnoid haemorrhage patients (Seule et al, 2014), suggesting that the metabolic rate is indeed affected enough to influence cerebral blood flow.
• Animal studies have also demonstrated that hypothermia reverses vasospasm (in rats)
• In patients with "poor-grade" SAH, good functional outcome was achieved in 48% with the combination of barbiturate coma and hypothermia to 33-34°C (Gasser et al, 2003)
• A more recent case series (Seule et al, 2010) found good outcomes in 57% of  severe SAH patients who developed vasospasm.
• In contrast, Karnatovskaia et al (2014) found no difference in neurological outcome within their case series.
• No recommendation in favour of this use of TH can be made with a straight face.

Therapeutic hypothermia for super-refractory status epilepticus

• Hypothermia is known to have antiepileptic effects.
• Case series (eg. Corry et al, 2008) have demonstrated its feasibility in humans (target temperature: 31–35°C)
• Neurocritical care society guidelines for status epilepticus (Brophy et al, 2012) identified only 4 articles in the literature, and were unable to make very strong recommendations.
• The HYBERNATUS trial mentioned in the college answer is now finished (Legriel et al, 2016). To quote one of my readers, "hypothermia made the EEG look better. That was all." Some might say "these are sedated patients with status epileptics, what more do you expect?" But in fact the investigators expected to find some sort of neuroprotective effect beyond simply controlling the seizures; and they could not. 

Therapeutic hypothermia for severe sepsis

• Anti-inflammatory effects of hypothermia were studied in an animal model of severe sepsis (Kwang et al, 2012).
• The hypothermic rats (30–32 °C) did better in terms of acute lung and liver injury.
• Human applications of this are limited by concern that ...firstly, a fever is an antibacterial physiological response, and secondly, that the haemodynamic instability of septic shock will be exacerbated by hypothermia.

Therapeutic hypothermia for meningitis

• Evidence of potential harm mentioned by the college in their answer was found by a 2013 RCT (Mourvillier et al). The investigators found a higher mortality in the hypothermia group.

Therapeutic hypothermia for neonatal asphyxia

• Following on from the success of TH in adult cardiac arrest, this modality has been applied to neonatal hypoxic-ischaemic encephalpathy.
• Shankaran et al (2005) performed an RCT; the group of neonates who were cooled 33.5°C for 72 hours; the rate of cerebral palsy was reduced from 19% to 15%, and mortality improved from 37% to 24%. In the long term, there was no increase in disability among hypothermia-exposed survivors when compared to surviving controls (Shankaran et al, 2012)
• TOBY trial (2014) confirmed that both survival and neurological outcome is improved

Therapeutic hypothermia for stroke

• The college answer points out that fever is associated with two-fold risk of death after haemorrhagic or ischaemic stroke. Pharmacologic methods of fever control have not shown improved outcome in stroke.
• In animal models of stroke, , mild or moderate hypothermia has been shown to decrease infarct size and lead to functional improvement when cooling was initiated within a few hours of ischemia onset (Clark et al, 2008). But... These were rats, and they were cooled to 24°C

Therapeutic hypothermia for acute hepatic encephalopathy

• This use of TH is an extension of the observation that TH reduces cerebral oedema in patients with traumatic brain injury.
• Some authors (Stravitz et al, 2008) have suggested that TH may be an effective bridge to liver transplant.
• Human case series support this assertion (Jalan et al, 1999); during their treatment there was no significant relapse of increased intracranial pressure.
• There are no RCTs, but a large-scale retrospective cohort (Karvellas et al, 2014) did not find any survival benefit.

Therapeutic hypothermia in ARDS

• Even as far back as 1993 (Villar and Slutsky) TH has been investigated  as a means of protecting the lung from inflammatory injury and improving gas exchange.
• More recent studies (Zhicheng et al, 2012) have confirmed that mild hypothermia improves gas exchange, lung compliance, duration of ventilation and the levels of IL-6 in local lung tissue.
• Of particular interest is the use of hypothermia to reduce the whole-body oxygen demand in situations where even veno-venous ECMO is powerless to oxygenate the patient (Hayek et al, 2015)

Intraoperative therapeutic hypothermia

Without going into too much detail, intraoperative uses of TH have included the following:

• Cardiothoracic surgery, routinely in use (including DHCA).
• Neurosurgery for aneurysm clipping: IHAST trial, 2005; no benefit ("good-grade" SAH patients)
• Vascular surgery, to protect the spinal cord during prolonged aortic cross-clamp

Suspended animation for delayed resuscitation

• In essence, this is a practice of stopping the circulation with deep hypothrmia, so as to buy time to the definitive management of the cause of the cardiac arrest.
• Animal studies have demonstrated success with up to 90 minutes of no-flow (Safar et al, 2002)
• Wu et al (2006) subjected dogs to rapid haemorrhage, and then used a 2°C saline aortic flush to achieve a brain temperature of 10°C. The dogs remained on ice for 2 hours, and were then revived on cardiopulmonary bypass.  Intact neurological outcome was achieved in 4 out of 6 dogs.