Question 20

College Answer

Proven role:

1)  cardiac arrest – out of hospital VF arrest improved neurological outcome and survival

32-34C

2)  Control of intracranial hypertension – Improves ICP, but no reduction in mortality

Areas under investigation

1)  Stroke patients

2)  Perinatal asphyxia

Practical issues:

a)  difficulty in achieving hypothermia rapidly

b)  shivering and the need for relaxants which can delay neurological assessment c)  Not proven for non-vf arrests

d)  Not proven for in-hospital arrests

e)  Hypothermia can cause diuresis with attendant electrolyte disorders

f)       Risk of arrhythmias

g)  Risk of infection

Discussion

In general, therapeutic hypothermia in cardiac arrest and the physiology of hypothermia overall are discussed elsewhere. This question also asks about the extended indications for therapeutic hypothermia, which are generally not very well known (being exotic and enjoying only very patchy support from the ICU senior medical community).

In late 2015, this question would be interpreted very differently, and would likely attract a slightly different answer from the candidates. A good example might resemble the college answer to Question 9 from the first paper of 2015. The discussion section for that SAQ is reproduced below, as the two questions are virtually identical, and a 2006-specific answer would be of no interest to the modern candidates.

Rationale for therapeutic hypothermia:

• Therapeutic hypothermia has been advanced a a means of improving survival and good neurological outcome following cardiac arrest.
• It has also been offered as a means of controlling intracranial hypertension which is refractory to other modalities.
• Therapeutic hypothermia modulates the activity of body proteins and electrolytes.
• This modulation is thought to have some beneficial effects in scenarios where inflammatory damage is anticipated.
• This also involves the down-modulation of the overall metabolic rate, which decreases the metabolic demands of the organism in situations where supply of metabolic substrate may be compromised.
• Decrease in oxygen consumption matches decreased demand with decreased supply in "penumbra" areas, at the watersheds, where hypoxic injury has caused oedema.\

Advantages of therapeutic hypothermia

• Decreased granulocyte migration into tissue
• Decreased cerebral oedema
• Intrinsic anticonvulsant effects of hypothermia

Well-accepted indications:

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

Evidence for use in cardiac arrest:

• Pseudorandomised unblinded trial in 1996 - promising results
• Bernard et al  demonstrated a survival benefit in out of hospital VF arrest survvors
•  A recent Cochrane review supports the use of therapeutic hypothermia, finding a 1.35 risk reduction for mortality.
• The recent TTM trial  has demonstrated non-inferiority of a more conservative hypothermia (36°C) with standard temperature goals, in terms of mortality.

Evidence for use in traumatic brain injury

• EUROTHERM 3235 trial (2015): 387 patients; hypothermia was used as a second-line therapy to reduce ICP.
• No survival benefit was observed.
• Recruitment was suspended early owing to safety concerns.
• ICP control was in fact better in the hypothermia group (they required rescue therapies less frequently)
• The meta-analysis mentioned by the college is possibly  this 2013 review by Georgiou et al; except there was no benefit in mortality when only high quality trial were included.

Extended indications:

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 controlled normothermia) 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 apparently ongoing, but no longer recruiting participants.

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 :

• 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

• 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.

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