Critically evaluate the use of therapeutic hypothermia in intensive care practice.

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College Answer

Maintenance of a target temperature to provide neuroprotection. A range of different temperatures employed with ‘mild hypothermia’ traditionally 32-34oC; more recently 36oC post TTM trial.

Rationale:

Hypothermia may lessen the brain injury through a number of mechanisms:

  • Cerebral metabolic rate decreases by ~6-10% per degree Celcius drop in temperature
  • Reduced release of excitatory amino acids / glutamate which mediate neuronal injury
  • Reduced ischaemia reperfusion induced reactive oxygen species release
  • Reduced inflammation – both cellular response and cytokine expression
  • Reduced apoptosis
  • Preservation of blood brain barrier (reduced NO, aquaporin 4, metallo-proteinases)

Clinical utility and evidence:

Post cardiac arrest:

  • Standard of care
  • HACA and Bernard studies in 2002 cooled VF/VT patients to 32-34 for 12-24 hrs.
  • TTM trial 2013 showed no difference between target 33 and 36 in patients with out of hospital arrest of presumed cardiac cause. Fever avoided for 72 hrs in TTM.
  • Current ARC/ILCOR guideline remains 32-34 but either approach reasonable.
  • Avoidance of hyperthermia may be more important than hypothermia.
  • ILCOR draft guidelines for 2015 recommend 32-36 for all arrests with unresponsiveness post ROSC for 24 hours (weak recommendation, very low quality evidence.)
  • Prehospital cooling with crystalloid confers no benefit with increased APO
  • Studies that suggest benefit of TTM in patients with cardiac arrest post hanging
  • HYPERION trial underway to evaluate TTM 32.5 – 33.5 in non-shockable cardiac arrest survivors

Traumatic brain injury:

  • Multiple studies have looked at TH to treat severe TBI i.e. prophylaxis.
  • Meta-analysis of trials spanning over 20 yrs suggests a beneficial effect on mortality and favourable outcome.
  • When limited to higher quality trials no significant mortality benefit.
  • BTF guidelines level III recommendation for prophylactic hypothermia with no significant decrease in mortality but association with higher GOS
  • Cooling associated with lower ICP and higher incidence of pneumonia
  • Most trials using 32-35 degrees for at least 48 hrs
  • POLAR awaited – TH for severe TBI
  • Eurotherm 3235 awaited – TH for Intracranial hypertension
  • TH commonly used to treat intracranial hypertension rather than as prophylaxis.
  • Contemporary data evaluating this practice is lacking
 

Other potential uses

Hepatic encephalopathy

  • Intracranial hypertension common in grade III/IV encephalopathy related to ALF
  • Some advocate cooling as a treatment of strategy to manage intracranial HT
  • Controversial
  • No RCTs

Meningitis

  • Evidence of potential harm

Stroke

  • Fever associated with two-fold risk of death after haemorrhagic or ischaemic stroke
  • Pharmacologic methods of fever control have not shown improved outcome
  • NINDS and European (EuroHYP-1) funded trials looking at induced hypothermia underway

Seizures

  • Case reports with HYBERNATUS trial underway evaluating TH for refractory SE

SAH

  • No good data to support the use of TH in SAH.
  • Small studies have looked at TH in patients with intracranial HT
  • Fever associated with worse outcomes

Neonatal encephalopathy

  • Results of RCTs recommend cooling 33-34 for 72hr

Adverse effects:

  • Bradycardia / Arrhythmias
  • Increased SVR and venous return with cold diuresis
  • Hypokalaemia during cooling and rebound hyperkalaemia during rewarming
  • Immunosuppression / infectious Complications
  • Coagulopathy
  • Altered drug metabolism / reduced clearance sedative drugs
  • Requirement for sedation +/- paralysis
  • Concern regarding rebound intracranial hypertension during warming phase
  • Challenge of achieving and maintaining target temperature

Practice:

  • Reasonable statement of candidates practice re TH

Additional comments:
Candidates  mentioned  detail  that  was  not  requested,  such  as  methods of  cooling.  Candidates also showed poor breadth of knowledge related to the potential use of hypothermia in conditions such as TBI / SAH / CVA.

Discussion

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:

Evidence for use in cardiac arrest:

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.

References

References

Andrews, Peter JD, et al. "Hypothermia for intracranial hypertension after traumatic brain injury." New England Journal of Medicine 373.25 (2015): 2403-2412.

Georgiou, A. P., and A. R. Manara. "Role of therapeutic hypothermia in improving outcome after traumatic brain injury: a systematic review." British journal of anaesthesia (2013): aes500.

Polderman, Kees H. "Application of therapeutic hypothermia in the ICU: opportunities and pitfalls of a promising treatment modality. Part 1: Indications and evidence." Intensive care medicine 30.4 (2004): 556-575.

Seule, M., et al. "Therapeutic hypothermia reduces middle cerebral artery flow velocity in patients with severe aneurysmal subarachnoid hemorrhage." Neurocritical care 20.2 (2014): 255-262.

Gasser, Stefan, et al. "Long‐Term Hypothermia in Patients with Severe Brain Edema After Poor‐Grade Subarachnoid Hemorrhage Feasibility and Intensive Care Complications." Journal of neurosurgical anesthesiology 15.3 (2003): 240-248.

Karnatovskaia, Lioudmila V., et al. "Effect of prolonged therapeutic hypothermia on intracranial pressure, organ function, and hospital outcomes among patients with aneurysmal subarachnoid hemorrhage." Neurocritical care 21.3 (2014): 451-461.

Kim, Jong Youl, and Midori A. Yenari. "Hypothermia for treatment of stroke." Brain Circulation 1.1 (2015): 14.

Todd MM, Hindman BJ, Clarke WR, Torner JC; Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005;352:135-45.

Clark, Darren L., et al. "Comparison of 12, 24 and 48 h of systemic hypothermia on outcome after permanent focal ischemia in rat." Experimental neurology 212.2 (2008): 386-392.

Shankaran, Seetha, et al. "Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy." New England Journal of Medicine 353.15 (2005): 1574-1584.

Shankaran, Seetha, et al. "Childhood outcomes after hypothermia for neonatal encephalopathy." New England Journal of Medicine 366.22 (2012): 2085-2092.

Azzopardi, Denis, et al. "Effects of hypothermia for perinatal asphyxia on childhood outcomes." New England Journal of Medicine 371.2 (2014): 140-149.

Mourvillier, Bruno, et al. "Induced hypothermia in severe bacterial meningitis: a randomized clinical trial." JAMA 310.20 (2013): 2174-2183.

Rim, Kwang Pil, et al. "Effect of therapeutic hypothermia according to severity of sepsis in a septic rat model." Cytokine 60.3 (2012): 755-761.

Corry, Jesse J., et al. "Hypothermia for refractory status epilepticus." Neurocritical care 9.2 (2008): 189-197.

Villar, Jesus, and Arthur S. Slutsky. "Effects of induced hypothermia in patients with septic adult respiratory distress syndrome." Resuscitation 26.2 (1993): 183-192.

White, H. D., C. D. Spradley, and A. Hayek. "Therapeutic Hypothermia For Refractory Hypoxia In Acute Respiratory Distress Syndrome Undergoing Extracorporeal Membrane Oxygenation." Am J Respir Crit Care Med 191 (2015): A4570.

Zhicheng, Fang, et al. "Effect of mild hypothermia treatment on mechanical ventilation of acute respiratory distress syndrome." Modern Journal of Integrated Traditional Chinese and Western Medicine 29 (2012): 002.

Stravitz, R. Todd, et al. "Therapeutic hypothermia for acute liver failure: toward a randomized, controlled trial in patients with advanced hepatic encephalopathy." Neurocritical care 9.1 (2008): 90-96.

Jalan, Rajiv, et al. "Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure." The Lancet 354.9185 (1999): 1164-1168.

Karvellas, C., et al. "A multicenter retrospective cohort analysis of therapeutic hypothermia in acute liver failure." Critical Care 18.Suppl 1 (2014): P200.

Wu, Xianren, et al. "Induction of profound hypothermia for emergency preservation and resuscitation allows intact survival after cardiac arrest resulting from prolonged lethal hemorrhage and trauma in dogs." Circulation 113.16 (2006): 1974-1982.