Therapeutic hypothermia: Benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury

doi:10.1016/j.injury.2011.03.027

Injury

Volume 42, Issue 9, September 2011, Pages 843-854

https://doi.org/10.1016/j.injury.2011.03.027 Get rights and content

Abstract

Therapeutic hypothermia involves the controlled reduction of core temperature to attenuate the secondary organ damage which occurs following a primary injury. Clinicians have been increasingly using therapeutic hypothermia to prevent or ameliorate various types of neurological injury and more recently for some forms of cardiac injury. In addition, some recent evidence suggests that therapeutic hypothermia may also provide benefit following acute kidney injury.

In this review we will examine the potential mechanisms of action and current clinical evidence surrounding the use of therapeutic hypothermia. We will discuss the ideal methodological attributes of future studies using hypothermia to optimise outcomes following organ injury, in particular neurological injury. We will assess the importance of target hypothermic temperature, time to achieve target temperature, duration of cooling, and re-warming rate on outcomes following neurological injury to gain insights into important factors which may also influence the success of hypothermia in other organ injuries, such as the heart and the kidney. Finally, we will examine the potential of therapeutic hypothermia as a future kidney protective therapy.

Introduction

Therapeutic hypothermia (TH) involves the controlled reduction of a patient's core temperature in an attempt to protect an organ at risk of injury. To date, TH has principally been used as a protective therapy following various brain insults; however there is emerging evidence that it may also be useful in the protection of other organs when at risk of injury.

The current main clinical indications for TH for cerebral protection in adults are out-of-hospital cardiac arrest1, 2 and, in neonates, hypoxic ischaemic encephalopathy³ with randomised clinical trials showing the neurological benefit of TH.¹ Furthermore, recent meta-analyses have suggested potential outcome benefit with TH following traumatic brain injury (TBI).4, 5 The safety and efficacy of TH have resulted in TH being increasingly applied by clinicians to comatose patients of various etiologies (i.e. stroke, hepatic encephalopathy, etc.) in an attempt to decrease brain injury.6, 7 These new but as yet unproven indications follow from the established use of TH to improve outcomes in operations involving significant risk of cerebral ischaemia during circulatory arrest in cardiac and neurosurgery.8, 9, 10 In addition to its protective neurological effects, hypothermia may decrease infarct size in patients with acute myocardial infarction after emergency percutaneous coronary intervention¹¹ and reduce the risk of renal failure after renal ischaemia–reperfusion injury in animals.12, 13

Although evidence is limited, studies suggest five key factors that could explain the failure of these previous studies and need to be addressed in future studies of TH: time to induction of hypothermia after injury, target temperature attained, duration of cooling, rate of re-warming and prevention of side effects/complications from hypothermia. In this article we will review the evidence for potential clinical applications of TH, describe its mechanisms of action and side effects, and, within this setting, discuss optimal methods for its implementation in future clinical trials. The focus is on TBI and on how the lessons learned with TBI may help effectively apply TH to the treatment of acute kidney injury.

Section snippets

Cooling: physiological aspects of induction, maintenance and re-warming

In order to successfully and safely implement cooling, awareness of the physiological effects and appropriate management of the side effects of hypothermia are required. There are 3 commonly recognised phases of hypothermic management: induction, maintenance and re-warming.

In the induction phase the aim is to reduce the temperature to target as quickly as possible. In TBI, clinical studies indicate that the temperature range associated with better outcomes appears to be 32–35 °C⁴ (Table 1). As

Potential mechanisms of the neuroprotective effects of therapeutic hypothermia and common side effects

In out-of-hospital cardiac arrest, hypoxic ischaemic encephalopathy in neonates, traumatic brain injury (TBI), stroke and hepatic encephalopathy, TH is used to reduce the potential neurological complications of evolving secondary brain tissue injury. The mechanisms of action of hypothermia are complex (Table 1) but principally they act to attenuate the cascade of destructive processes (secondary injury), which occurs in the minutes to hours following initial tissue injury (primary injury). We

What is the clinical evidence?

Hypothermia is the first treatment shown to be potentially efficacious in clinical trials for postischaemic injury. We will examine the evidence for the use of TH for neurological injury, ischaemic cardiac injury and the early evidence of benefit in acute kidney injury.

Neurological injury

Out-of-hospital cardiac arrest: After positive results from animal studies33, 79, 80 small clinical trials in patients who remained comatose following cardiac arrest showed improved outcomes compared to historical controls.81, 82, 83, 84, 85 Subsequently, randomised controlled trials showed positive neurological results for cooling after cardiac arrest.1, 2 The initial cardiac rhythm in these studies was ventricular fibrillation or pulseless ventricular tachycardia. Bernard et al.¹ recruited 77

Cardiac injury

Animal studies and preliminary human studies suggest a protective effect of hypothermia on the ischaemic heart,¹⁴⁰ and several studies have shown that mild hypothermia is feasible and safe to apply in the setting of acute myocardial infarction.11, 141 However, mild hypothermia has not been shown in prospective randomised trials to significantly reduce infarct size or mortality rate.¹⁴² Based on current evidence, the use of hypothermia to reduce infarct size or improve heart function cannot be

Kidney injury

Whilst some of the mechanisms of action of hypothermia previously mentioned are more applicable to brain injury, many of these protective mechanisms could potentially provide benefit if hypothermia was used prophylactically for the kidneys after injury or in patients at high risk for kidney injury undergoing procedures recognised as injurious for the kidneys.

In a renal ischemia-reperfusion injury model of hypothermia, the temperature of the rats during the ischemia phase significantly affected

Hypothermia and AKI

AKI is common in the ICU and occurs in approximately 36% of critically ill patients.148, 149 AKI is independently associated with increased mortality,¹⁵⁰ and with prolonged length of stay.146, 151 It increases both the human and financial costs of care. Therefore, it is important to investigate treatments with potential to ameliorate or prevent AKI.

The most extensively used and validated consensus definition and method of classifying AKI is the RIFLE classification system.¹⁵² The serum

Prophylactic hypothermia: POLAR and POLAR-acute kidney injury

POLAR (Prophylactic HypOthermia to Lessen trAumatic brain injuRy), is a randomised, blinded, controlled trial of hypothermia in ICU patients with severe traumatic brain injury (TBI). The trial is being conducted at 6 sites in Australia and New Zealand and recruitment has commenced (ACTRN12609000764235). POLAR is endorsed by the Australian and New Zealand Clinical Trials Group (ANZICS CTG) and has NHMRC and Victorian Neurotrauma Initiative funding. The trial has a planned cohort of 500 patients

Conflict of interest statement

Alistair Nichol and Stephen Bernard are investigators of the POLAR trial, a National Health and Medical Research Council/Victorian Neurotrauma Initiative funded clinical trial of Hypothermia in Traumatic Brain Injury (NCT00987688). Elizabeth Moore, Alistair Nichol and Rinaldo Bellomo are investigators of the Renal Substudy of the POLAR trial.

Acknowledgements

The authors would like to thank the National Health and Medical Research Council and the Victorian Neurotrauma Initiative for their support of the POLAR trial. We also thank the Intensive Care Foundation for funding the Renal substudy of this trial.

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Citation Excerpt :
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ReviewTherapeutic hypothermia: Benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury

Abstract

Introduction

Section snippets

Cooling: physiological aspects of induction, maintenance and re-warming

Potential mechanisms of the neuroprotective effects of therapeutic hypothermia and common side effects

What is the clinical evidence?

Neurological injury

Cardiac injury

Kidney injury

Hypothermia and AKI

Prophylactic hypothermia: POLAR and POLAR-acute kidney injury

Conflict of interest statement

Acknowledgements

J Am Coll Cardiol

Transplant Proc

Lancet

Lancet

Prog Neurobiol

Prog Cardiovasc Dis

Brain Res: Brain Res Rev

Brain Res: Brain Res Rev

Trends Neurosci

J Surg Res

Exp Neurol

Lancet

Exp Neurol

Brain Res

J Am Coll Cardiol

Am J Emerg Med

Ann Emerg Med

J Am Coll Cardiol

Resuscitation

Early Hum Dev

Pediatr Neurol

Lancet

J Obstet Gynecol Neonatal Nurs

Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia

N Engl J Med

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

N Engl J Med

Cooling for newborns with hypoxic ischaemic encephalopathy

Cochrane Database Syst Rev

Guidelines for the management of severe traumatic brain injury

J Neurotrauma

Hypothermia treatment for traumatic brain injury: a systematic review and meta-analysis

J Neurotrauma

New indications for the use of therapeutic hypothermia

Critical Care (London, England)

Induced hypothermia in critical care medicine: a review

Crit Care Med

Antegrade or retrograde cerebral perfusion as an adjunct during hypothermic circulatory arrest for aortic arch surgery

Expert Rev Cardiovasc Ther

Deep hypothermic circulatory arrest for complex cerebral aneurysms: lessons learned

Neurosurgery

Neuroprotective effect of mild hypothermia in patients undergoing coronary artery surgery with cardiopulmonary bypass: a randomized trial

Circulation

Degree and time sequence of hypothermic protection against experimental ischemic acute renal failure

Circ Res

Therapeutic hypothermia and controlled normothermia in the intensive care unit: practical considerations, side effects, and cooling methods

Crit Care Med

Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies

Clin Pharmacokinet

Mechanisms of action, physiological effects, and complications of hypothermia

Crit Care Med

Hypophosphatemia and hypomagnesemia induced by cooling in patients with severe head injury

J Neurosurg

The importance of magnesium in critically ill patients: a role in mitigating neurological injury and in the prevention of vasospasms

Intensive Care Med

Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis

J Appl Physiol

Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade

J Cereb Blood Flow Metab

Non-pharmacologic (physiologic) neuroprotection in the treatment of brain ischemia

Ann N Y Acad Sci

Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits

Stroke

Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury

J Cereb Blood Flow Metab

Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain

Review
Therapeutic hypothermia: Benefits, mechanisms and potential clinical applications in neurological, cardiac and kidney injury