Metabolic downregulation: a key to successful neuroprotection?
Topic: Hyperthermia

The search for effective neuroprotectants remains frustrating, particularly with regard to specific pharmaceuticals. However, laboratory studies have consistently shown remarkable neuroprotection with 2 nonpharmacological strategies-therapeutic hypothermia and ischemic preconditioning. Recent studies have shown that the mechanism of protection underlying both of these treatments is correlated to downregulation of cellular and tissue metabolism. Thus, understanding the mechanisms underlying such robust protective effects could lead to appropriate translation at the clinical level. In fact, hypothermia is already being used at many centers to improve neurological outcome from cardiac arrest.

PICO
Population: Patients with neurological conditions requiring neuroprotection
Intervention: Therapeutic hypothermia and ischemic preconditioning
Comparison: Pharmaceutical neuroprotectants
Outcomes: Improved neurological outcome, downregulation of cellular and tissue metabolism

Included studies:
title: Lack of effect of induction of hypothermia after acute brain injury.
abstract: Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury.
title: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
abstract: Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation.
title: Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach.
abstract: We undertook this study to evaluate the feasibility of inducing and maintaining moderate hypothermia with the use of endovascular rather than surface cooling.
title: Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling.
abstract: To report results of a randomized pilot clinical feasibility trial of endovascular cooling in patients with ischemic stroke.
title: Feasibility and safety of moderate hypothermia after massive hemispheric infarction.
abstract: Moderate hypothermia decreases ischemic damage in experimental stroke models. This multicenter study was performed to evaluate (1) the safety and feasibility of moderate hypothermia and (2) its potential to reduce intracranial hypertension in acute stroke patients.
title: Relationship between intracranial pressure, mild hypothermia and temperature-corrected PaCO2 in patients with traumatic brain injury.
abstract: To study the effects of mild hypothermia and associated changes in temperature-corrected PaCO2 (cPaCO2) on intracranial pressure (ICP), mean velocity of the middle cerebral artery (Vm), and venous jugular saturation in O2 (SjvO2) in patients with severe traumatic brain injury (TBI).
title: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
abstract: Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest.
title: Preconditioning the human myocardium.
abstract: Ischaemic preconditioning (short periods of ischaemia with intermittent reperfusion) has been shown paradoxically to protect the myocardium from a subsequent longer ischaemic insult. The protection associated with preconditioning is one of the most powerful mechanisms of protection known and has been shown in every animal species investigated. However, there is no direct evidence that ischaemic preconditioning occurs in the human heart. We studied whether it was possible to precondition the human heart in a setting of coronary artery bypass surgery. The measurement of adenosine triphosphate in biopsy specimens was used as our endpoint. We believe that our results are the first to show that it may be possible to precondition and protect the human myocardium with short controlled periods of intermittent ischaemia and reperfusion.
title: Relevance of transient ischemic attack to early neurological recovery after nonlacunar ischemic stroke.
abstract: We hypothesized that previous transient ischemic attack (TIA) had a favorable effect on early outcome after acute nonlacunar ischemic stroke.
title: Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia.
abstract: External cooling is commonly used to force induction of mild hypothermia but requires equipment, has a slow onset of action, and must be prolonged to provide permanent neurologic benefits after hypoxic-ischemia. It is unknown whether the method for inducing mild hypothermia affects neurologic outcome after near-drowning. The objective of the study was to induce mild hypothermia with neurotensin analog NT77 or external cooling in a rat model of near-drowning. We hypothesize that NT77 would be more effective for improving neurologic outcome than external cooling of the same duration.