J Neurocrit Care.  2019 Dec;12(2):67-73. 10.18700/jnc.190100.

Targeted temperature management for ischemic stroke

• Hong JM

• KMID: 2470467
• DOI: http://doi.org/10.18700/jnc.190100

Abstract

Therapeutic hypothermia (TH) or targeted temperature management is an intentional cooling or temperature control technique using a thermostatic equipment (i.e., surface, endovascular, and focal devices) for specific therapeutic purposes. Given the modifiable determinants in the therapeutic process of acute ischemic stroke, hemorrhagic stroke, and subarachnoid hemorrhage, several studies strongly reported that fever is closely associated with more harmful neurological outcomes. Fever or hyperthermia can deteriorate the cellular ischemic cascade, causing more cerebral damage owing to increased metabolic demands, enhanced release of excitatory neurotransmitters, and increased toxic free radical production. Despite the disappointing results of various clinical trials on TH in the stroke field, many studies have repeatedly clarified its fundamental mechanisms, which proved its strong neuroprotection in experimental stroke models. In particular, the potential effectiveness of TH can be revisited in the era of endovascular thrombectomy for patients undergoing emergent large-vessel occlusion because neuroprotection is maximized in ischemia-reperfusion injury models. This review aims to incorporate current literature into risks and benefits in patients with ischemic stroke.

Keyword

Hypothermia; Hypothermia, induced; Reperfusion injury; Reperfusion

MeSH Terms

Fever
Humans
Hypothermia
Hypothermia, Induced
Neuroprotection
Neurotransmitter Agents
Reperfusion
Reperfusion Injury
Risk Assessment
Stroke*
Subarachnoid Hemorrhage
Thrombectomy
Neurotransmitter Agents

Figure

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  Fig. 1. Possible tissue damage mechanisms that therapeutic hypothermia (TH) can alleviate in ischemic stroke from acute stage to recovery phase [10]. (A) Acute events, such as loss of oxygen and glucose after stroke, can lead to energy loss (adenosine triphosphate [ATP] loss) and ion pump failure. The resulting loss of concentration gradients allows ions (Na+/K+) to flow down their concentration gradients, leading to cellular swelling (cytotoxic edema) and release of excitatory amino acids. Reperfusion injury after recanalization may also occur, and tissue hypoxia can increase anaerobic metabolism. All of these events will lead to acute cell death. TH can alleviate almost all ischemic cascades that lead to cell death. (B) There are possible mechanisms that TH can alleviate the recovery phase of ischemic stroke. Ischemia activates both intrinsic and extrinsic pathways that will lead to cell apoptosis. It also triggers reactive oxygen species (ROS) production and inflammatory reaction. These promote endothelial cell damage and blood-brain barrier (BBB) disruption. As a result, TH has been associated with suppression of both apoptotic and inflammatory pathways, while upregulating cell survival pathways. BAX, Bcl2 associated X protein; MMP, matrix metalloproteInase.

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  Fig. 2. Physiological changes (open circle) according to temperature variation and possible complications (closed circle) during the three phases of therapeutic hypothermia: induction, maintenance, and rewarming [14]. Possible cooling complications may present as reverse patterns of rewarming complications (hyperkalemia, hypoglycemia, and rebound of increased intracranial pressure, among others). ICP, intracerebral pressure.

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  Fig. 3. A simplified diagram of the symptom onset, infarct core volume, and potential neuroprotectant (i.e., therapeutic hypothermia) according to the inclusion criteria described in previous successful endovascular treatment trials.35 The red zone represents the fast progressor of the infarct core, the yellow zone the intermediate progressor, and the green zone the slow progressor. Reduction of reperfusion injury can be more effective in patients who are not classified as either fast or slow progressors, such as those in the yellow zone (potentially neuroprotective zone). However, massive reperfusion injury can easily occur in the red zone area (therapeutically futile zone).

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