In clinical practice today, there is no therapy that will cure traumatic brain injury (TBI) or spinal cord injury (SCI) . Furthermore, there are no clinically available neuro rescue or neuroprotective therapies. Management of patients suffering from either TBI or SCI is based on optimizing general physiology and avoiding exacerbating conditions, such as seizure, hypotension, or hypoxia. Induced hypothermia or targeted temperature management is a promising potential therapy for TBI and SCI. Preclinical animal models, especially rats and mice, of both TBI and SCI provide provocative evidence that induced hypothermia is highly beneficial for improving both neurological outcome and survival. Unfortunately, similar evidence in humans is lacking. There have been a number of clinical trials conducted but the outcomes have not supported widespread clinical adoption. Nevertheless, the ease of application, relatively low toxicity, dramatic benefit in preclinical models, and lack of any other effective therapeutic options make hypothermia still worthy of consideration.

The central nervous system (CNS) is comprised of the brain and spinal cord. Both have gray matter and white matter. Gray matter is primarily neurons whereas white matter is axons, glia, and astrocytes. The CNS is highly dynamic with a consequently high metabolic demand. To meet this demand, the CNS receives 15 % of cardiac output and accounts for 20–25 % of total body oxygen and 25 % of glucose consumption [1]. Jain and colleagues, employing a noninvasive technique that uses magnetic resonance susceptometry-based oximetry and venous oxygen saturation demonstrate that in humans, global cerebral metabolic rate (CMRO₂) is about 130 mol per 100 g per min [2]. Others report cerebral oxygen consumption rate in adults as 3.5 ml per 100 g per min [3]. The gray matter uses about 94 % of CNS oxygen consumption whereas the white matter uses approximately 6 % [3]. Almost 80 % of gray matter oxygen consumption is devoted to glutamate-mediated neurotransmission [1]. Under normal conditions, the blood flow to the CNS is autoregulated to about 50 ml per 100 g tissue per minute. Autoregulation is the process whereby cerebral blood flow is maintained at this constant rate over a wide range of systemic blood pressures.

When injured, the CNS becomes pressure passive. Autoregulatory function is compromised so the CNS is dependent on the systemic blood pressure for adequate perfusion. So, when the CNS is injured, systemic blood pressure rises. The injured tissue is able to receive the perfusion it requires whereas the uninjured tissue is able to autoregulate so as not to be over perfused [4].

Injury has 2 phases—primary and secondary [4]. Primary injury refers to tissue destruction resulting directly from the inciting event. This occurs virtually instantaneously and is complete very soon after injury. Secondary injury is the cascade of events that include inflammation, free radical production, and release of excitatory mediators such as calcium and glutamate. This develops shortly after injury and develops over time in hours to days. The best approach for mitigating primary injury is prevention. Pretreatment may be an option analogous to aspirin for primary prevention of sudden coronary syndrome. However, a clinically effective TBI or SCI pretreatment therapy has not yet been identified. Secondary injury is an opportunity to treat. The period of development is a window in which an effective treatment can be ameliorative.

Hypothermia is believed to reduce neuroinflammatory processes, cause a reduction in CMRO₂, and improve the efficiency of glucose and energy metabolism [5]. Hibernating animals have been shown to tolerate very low perfusion states for prolonged periods. This became a basis for investigating induced hypothermia as a potential treatment for TBI and SCI. Many basic science investigators have and are exploring this field. In 1994, Dietrich and colleagues showed in a TBI rat model that reduction of core body temperature to 30 °C resulted in significantly less neuron necrosis and brain contusion volume [6]. Since then, a number of investigators have confirmed these findings in rats and other animal subject species.

In 2002, two landmark studies were published demonstrating human clinical efficacy for induced hypothermia or targeted temperature management in patients who suffer out-of-hospital cardiac arrest and remain unconscious. One study was performed by Bernard and colleagues in which 77 patients were randomized to either hypothermia to 33 ^oC or normothermia [7]. Hypothermia was induced within 2 h of return-to-spontaneous circulation and maintained for 12 h. They found that 49 % of the hypothermia patients were able to leave the hospital to either home or a rehabilitation facility versus only 26 % of the normothermia patients. The other study enrolled 275 patients and also randomized them to either induced hypothermia to 32–34 ^oC [8]. In this group, hypothermia was induced within 4 h of return-to-spontaneous circulation and maintained for 24 h. They were rewarmed over 8 h. The hypothermia group did much better than the normothermia. About 41 % of hypothermia patients died as compared to 55 % of normothermia and, of those who survived, 55 % had favorable neurological recovery versus 39 %, respectively.

A Cochrane database systematic review was conducted in 2012 by Arrich et al. [9]. They confirmed the efficacy of induced mild hypothermia for improving outcome after cardiac arrest . Since its efficacy has been revealed, this therapy has become part of clinical practice guidelines for managing adult cardiac arrest [10].

Unfortunately, a recent 2015 study by Moler and co-workers did not demonstrate the same efficacy when induced hypothermia was used for pediatric patients who suffered cardiac arrest [11].

Thus, for adult patients with impaired consciousness after cardiac arrest , targeted temperature management , or induced hypothermia provides clear benefit.

In 1997, Marion and colleagues demonstrated the first conclusive evidence showing that mild hypothermia had a benefit in improving clinical outcome in patients who suffered TBI [12]. Unfortunately, it was temporary. There were better outcomes with induced hypothermia at 3 and 6 months after injury. However, this benefit was not sustained so that by 12 months after injury, there was no difference between the hypothermia group versus the normothermia group. Importantly, very severely impaired patients, i.e., those with admission GCS scores of 3–4, did not have any benefit at any time with hypothermia.

An interesting finding of the 1997 Marion et al. study was that both glutamate and IL-1 levels were significantly decreased in the hypothermia group [12]. Glutamate is an excitatory amino acid implicated in secondary neuro-injury. IL-1 is an important proinflammatory cytokine. This suggests that hypothermia did reduce excitatory amino acid release and neuroinflammation as previously hypothesized. However, the study was not designed to determine if lower hypothermia levels would have led to even more glutamate and IL-1 suppression or if even that would have had greater clinical impact.

In 2001, Clifton and colleagues studied whether an earlier induction and longer period of hypothermia would be beneficial [13]. They achieved hypothermia within 8 h of injury and maintained it for 24 h. Unfortunately, outcome and mortality were not significantly different between the 2 groups.

In 2002, post hoc analysis of the 2001 Clifton et al. study revealed that patients who were hypothermic on admission and then subsequently maintained in a hypothermic state had better clinical outcomes [14]. This suggested that the induction of hypothermia very quickly after injury with subsequent maintained cooling could be beneficial. This seemed rational as preclinical animal studies induced hypothermia within minutes after injury and outcomes were significantly better.