Next Article in Journal
Murine K2P5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K2P3.1- and KV1.3-Dependent Mechanisms
Next Article in Special Issue
The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury
Previous Article in Journal
The miR-200 Family: Versatile Players in Epithelial Ovarian Cancer
Previous Article in Special Issue
Evaluation of Injured Axons Using Two-Photon Excited Fluorescence Microscopy after Spinal Cord Contusion Injury in YFP-H Line Mice
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Therapeutic Hypothermia in Spinal Cord Injury: The Status of Its Use and Open Questions

1
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA
2
The Department of Neurological Surgery, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA
3
The Neuroscience Program, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA
4
The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, the Lois Pope Life Center, Locator code (R-48), PO BOX 016960, Miami, FL 33136, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the work.
Int. J. Mol. Sci. 2015, 16(8), 16848-16879; https://doi.org/10.3390/ijms160816848
Submission received: 30 June 2015 / Revised: 10 July 2015 / Accepted: 14 July 2015 / Published: 24 July 2015
(This article belongs to the Special Issue Neurological Injuries’ Monitoring, Tracking and Treatment)

Abstract

:
Spinal cord injury (SCI) is a major health problem and is associated with a diversity of neurological symptoms. Pathophysiologically, dysfunction after SCI results from the culmination of tissue damage produced both by the primary insult and a range of secondary injury mechanisms. The application of hypothermia has been demonstrated to be neuroprotective after SCI in both experimental and human studies. The myriad of protective mechanisms of hypothermia include the slowing down of metabolism, decreasing free radical generation, inhibiting excitotoxicity and apoptosis, ameliorating inflammation, preserving the blood spinal cord barrier, inhibiting astrogliosis, promoting angiogenesis, as well as decreasing axonal damage and encouraging neurogenesis. Hypothermia has also been combined with other interventions, such as antioxidants, anesthetics, alkalinization and cell transplantation for additional benefit. Although a large body of work has reported on the effectiveness of hypothermia as a neuroprotective approach after SCI and its application has been translated to the clinic, a number of questions still remain regarding its use, including the identification of hypothermia’s therapeutic window, optimal duration and the most appropriate rewarming rate. In addition, it is necessary to investigate the neuroprotective effect of combining therapeutic hypothermia with other treatment strategies for putative synergies, particularly those involving neurorepair.

1. Spinal Cord Injury (SCI) Epidemiology and Pathophysiology

Spinal cord injury (SCI) is a major health problem around the world. In the United States, it is estimated that 12,000 to 20,000 new SCIs occur each year, and currently over 200,000 Americans are living with SCI [1]. The most common causes of SCI are motor vehicle accidents, falls and sports injuries. For people younger than 65, the leading cause of SCI is motor vehicle accidents. Among people older than 65, SCI is mostly induced by falls [1]. SCI often results in a diverse range of neurological symptoms that depend on the severity and specific spinal cord level of the injury. Cervical SCI often results in tetraplegia, difficulty breathing, and dysregulation of autonomic functions including heart rate, blood pressure and body temperature. Thoracic and lumbosacral SCI often produces locomotor dysfunction in the legs and hips, the loss of control of the bowel and bladder, as well as sexual dysfunction.
Pathophysiologically, tissue damage after SCI is divided into two separate phases; the primary injury and the secondary injury. The primary injury occurs at the moment of SCI impact. It is commonly related to spinal cord compression/transection due to a vertebral bone fracture or distraction/stretching of the spinal column [2,3,4]. The secondary mechanisms of SCI are composed of a cascade of temporal events that include neurogenic shock [5,6], hemorrhage and ischemia-reperfusion [7,8], an increase of intracellular calcium and calcium-mediated activation of proteases (e.g., calpain) and lipases [9,10,11,12,13], mitochondrion dysfunction, the generation of free radicals and nitric oxide as well as other oxidants [14], the release of excitatory neurotransmitters (e.g., glutamate) and excitotoxicity [15,16], which in turn results in the apoptosis of neurons, oligodendrocytes, microglia and astrocytes [17,18,19], Wallerian degeneration of injured axons [20], the infiltration of neutrophils and the migration of macrophages and microglia [21,22,23,24] as well as astrocyte activation and scar formation [25]. These secondary pathomechanisms are associated with the majority of the morbidity and mortality after SCI.

2. Treating SCI and the Application of Hypothermia

To date, the treatments for SCI have been limited to methylprednisolone, surgical interventions and rehabilitation. However, these clinical approaches are not sufficient to provide significant recovery of function after SCI to the majority of individuals. Accordingly, it is necessary to develop novel therapeutic interventions to delay the progression of the pathophysiological processes associated with secondary injury to limit the degree of SCI-induced neurological dysfunction, such as hypothermia. Previously, the therapeutic use of hypothermia has been investigated clinically in cardiac arrest [26,27], neonatal hypoxic ischemic encephalopathy [28,29], hepatic encephalopathy [30,31], aneurysmal brain surgery [32], hemorrhagic stroke [33,34], traumatic brain injury [35,36,37,38] and SCI [39,40,41,42].
Based upon the level of temperature reduction, hypothermia can be divided into three levels: profound hypothermia (less than 30 °C), moderate hypothermia (30–32 °C) and modest hypothermia (32–34 °C). Early hypothermia studies on the surgical treatment of aneurysms of the transverse aortic arch compared the mortality between hypothermia administered at 12–16 or 24–26 °C. It was reported that the 12–16 °C hypothermia group had 50% mortality, as opposed to 20% mortality in the 24–26 °C hypothermia group [43]. In an in vitro murine spinal cord culture model, Lucas [44] observed that when the temperature was below 17 °C, the neuronal perikarya and dendrites swelled, with the majority of the swollen neurons dying during the phase of rewarming to 37 °C. Most recently, it has been reported in a piglet hypoxia-ischemia model that mild (35 °C) and moderate (33.5 °C) whole body cooling reduced brain cell death and microglia activation, compared to overcooling (30 °C), which was associated with detrimental pathological effects within some brain regions, such as the mid-temporal cortex, periventricular white matter, caudate, putamen and thalamus [45]. These studies have suggested that the temperature of hypothermia should be limited to the mild to moderate range so as to obviate the adverse effects associated with low temperatures and/or the transition back to regular body temperature. Therefore in recent investigations, modest hypothermia (32–34 °C) has been the preferred target for cooling strategies to provide neuroprotection.

3. The Experimental and Clinical Application of Hypothermia in SCI

To date, the neuroprotective effect of hypothermia has been demonstrated in both experimental and human SCI studies.

3.1. Hypothermia in Experimental SCI

Hypothermia has been investigated in a wide diversity of animal SCI models. The earliest hypothermia studies were focused on local hypothermia, in which neurological benefit was observed in dogs, monkeys and pigs after SCI [46,47,48,49,50]. However, compared to local hypothermia, a superior neurological protective effect was observed when hypothermia was applied systemically in animal SCI models utilizing rabbits, pigs, dogs and rats [51,52,53,54]. In a rat thoracic spinal cord contusion model, Yu and colleagues [54] applied modest systemic hypothermia (32–33 °C) at 30 min post-injury for a period of 4 h. This application of modest systemic hypothermia improved locomotor function as demonstrated by higher Basso-Beattie-Bresnahan (BBB) locomotor scores as well as a significant reduction in the area of tissue loss at both seven days and 44 days post-injury [54].
Previously, our laboratory utilized a rat cervical spinal cord contusion injury model, with the induction of mild systemic hypothermia (33 °C) beginning within 5 min of injury for a duration of 4 h, with slow rewarming at the rate of 1 °C per hour [42]. This acute, mild hypothermia paradigm resulted in an improvement in limb function as demonstrated by significantly greater upper body strength and a faster recovery in BBB scores during the one to three weeks post-cervical contusion period (Figure 1) [42]. Additionally, histological evaluation for the injured spinal cord segment from rats that survived 10 weeks after cervical SCI revealed a histological improvement with increased preservation of both white matter and gray matter, as well as higher numbers of surviving ventral motor neurons (Figure 2) [42] and intact axons (Figure 3) [42]. Batchelor and colleagues [55] utilized a rat spinal cord compression model to show that mild systemic hypothermia (33 °C) could rapidly decrease intracanal pressure, indicating that hypothermia may be a useful approach to acutely decompress the spinal cord before surgical decompression. In addition, Maybhate and colleagues [56] applied transient systemic hypothermia (32 ± 0.5 °C) for 2 h beginning at 2 h post-injury in a rat thoracic spinal cord contusion model. They observed that early systemic hypothermia provided significant neuroprotection as demonstrated (1) electrophysiologically, the hypothermia group presented higher amplitudes in somatosensory evoked potentials; (2) functionally, the hypothermia group showed much better BBB scores immediately after injury and at four weeks post-injury; and (3) histologically, more tissue was maintained in the hypothermia group.
Figure 1. Open field locomotor ability was significantly improved acutely but not persistently following hypothermia. Locomotor performance was assessed from one week post-injury through eight weeks according to the Basso-Beattie-Bresnahan (BBB) scale. Although a significant increase in BBB scores was observed transiently one to three weeks after injury with hypothermia over normothermic controls, both groups achieved similar behavioral endpoints by eight weeks. Data are expressed as average ± standard error of the mean. Group numbers: n = 9 normothermic injured group and n = 9 hypothermic injured group. ** p < 0.01, * p < 0.05 compared with normothermic controls. Reprinted with permission from [42], copyright Wiley-Liss, Inc., 2009.
Figure 1. Open field locomotor ability was significantly improved acutely but not persistently following hypothermia. Locomotor performance was assessed from one week post-injury through eight weeks according to the Basso-Beattie-Bresnahan (BBB) scale. Although a significant increase in BBB scores was observed transiently one to three weeks after injury with hypothermia over normothermic controls, both groups achieved similar behavioral endpoints by eight weeks. Data are expressed as average ± standard error of the mean. Group numbers: n = 9 normothermic injured group and n = 9 hypothermic injured group. ** p < 0.01, * p < 0.05 compared with normothermic controls. Reprinted with permission from [42], copyright Wiley-Liss, Inc., 2009.
Ijms 16 16848 g001
Most recently, Saito and colleagues [57] have shown in a spinal cord ischemia model that very mild hypothermia of only a 1 °C decrease in body temperature to 36.3 °C, resulted in greater preservation of motor neurons, decreased white matter vacuolation, reduced astrogliosis in both white matter and gray matter, and led to a concomitant improvement in locomotor function. Similarly, Grulova and colleagues [41] have shown that systemic hypothermia of 32.0 °C, could promote neuronal survival and improve locomotor function, as well as urinary bladder activity in a rat thoracic spinal cord compression model.
All of these animal experiments have provided support for the beneficial neuroprotective effects of mild and moderate hypothermia after SCI and set the stage for translating this therapeutic approach into the clinic for SCI management.
Figure 2. Hypothermia increased the numbers of preserved ventral motor neurons rostral and caudal to the injury site at 10 weeks post cervical spinal cord injury (SCI). Counts of cells labeled for NeuN (a neuron-specific marker) from transverse sections rostral (R) and caudal (C) to and within the injury epicenter of the cervical cord showed that acute application of mild systemic hypothermia could significantly increase the numbers of NeuN-immunoreactive neurons in the ventral horn (laminae VII–IX) at distances of 900 µm and greater from the injury epicenter compared with normothermic controls. Almost no preserved ventral motor neurons, however, were detected within the immediate injury site in both SCI groups. Recordings from uninjured controls are provided for comparison, and the data are expressed as the average ± standard error of the mean. *** p < 0.001, ** p < 0.01 compared with normothermic controls. Reprinted with permission from [42], copyright Wiley-Liss, Inc., 2009.
Figure 2. Hypothermia increased the numbers of preserved ventral motor neurons rostral and caudal to the injury site at 10 weeks post cervical spinal cord injury (SCI). Counts of cells labeled for NeuN (a neuron-specific marker) from transverse sections rostral (R) and caudal (C) to and within the injury epicenter of the cervical cord showed that acute application of mild systemic hypothermia could significantly increase the numbers of NeuN-immunoreactive neurons in the ventral horn (laminae VII–IX) at distances of 900 µm and greater from the injury epicenter compared with normothermic controls. Almost no preserved ventral motor neurons, however, were detected within the immediate injury site in both SCI groups. Recordings from uninjured controls are provided for comparison, and the data are expressed as the average ± standard error of the mean. *** p < 0.001, ** p < 0.01 compared with normothermic controls. Reprinted with permission from [42], copyright Wiley-Liss, Inc., 2009.
Ijms 16 16848 g002
Figure 3. Retrograde tracing analysis reveals that acute hypothermia resulted in greater sparing of brainstem axons projecting caudal to the injury site at 10 weeks post cervical spinal cord injury. (A) Retrograde labeling of neuronal somata with fast blue (FB), provided caudal to the lesion, shows that there was a greater sparing of brainstem projections (indicated by an increase in numbers of labeled neuronal perikarya) when acute hypothermia was applied. Investigation of specific brainstem neuronal populations revealed a significant increase in retrogradely labeled neurons in the reticular formation (B) but not the raphe (C) or vestibular nuclei (D) after hypothermia treatment. Recordings from uninjured controls are provided for comparison, and the data are expressed as the average ± standard error of the mean. *** p < 0.001 compared with normothermic controls. Reprinted with permission from [42], copyright Wiley-Liss, Inc., 2009.
Figure 3. Retrograde tracing analysis reveals that acute hypothermia resulted in greater sparing of brainstem axons projecting caudal to the injury site at 10 weeks post cervical spinal cord injury. (A) Retrograde labeling of neuronal somata with fast blue (FB), provided caudal to the lesion, shows that there was a greater sparing of brainstem projections (indicated by an increase in numbers of labeled neuronal perikarya) when acute hypothermia was applied. Investigation of specific brainstem neuronal populations revealed a significant increase in retrogradely labeled neurons in the reticular formation (B) but not the raphe (C) or vestibular nuclei (D) after hypothermia treatment. Recordings from uninjured controls are provided for comparison, and the data are expressed as the average ± standard error of the mean. *** p < 0.001 compared with normothermic controls. Reprinted with permission from [42], copyright Wiley-Liss, Inc., 2009.
Ijms 16 16848 g003

3.2. Hypothermia in Human SCI

In order to translate hypothermia from animal experimentation into the clinic, it is also necessary to test the safety and efficacy of this approach in small cohorts of SCI patients. The first trial of hypothermia on human beings was performed in a clinical case study involving a patient with an extensive spinal epidural abscess [58]. Later, Demian and colleagues [59] reported that localized spinal cord cooling resulted in an impressively beneficial effect for three acute cervical SCI patients, without a significant change in whole body temperature, vascular dynamics or respiration parameters. Later, more patients were tested with local hypothermia via irrigating the subdural space with cold saline at 5 °C for about 2 h [60,61]. Romodanov and colleagues [62] performed a spinal cord hypothermia study on 113 patients and reported that hypothermia decreased spinal cord bleeding and edema, reduced muscle spasticity, improved the motor function of the affected limbs, and produced an analgesic effect. Similar beneficial effects were observed when local hypothermia was performed on the spinal cord in the postoperative period [63]. Cherkashina [64] stated that the beneficial effect of local hypothermia was due to a decreased excitability of spinal cord alpha motoneurons, increased local blood flow in the spinal cord and a raised vascular tension. It has been demonstrated that hypothermic circulatory arrest can effectively prevent the development of SCI associated with extensive aortic resection [65] and decrease the incidence of neurologic deficits after thoracoabdominal aneurysm repair [66,67,68].
Following, and with continued testing of local hypothermia, systemic hypothermia moved from experimental studies to the clinic. Hayes and colleagues [69] used the circulation of propylene glycol through a “microclimate” head and vest garment on patients with chronic compressive or contusive SCI to induce mild hypothermia (−1 °C). For some SCI patients, this systemic mild cooling approach increased the amplitude of cortical somatosensory evoked potentials, suggesting that cooling could improve central conduction in some SCI patients with conduction deficits [69]. The most recent published studies examining systemic hypothermia as a treatment for human SCI have come from The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine [39,40,70,71,72,73,74,75]. Levi and colleagues [73] reported that patients with acute cervical SCI could be cooled relatively safely using endovascular catheters and that there was an excellent correlation between intravascular temperature and intrathecal cerebrospinal fluid temperature. This technique cooled the patient to the target temperature (33 °C) in 2.72 ± 0.42 h, and could be maintained for 48 h without increasing the risk of cardiac arrhythmias, deep vein thrombosis or pneumonia [73]. Cappuccino and colleagues [70] reported a case study of a National Football League player who suffered from a complete cervical SCI resulting from a C3/4 fracture dislocation with complete motor paralysis and sensory loss (American Spinal Injury Association (ASIA) Impairment Scale A). This patient received moderate systemic hypothermia (33.5 °C) immediately after SCI, in addition to traditional surgical decompression and methylprednisolone. After 36 h of hypothermia, a rapid neurologic improvement was observed in the individual, and with rehabilitation, there was an overall ASIA conversion from A to D [70]. In another study involving a small group of five iatrogenic SCI patients, Madhavan and colleagues [74] carried out moderate systemic hypothermia (33 °C) immediately post-surgery with maintenance for 24 h postoperatively. Patients were rewarmed at a rate of 0.1 °C per hour and four were also administered methylprednisolone. This management paradigm showed patient ASIA score improvements of 1–2 grades [74]. Recently, Dididze and colleagues [40] reported on the results of a case-controlled study comprising thirty-five acute cervical SCI patients who, on admission, were AISA A. These individuals received modest, intravascular hypothermia (33 °C) via a femoral vein catheter beginning at 5.76 ± 0.45 h post-injury (four cases with delayed admission were excluded). The body temperature was maintained at 33 °C for 48 h, followed by slow rewarming at the rate of 0.1 °C per hour (taking about 24 h to return to 37 °C). In this study, four patients converted from International Standards for Neurological Classification of Spinal Cord Injury scale (ISNCSCI) A to ISNCSCI B within the first 24 h. In the other 31 patients with consistent ISNCSCI A during the first 24 h, 35.5% of the patients (11/31) showed an increase of at least one grade in ISNCSCI at latest follow up, 10.07 ± 1.03 months (Figure 4) [40]. Among those four patients who improved from ISNCSCI A to ISNCSCI B within the first 24 h, one increased to ISNCSCI C, two upgraded to ISNCSCI D and one converted to ISNCSCI E [40]. Respiratory complications were similar among retrospective and prospective groups, and the thromboembolic complication rate was 14.2% [40]. All these preliminary human studies showed evidence of the beneficial therapeutic effect of systemic hypothermia in acute SCI. Due to the limited number of patients involved in these studies, however, a multi-center, randomized and blinded study is required to evaluate whether systemic hypothermia is appropriate for the treatment for acute SCI.
Figure 4. ISNCSCI outcome in 31 patients with initial and stable ISNCSCI A who did not improve within first 24 h from admission. Reprinted with permission from [40], Nature Publishing Group, 2013.
Figure 4. ISNCSCI outcome in 31 patients with initial and stable ISNCSCI A who did not improve within first 24 h from admission. Reprinted with permission from [40], Nature Publishing Group, 2013.
Ijms 16 16848 g004

4. Mechanisms of Hypothermia-Mediated Protection

As described above, hypothermia has provided a significant benefit in both experimental and human SCI. The neuroprotective action of hypothermia has been ascribed to its effect on a number of pathomechanisms including, the slowing of metabolism, decreasing cellular stress and reducing the generation of free radicals, ameliorating inflammation and inhibiting excitotoxicity that can reduce apoptosis, preserving the blood spinal cord barrier, preventing vasogenic edema, inhibiting astrogliosis, decreasing axonal damage, promoting neurogenesis as well as increasing angiogenesis [76,77,78].

4.1. Slowing down the Rate of Metabolism and Decreasing the Generation of Free Radicals

Hypothermia lowers the metabolic rate of neurons after SCI, inhibiting the generation of lactate, hydrogen and phosphate, as well as preserving glucose. In a dog thoracoabdominal aortic clamping model, Dzsinich and colleagues [79] showed that levels of glucose, lactate, pCO2 and Neuron Specific Enolase (NSE) in the cerebrospinal fluid (CSF) was significantly altered. Regional spinal cord hypothermia with icy peridural irrigation reduced the presence of anaerobe metabolites found in the CSF [79]. Similarly, in a rabbit spinal cord ischemia and reperfusion model, Allen and colleagues [80] reported that regional spinal cord hypothermia with cold heparinized saline perfusion could inhibit decreases in adenosine triphosphate and glucose concentrations, while preserving intracellular concentrations of glutamate and aspartate, to prevent the incidence of paraplegia. Further, in humans with a spinal cord ischemic injury, a study demonstrated that the combination of a distal femoral bypass and hypothermia (30 °C) reduced the lactate concentration in CSF [81]. All these findings are consistent with the effect of hypothermia on attenuating neuronal metabolic rate.
In addition to slowing down neuronal metabolism, hypothermia also decreases the generation of free radicals, such as super oxide, nitric oxide and hydroxal radicals. As described previously, the generation of free radicals is a secondary pathological mechanism of SCI [14]. In an in vitro guinea pig spinal cord compression injury model, the amount of reactive oxygen species increased dramatically within 5 s following compression of the spinal cord [82]. Hypothermia, however, significantly inhibited superoxide and lipid peroxidation [82,83]. The tissue content of malonildialdehyde (MDA) is a reliable parameter for measuring lipid peroxidation. In a rat spinal cord compression model, Tüzgen and colleagues [83] utilized chilled normal saline solution to induce epidural cooling, and demonstrated that the tissue MDA levels decreased significantly after application. These findings suggested that hypothermia could play a significant role in inhibiting lipid membrane peroxidation and the subsequent generation of free radicals.

4.2. Inhibiting Excitotoxicity and Neural Cell Apoptosis

Hypothermia also provides a neuroprotective benefit by decreasing the release of excitatory neurotransmitters and ensuing excitotoxicity. Glutamate excitotoxicity plays an important role in the pathogenesis of SCI [2,84]. Excessive release of glutamate and excitotoxicity is a major pathological event in cellular damage after acute SCI [85]. In a rat spinal cord ischemia model, Ishikawa and Marsala [86] reported that mild hypothermia (33 °C) prevented the release of glutamate during ischemia and after reperfusion. Similarly, in a rabbit spinal cord ischemia model, Wakamatsu and colleagues [87] observed that the concentration of glutamate was decreased after moderate hypothermia (32 °C). Alternatively to in vivo paradigms, Nishi and colleagues [88] performed whole-cell patch-clamp recordings in a spinal cord slice ischemia model, and observed that excitatory synaptic transmission was significantly suppressed by hypothermia when given from 28 to 32 °C and when further decreased to 24 °C, resulting in reduced neuronal death. All these findings from in vivo and in vitro experiments are consistent with the hypothermia’s beneficial mechanism in inhibiting the release of excitatory neurotransmitters and subsequent excitotoxicity.
In addition to decreasing excitotoxicity, hypothermia also works by antagonizing the apoptotic signaling machinery within neurons and glia following SCI. Neuronal and glial apoptosis and death has been demonstrated as a prominent feature after SCI. Specifically after SCI, an increase in the expression of apoptotic molecules p53 and Bax, together with the activation of caspase-3 and caspase 8, the cysteine proteases that execute the apoptotic cell death program, has been observed [89,90,91,92]. In a rat spinal cord contusion injury model, Ok and colleagues [93] reported that both moderate, epidural hypothermia (28 °C for 48 h) and moderate systemic hypothermia (32 °C for 48 h) significantly decreased the expression of caspase-8 and caspase-9, while moderate systemic hypothermia additionally reduced the expression of caspase-3. On the other hand, Wang and colleagues [94] showed that hypothermia could also retard neuron apoptosis by increasing the expression of anti-apoptotic bcl-2 and inhibiting the expression of p53 in a rabbit spinal cord ischemia model. All these experimental findings suggest that hypothermia could inhibit apoptosis in injured spinal cord.

4.3. Ameliorating Inflammation

Along with the prevention of apoptosis, inflammation must also be controlled. Hypothermia produces a profound dampening of the inflammatory response. Microglia/macrophage activation is a common secondary pathological process following SCI [95,96]. It has been demonstrated that the infiltration of microglia/macrophages at the site of SCI and their contact with dystrophic axons can result in extensive axon retraction [22,97]. In a rat spinal cord contusion model, Ok and colleagues [92] reported that after treatment with either moderate epidural hypothermia (28 °C for 48 h) or moderate systemic hypothermia (32 °C for 48 h), numbers of OX-42 positive cells (microglia/macrophages) were significantly decreased, as was the expression of the p38 mitogen-activated protein kinases, which are involved in immune cell activation [98,99]. Morino and colleagues [78], utilizing a mild spinal cord compression model, revealed that mild hypothermia (33 °C for 1 h) inhibited the proliferation of microglia and decreased levels of tumor necrosis factor-alpha (TNF-α). This was in turn associated with an improvement in motor function. To measure the effect of hypothermia on neutrophil activity, Chatzipanteli and colleagues [76] utilized a T10 thoracic spinal cord contusion model. They observed that myeloperoxidase (MPO) activity (a marker of neutrophil accumulation) was elevated at 3 and 24 h post-injury in the normothermia group. MPO activity in the hypothermia group (32.4 °C for 3 h) was significantly decreased at 24 h post-injury within the injured spinal cord segment [76]. All these reports suggest the role hypothermia can play in ameliorating the inflammatory response after SCI.

4.4. Preserving the Blood Spinal Cord Barrier and Preventing Edema

Hypothermia can also provide a neuroprotective effect through its ability to preserve the blood-spinal cord barrier (BSCB) and ameliorate local edema. Normally, the BSCB regulates the fluid microenvironment within the spinal cord [100]. SCI results in the disruption of the BSCB, increasing its permeability to proteins and molecules, and producing edema [101,102]. Yu and colleagues [103] utilizing a T8-9 spinal cord compression model, showed that moderate, systemic hypothermia (30 °C), via wetting the animals with a 20% ethanol/water solution at room temperature (20 °C), decreased the extravasation of the plasma proteins albumin, fibrinogen and fibronectin. In a clinical study involving 61 spinalized patients treated during the postoperative period, Iumashev and colleagues [63] demonstrated that local spinal cord application of hypothermia prevented edema formation. Similarly, a reduction in spinal cord edema was also reported in a study involving spinal cord hypothermia conducted in 113 patients [62]. Therefore, both experimental and human studies suggest that hypothermia could provide protective effects via the preservation of the BSCB.

4.5. Inhibiting Astrogliosis and Increasing Angiogenesis

Another beneficial mechanism of hypothermia is to retard astrogliosis and scar formation. Reactive astrogliosis is a hallmark feature of SCI, taking place at the lesion site days to weeks after injury and providing a major impediment to endogenous axon growth [104,105]. The application of hypothermia has been shown to inhibit astrogliosis. In a rat spinal cord ischemia model, Saito and colleagues [57] reported that the percent staining area positive for glial fibrillary acidic protein (GFAP) was decreased in both gray and white matter after mild hypothermia (1 °C decrease in body temperature to 36.3 °C, initiated 15 min prior to ischemia and maintained during ischemia).
In addition to inhibiting astrogliosis, it has been reported that hypothermia can promote the expression of pro-angiogenic factors. Vascular disruption is a common traumatic event after SCI, resulting in hemorrhage, a reduction in spinal cord blood flow and ischemia [106,107,108]. Accordingly, inducing angiogenesis is a therapeutic strategy to promote spinal cord repair. In a rat compression SCI model, Kao and colleagues [109] applied systemic hypothermia (33 °C), and observed an increase in the expression of vascular endothelial growth factors and the number of bromodeoxyuridine-positive endothelial cells, suggesting that hypothermia can exert a beneficial effect by promoting angiogenesis.

4.6. Decreasing Axonal Damage and Promoting Neurogenesis

Hypothermia can also provide a protective benefit through reducing axonal damage after SCI. Axonal injury is characterized by axonal cytoskeletal disorganization, impaired axonal transport as well as axonal swelling, disconnection, dieback and degeneration [110,111,112]. In a rat spinal cord compression model, Westergren and colleagues [113] performed systemic hypothermia and reduced the core temperature from 38 to 30 °C. The number of abnormal axons as identified by the accumulation of beta-APP, ubiquitin and PGP-9.5, were much lower in the peri-injury zone after hypothermia treatment, indicating an axonal protective effect of hypothermia [113].
Hypothermia may also influence neurogenesis after SCI. Neural cell death is a common pathological process following SCI, characterized by apoptosis and/or necrosis [114]. Neurogenesis provides the potential to produce new cells, replacing the dead neural cells and restoring function. In a rat spinal cord compression model, Kao and colleagues [109] showed that systemic hypothermia (33 °C) produced an increase in the numbers of both glial cell line-derived neurotrophic growth factors and bromodeoxyuridine-neuronal-specific nuclear protein double positive cells within the injured spinal cord at four days after SCI.
In summary, hypothermia has shown protective effects after SCI through a variety of mechanisms, including the slowing of neuronal metabolic rate, the inhibition of free radical production, a decrease in excitotoxicity, inflammation, apoptosis and astrogliosis, a preservation of blood-spinal cord-barrier and axonal protection as well as providing a foundation for neurorepair through promoting angiogenesis and neurogenesis.

5. The Combined Use of Hypothermia with Other Therapeutic Approaches

Due to the known mechanisms of hypothermia’s effects after SCI, researchers have taken an interest in combining hypothermia with other therapeutic approaches that would provide synergistic benefit. These approaches include combining hypothermia with free radical scavengers, hyperbaric oxygen, alkalinization, local anesthesia, antioxidants and cell transplantation.

5.1. Hypothermia and Antioxidants

As described previously, the increased generation of free radicals plays an important role in the pathogenesis of SCI. Hypothermia alone has been demonstrated to decrease the generation of free radicals, such as super oxide, nitric oxide and hydroxyl radicals. Recent studies have reported that the combination of hypothermia with radical scavengers or antioxidants, can provide beneficial synergistic effects after SCI. For example, while the injection of the radical scavenger edaravone or the application of topical cooling with transvertebral cooling pads have each been demonstrated to decrease spinal cord damage, their combination provides a greater protective effect [115]. Another antioxidant approach is the use of hyperbaric oxygen. Topuz [116] reported that the combination of hypothermia and hyperbaric oxygen prevented the elevation of MDA levels in spinal cord tissue, and increased the activity of antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT). The combination of hypothermia and hyperbaric oxygen was shown to be superior to either approach alone, indicating their synergistic benefits in ameliorating spinal cord secondary damage [115]. In addition to hyperbaric oxygen, administration of N-acetylcysteine (NAC) has also been employed with hypothermia. Previously, NAC has been primarily used in the treatment of acetaminophen poisoning and chronic bronchitis [117,118]. Cuzzocrea and colleagues [119] demonstrated that NAC could improve neuronal survival in the hippocampus of Mongolian gerbils subjected to transient cerebral ischaemia. Cakir and colleagues [120] later combined NAC with hypothermia (34–35 °C) to treat rabbits exposed to spinal cord ischemia-reperfusion injury, discovering that this combination could provide significantly greater recovery of motor function, with accompanying preservation of neurons and minimal immune cell infiltration.

5.2. Hypothermia and Alkalinization

Another combinational approach that has been evaluated with hypothermia is alkalinization. SCI is associated with the release of excitatory amino acids such as glutamate and aspartate, which acidify the extracellular environment [121,122]. This decrease in pH within the microenvironment subsequently facilitates the influx of calcium ions into neurons and induces neurotoxicity [123]. Therefore, alkalinization is able to block calcium-induced neurotoxicity and provide neuroprotection [124,125]. Recently, Kuffler [126,127] compared the neuroprotective effects of hypothermia and alkalinization, either alone or in combination, in an adult human dorsal root ganglion ischemia model. It was demonstrated that when applied individually, hypothermia provided a four-fold increase in neuroprotection and alkalinization provided an eight-fold increase. However, their combination enhanced neuroprotection by 26-fold. These data suggest that neuroprotection could be greatly augmented when hypothermia was combined with alkalinization.

5.3. Hypothermia and Anesthetics

Combining hypothermia with anesthetics has also shown promise. Recently anesthetics have been evaluated to determine whether they can ameliorate pathological changes after SCI [128]. For example, ketamine has been demonstrated to be neuroprotective after SCI in rats through antagonizing inflammation (decreasing TNF-α and IL-6), reducing oxygen free radicals (lowered MDA levels) and anti-apoptotic effects (fewer TUNEL-positive cells) [128]. Another anesthetic, Bupivacaine, works by blocking potassium conduction, reducing neuronal depolarization and preserving glucose and oxygen to help maintain normal membrane potentials [129]. In a rat transient spinal cord ischemia model, Lee and colleagues [130] showed that when intrathecal bupivacaine (0.5%) was accompanied by hypothermia, motor and sensory deficit scores were significantly less than when either single treatment was used. A similar synergistic effect after SCI in the rat was observed when the delta-opioid agonist SNC80 was administered intrathecally under mildly hypothermic (35 °C) conditions [131]. These findings indicate that the combination of anesthetics with hypothermia can provide enhanced neuroprotection after SCI.

5.4. Hypothermia and Cell Transplantation

While the majority of combination approaches used with hypothermia have focused on enhancing neuroprotection, cell transplantation offers a strategy that can provide added benefit through the complementary mechanism of neurorepair. In a rat SCI model, Wang and colleagues [104] combined the transplantation of bone marrow mesenchymal stem cells with mild hypothermia (33–35 °C) and reported a synergistic effect. Histologically, animals in this combined treatment group showed no cavity formation and a significantly greater axonal preservation than the animals receiving only bone marrow mesenchymal stem cell transplantation [104]. Functionally, BBB scores after SCI showed improved locomotor recovery when mild hypothermia was combined with bone marrow mesenchymal stem cell transplantation than when bone marrow mesenchymal stem cell transplantation was used alone [104]. In another study by Wang and Zhang [132], neural stem cell (NSC) transplantation was combined with mild systemic hypothermia (34 ± 0.5 °C) in a rat spinal cord hemisection model. Hind limb motor function was found to be superior in the combined treatment paradigm compared to those animals that only received NSC transplantation. Histologically, more axonal-like structures were observed in the lesion with the combined treatment of NSC transplantation and hypothermia, compared to NSC transplantation alone. The enhanced neuroprotective effect of such a combinational treatment may be due to the fact that hypothermia optimizes the microenvironment of the injured spinal cord for repair, and supports the survival of the implanted cells.

5.5. Other Potential Combinatory Approaches that May Provide Synergistic Benefit with Hypothermia after SCI

In addition to the above combinatory approaches, many other promising medications and cell therapies could be utilized in combination with hypothermia for SCI repair. These therapies include lead clinical candidates erythropoietin, riluzole, the calpain inhibitor AK295 [133], minocycline [134], the Rho inhibitor Fasudil [135], and Schwann cell (SC) transplantation. The evaluation of these putative combinations in experimental SCI paradigms may pave the way for more effective therapies that can be readily moved into clinical investigations.

6. Currently Unanswered Questions Regarding the Optimal Use of Hypothermia in SCI

Aside from exploring novel combinational approaches with hypothermia for enhanced therapeutic effect, a number of questions remain regarding optimal hypothermia application after SCI. These include the relationship between the therapeutic window and duration of hypothermia as well the rate of rewarming to normothermia so as to optimize its therapeutic potential.

6.1. Therapeutic Window

The time window during which cooling should be started after SCI has not been well standardized in both experimental and human studies. Albin [47] and White [136], in a monkey spinal cord weight drop SCI model, considered that a 4 h period after injury was the critical time window in which cooling needed to be initiated. Once initiated, hypothermia should then be maintained for a minimum of 3 h to provide protection and functional benefit. During the recent decade of experimental SCI research, the majority of studies have targeted the use of systemic hypothermia immediately post-injury [41,42,55,56,57,78,93,109,137,138], though the therapeutic window has been extended in a few investigations to either 1 h [139,140] or 2 h post-injury [56]. In studies by our group, hypothermia was started at 5 min post-injury and maintained at 33 °C for 4 h [42]. In SCI work by Maybhate and colleagues [56], hypothermia was initiated approximately 2 h post-injury and maintained at 32 °C for 2 h. Both experimental studies showed beneficial histopathological effects and improved locomotor function, though the relationship between the timing of hypothermia post-SCI and its duration for therapeutic effect was not examined in either work through the use of manipulations of these parameters. It remains unclear in many SCI paradigms what time window for hypothermia after SCI will have the most beneficial effect, or what time window will be too late to have therapeutic effect.
In contrast to animal studies, the time window from the moment of SCI to the induction of hypothermia has often been much later in human, and the duration of hypothermia has been extended to 24 h and beyond (Table 1, [40,70,72,73,74,75]). In a recent clinical study, Dididze and colleagues [40] started modest systemic hypothermia (33 °C) within 5.76 ± 0.45 h of SCI, excluding cases in which the delay to treatment would be greater than 18 h. With this therapeutic window, evidence of a neurologic protective effect was observed when hypothermia was maintained for 48 h. This delayed initiation of hypothermia in clinical practice is often related to the patient’s time of transportation to clinical care as well as the time required to receive patients’ consent to accept hypothermia as an experimental treatment.
To date, however, this paradigm has not been investigated in experimental SCI and it remains unanswered whether the therapeutic window of hypothermia can be extended after SCI if the duration of hypothermia is prolonged. Previous use of hypothermia in TBI studies have suggested that cooling initiated beyond 8 h after trauma could be too late to still be effective [141]. In a rat cardiac arrest model, Che and colleagues [142] initiated therapeutic hypothermia (33 ± 1 °C) at 0, 1, 4, or 8 h after the recovery of spontaneous circulation and maintained it for 24 or 48 h. The seven-day survival rates were 45%, 36%, 36% and 14%, respectively, compared to 17% for the normothermia group, with no statistical difference between rats treated with 24 h therapeutic hypothermia and those treated with 48 h therapeutic hypothermia [142]. The survival with good neurologic outcome rates were 24%, 24%, 19% and 0%, respectively, compared to 2% for the normothermia group, and again with no statistical difference between rats treated with 24 h therapeutic hypothermia and those treated with 48 h therapeutic hypothermia [142]. Therefore, it appeared that no beneficial effects in the survival and neurological outcome was observed when hypothermia was initiated 8 h after the return of spontaneous circulation when it was maintained for up to 48 h [142].
Table 1. Initiation, duration and rewarming rate for systemic hypothermia in human SCI (2005–2015).
Table 1. Initiation, duration and rewarming rate for systemic hypothermia in human SCI (2005–2015).
YearSystemic HypothermiaInitiation of HypothermiaDuration of HypothermiaRewarming Rate
2015----
2014----
2013Dididze et al., 2013 [40]5.76 (±0.45) h from injury.33 °C for 48 h0.1 °C per hour until normothermia (T 37 °C)
2012Madhavan et al., 2012 [74]Immediately post surgery.33 °C for 24 h0.1 °C per hour until normothermia (T 37 °C)
2011Tripathy and Whitehead, 2011 [75]Case 1: The 3rd day post cervical SCICase 2: The 5th days of surgery after cervical SCI.Case 1: a target temperature of 37.0–40.5 °C for 14 days Case 2: 37.0 °C for 10 daysCase 1: stopped at 40 °CCase 2: terminated on the 16th day of admission and gradually normalized by the 28th day
2010Levi et al., 2010 [72]The mean (standard error of the mean [SEM]) initiation time to catheter insertion was 9.17 (±2.24) h. If one excludes the 2 most aberrant outliers, the average time for initiation of hypothermia was 6.15 (±0.7) h.33 °C for 48 h0.1 °C per hour until normothermia (T 37 °C)
Cappuccino et al., 2010 [70]Temperature ranged between 34.5 and 35.2 °C with passive cooling during the surgery which was approximately 3 h after the cervical SCI, and then over 20 h post- injury lowed to 33.5 °C.33.5 °C for 36 hslowly rewarmed and eventually extubated on postoperative day 3
2009Levi et al., 2009 [73]The average time between injury and induction of hypothermia was 9.17 ± 2.24 h.33 °C for 47.6 ± 3.1 h0.1 °C per hour until normothermia (T 37 °C)
2007----
2006----
2005----
2004----
However, the initiation of hypothermia in SCI patients is more delayed practically, since it takes time to transfer and stabilize SCI patients before an intervention can be given, making it difficult to start hypothermia in the early hours post SCI. Therefore, it is necessary to investigate the efficacy of hypothermia with more extended therapeutic windows in experimental paradigms. A recent rat SCI study [143] tested the combination of delayed hypothermia (started 210 min after SCI, duration 3 h) with methylprednisolone (30 mg/kg, intravenously), given immediately after SCI. This combinational therapeutic paradigm showed much lower lipid peroxidation (MDA levels) than an early hypothermia application (started 30 min after SCI, duration of 3 h). This finding suggested that the immediate administration of the protective drug methylprednisolone has the potential to extend the therapeutic window of hypothermia.

6.2. The Duration of Hypothermia

The duration of hypothermia is another related parameter of hypothermia administration that is an important consideration for therapeutic effect. Currently, there has been no standard criteria to follow regarding the optimal period of hypothermia required for protection with either local cooling or systemic hypothermia administration and significant variation exists between experimental studies and human application.
In a dog thoracic spinal cord compression model, Wells and Hansebout [144] initiated local hypothermia (6 °C) at 4 h after compression injury and maintained it for 1, 4 or 18 h. The greatest degree of functional recovery was achieved in the 4 h duration group, rather than 1 or 18 h [145]. In experimental SCI studies using systemic hypothermia, the duration of hypothermia employed has been highly variable across published reports over the last decade (Table 2), being from minutes through to 48 h [41,42,55,56,57,78,93,109,132,137,139,141,145,146,147,148,149]. Recently, Vipin and colleagues [150] utilized uninjured rats to study the potential adverse effects of prolonged, semi-invasive, local hypothermia (30 ± 0.5 °C, durations of 5 or 8 h). No adverse effects were identified in the rats that underwent 5 or 8 h of hypothermia, with no statistical differences in measured somatosensory evoked potentials, histological parameters or BBB locomotor scores [150]. However, well-designed studies are still required to evaluate the most optimal hypothermia duration for maximal beneficial effect at clinically relevant therapeutic windows.
In human SCI studies, the duration of hypothermia has usually been at least 24 h (Table 1, [40,70,72,73,74,75]). As previously mentioned, in a sports-related cervical SCI case, Cappuccino and colleagues [70] maintained the patient at 33.5 °C for 36 h and they showed a rapid and significant neurological recovery from ASIA A to D; and Dididze and colleagues in a recent clinical investigation [40] initiated systemic modest hypothermia (33 °C) within 5.76 ± 0.45 h after SCI and maintained hypothermia for a duration of 48 h. In this study 43% (15 out of 35 patients) showed a recovery of at least one ISNCSCI grade.
Table 2. Initiation, duration and rewarming rate for systemic hypothermia in experimental SCI (2005–2015).
Table 2. Initiation, duration and rewarming rate for systemic hypothermia in experimental SCI (2005–2015).
YearSystemic HypothermiaInitiation of HypothermiaDurationRewarming Rate
2015Wang and Zhang 2015 [133]Probably immediately post-injury34 ± 0.5 °C for 6 h-
2014Bazley et al., 2014 [140]1 h post-injury and then 30 min induction phase 32 °C for 2 h30 min to 37 °C
2013Grulova et al., 2013 [41]Immediately post-injury31–32 °C was approximately 30 min2 °C/h for 3 h to 37 °C
Batchelor et al., 2013 [138]82 min before the induction of injury to 30 min post-injury28 to 34 °C from 31 min to 7.5 h-
Saito et al., 2013 [57]Hypothermia was induced 15 min before ischemia 36.3 °C during ischemia (14 min)rewarmed in 30 min
2012Ok et al., 2012 [93]Upon awaking from anesthesia32 °C for 48 h1 °C/h to normothermia
Maybhate et al., 2012 [56]Approximately 2.0 h post-injury(32 ± 0.5 °C) for 2 h28 ± 5 min to 37 ± 0.5 °C
2011Batchelor et al., 2011, [55]30 min following spacer insertion (spinal cord compression)33 °C for 3.5 h30 min to 37 °C
Kao et al., 2011 [109]From the compression termination period33 °C for 2 hRecover naturally
2009Horiuchi et al., 2009 [147]During ischemia35 °C or 32 during ischemiaRewarmed to 38 °C in 30 min
Lo et al., 2009 [42]5 min post-injury33 °C for 4 h1 °C per hour
Duz et al., 2009 [146]After spinal cord injury27–29 °C for 1 hRecover naturally
2008Morino et al., 2008 [78]The beginning of the compression33 °C for 1 hRecover naturally
2004Tsutsumi et al., 2004 [141]1 h after spinal cord ischemia-reperfusion32.5 ± 0.5 °C for 6 h1 h to normal temperature
Strauch et al., 2004 [150]Through the ischemia (clamping) period32.0 °C through the ischemia (clamping) period90–100 min
Shibuya et al., 2004 [149]At 10 min after the end of compression, lower body temperature to a target level over 20 min 32 °C for 4 h40 min to 37 °C
2003Maeda et al., 2003 [148]During the ischemic period35 °C for 30 min during the ischemic period Gradually returned to 39 °C within 2 h
In TBI, Mclntyre and colleagues [151] examined therapeutic hypothermia of a duration of at least 24 h in a randomized control trial. They reported that compared with normothermia, 24 h of therapeutic hypothermia (32–33 °C) followed by rewarming over a subsequent 24 h, reduced the risk of a poor neurological outcome after TBI. Hypothermia longer than 48 h also reduced the risk of death. Che and colleagues [142] showed in a cardiac arrest model that the number of surviving neurons was greater when the duration of therapeutic hypothermia was 48 h compared to 24 h, suggesting that a prolonged therapeutic duration is associated with better neurological outcome. However, larger clinical investigations are needed to determine the most appropriate duration of systemic hypothermia that could be both safe and neuroprotective for acute SCI patients. Identifying whether longer durations of hypothermia can also achieve an extension in the therapeutic window for hypothermia administration would also be important to evaluate and allow its therapeutic use to be extended to a broader SCI population.

6.3. The Rate of Rewarming

In addition to the time window to initiate hypothermia and its duration, another important topic that deserves consideration is the rate of rewarming from hypothermia back to normothermia. Previous work in TBI has demonstrated that greater neuroprotection was achieved with slower rewarming, in contrast to rapid rewarming, which resulted in a deleterious effect [152,153]. In a rat weight drop TBI model, Suehiro and Povishock [153] compared the effects of slow rewarming with fast rewarming on axonal injury. Systemic hypothermia (32 °C) was initiated immediately after TBI and maintained for a 1 h duration. Animals were then allocated to either a slow rewarming group (90 min, group 1) or fast rewarming group (20 min, group 2), or fast rewarming (20 min) with the intrathecal cyclosporine A (CsA) infusion before rewarming (group 3). CsA is an immunophilin ligand that possesses the ability to provide mitochondrial protection by inhibiting the permeability transition pore on the inner mitochondrial membrane. At 24 h post-injury, less axonal damage, as visualized by fewer APP-immunoreactive axonal profiles, was identified within the corticospinal tract in the slow rewarming group (group 1) compared to the fast rewarming group (group 2); exacerbated axonal damage by fast rewarming (group 2) could be significantly reduced, however, by the use of CsA (group 3) (Figure 5 and Figure 6, respectively) [152]. Additionally, Suehiro and colleagues [154] demonstrated that slow rewarming after therapeutic hypothermia provided better protection of cerebral microcirculation and maintained normal arteriolar vascular responses. In contrast, rapid rewarming (within 30 min), impaired cerebral vascular responses to acetylcholine and arterial hypercapnia [155]. Similarly, in a recent human TBI study, it was shown that a rapid rewarming rate (faster than 0.25 °C/h) was associated with worse outcomes as demonstrated by a higher mortality rate, longer length of stay in the intensive care unit (ICU) and lower Glasgow Coma Scale (GCS) scores at hospital discharge [156].
Figure 5. In these light microscopic images, we see the protective effects of hypothermic intervention followed by slow rewarming (a) versus the damaging effects associated with hypothermia followed by rapid rewarming (b) In both a and b, the damaged immunoreactive axons are labeled with arrows, with a striking demonstration of reduced axonal burden in a versus b. Reprinted with permission from [152], copyright Mary Ann Liebert, Inc., 2009.
Figure 5. In these light microscopic images, we see the protective effects of hypothermic intervention followed by slow rewarming (a) versus the damaging effects associated with hypothermia followed by rapid rewarming (b) In both a and b, the damaged immunoreactive axons are labeled with arrows, with a striking demonstration of reduced axonal burden in a versus b. Reprinted with permission from [152], copyright Mary Ann Liebert, Inc., 2009.
Ijms 16 16848 g005
In the field of SCI, however, there are no standards to follow in terms of the most optimal rewarming rate to employ after hypothermia administration. While some studies have used natural rewarming at room temperature or on a heating pad with no temperature records on timed recovery (Table 1, [78,109,145]), others have rewarmed the animals for a period of about 30 min (Table 1, [55,56,57]). There have also been reports of more standardized protocols involving rewarming animals at a rate of 1 °C/h [42,93] or 2 °C/h [41]. In a rat cervical SCI study from our group, Lo and colleagues [42] rewarmed animals at 1 °C per hour over a period of approximately 4 h back to normothermia, a slow rewarming paradigm. However, there have been no reports to compare the effect of fast rewarming and slow rewarming in SCI animal experiments. In human SCI, Dididze and colleagues [40] carried out rewarming even more slowly, at 0.1 °C/h for SCI patients, taking about 40 h to rewarm an individual from 33 to 37 °C. In light of the results from TBI studies that demonstrated improved axonal protective effects and the maintenance of the vascular responses by slow rewarming [152,153,154], it is possible that slow rewarming will be more beneficial than rapid rewarming after SCI. Further work is required to investigate the optimal rewarming rate and its standardization for human SCI application.
Another crucial consideration is that rewarming should not exceed 37 °C. In a human TBI study, Lavinio and colleagues [157] reported that after moderate hypothermia (34.2 °C), rewarming above the brain temperature threshold of 37 °C was associated with an increase in the average cerebrovascular pressure reactivity index (PRx), indicating a significant derangement of cerebral autoregulation. Further, a SCI study in rats has demonstrated that systemic hyperthermia itself worsened locomotor outcome and increased tissue damage [158]. Therefore, rewarming durations and temperature limits are important considerations for recovery after hypothermia application in SCI.
Figure 6. This bar graph shows a comparison of the numbers of amyloid precursor protein (APP) immunoreactive axonal profiles in the pontomedullary junction in three different treatment groups. Group 1 animals were subjected to traumatic brain injury (TBI) followed by 1 h of hypothermia and slow rewarming. In contrast, Group 2 animals were subjected to TBI and the same hypothermic intervention followed by rapid rewarming. Group 3 animals were also subjected to TBI followed by hypothermia and rapid rewarming with the concomitant infusion of cyclosporine A (CsA). Note that Group 1 animals showed a reduced burden of axonal damage associated with the use of hypothermia and slow rewarming, whereas these axonal numbers were dramatically increased following the same insult and hypothermic intervention, now with the inclusion of a rapid rewarming rate. Lastly, Group 3 was treated in the same fashion as Group 2, with the exception that CsA was administered prior to the initiation of rapid rewarming. Collectively, this figure illustrates the damaging effects of rapid posthypothermic rewarming and its attenuation via the use of the immunophilin ligand CsA. Reprinted with permission from [152], copyright Mary Ann Liebert, Inc., 2009.
Figure 6. This bar graph shows a comparison of the numbers of amyloid precursor protein (APP) immunoreactive axonal profiles in the pontomedullary junction in three different treatment groups. Group 1 animals were subjected to traumatic brain injury (TBI) followed by 1 h of hypothermia and slow rewarming. In contrast, Group 2 animals were subjected to TBI and the same hypothermic intervention followed by rapid rewarming. Group 3 animals were also subjected to TBI followed by hypothermia and rapid rewarming with the concomitant infusion of cyclosporine A (CsA). Note that Group 1 animals showed a reduced burden of axonal damage associated with the use of hypothermia and slow rewarming, whereas these axonal numbers were dramatically increased following the same insult and hypothermic intervention, now with the inclusion of a rapid rewarming rate. Lastly, Group 3 was treated in the same fashion as Group 2, with the exception that CsA was administered prior to the initiation of rapid rewarming. Collectively, this figure illustrates the damaging effects of rapid posthypothermic rewarming and its attenuation via the use of the immunophilin ligand CsA. Reprinted with permission from [152], copyright Mary Ann Liebert, Inc., 2009.
Ijms 16 16848 g006

7. Conclusions

In summary, hypothermia is a promising neuroprotective treatment for SCI. There is a strong potential to combine hypothermia with other therapeutic approaches, such as pharmaceuticals and cellular transplantation for more robust effects on histological and functional outcomes. Particularly, it is beneficial to investigate the potential synergistic neuroprotective effect for SCI through the combination of hypothermia with erythropoietin and derivatives, riluzole (a sodium channel-blocking benzothiazole anticonvulsant medication), calpain inhibitors (e.g., AK295, MDL28170, SJA6017), minocycline, Rho kinase inhibitors (Fasudil) or Schwann cell transplantation. Further, large multicenter trials are required to investigate a standardized and optimized protocol to achieve the most beneficial effect of clinical hypothermia therapy for SCI. Specifically, the therapeutic window, approaches to extend this window, the optimal duration of hypothermia as well as the standardization of the rewarming protocol are all at the forefront of the current research gap.

Acknowledgments

Special acknowledgment is given to Elliott Delgado for help with proof-reading.

Author Contributions

Jiaqiong Wang and Damien D. Pearse conceptualized the idea and organization of this manuscript. Jiaqiong Wang drafted the manuscript and Damien D. Pearse provided guidance, revisions and amendments.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Centers for Disease Control and Prevention. Brunner & Suddarth’s Textbook of Medical-Surgical Nursing, 13th ed.; Hinkle, J.L., Cheever, K.H., Eds.; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2012. [Google Scholar]
  2. Dumont, R.J.; Okonkwo, D.O.; Verma, S.; Hurlbert, R.J.; Boulos, P.T.; Ellegala, D.B.; Dumont, A.S. Acute spinal cord injury, part I: Pathophysiologic mechanisms. Clin. Neuropharmacol. 2001, 24, 254–264. [Google Scholar] [CrossRef] [PubMed]
  3. Tator, C.H. Pathophysiology and pathology of spinal cord injury. In Neurosurgery, 2nd ed.; Wilkins, R.H., Rengachary, S.S., Eds.; Williams & Wilkins: Baltimore, MD, USA, 1996; pp. 2847–2859. [Google Scholar]
  4. Tator, C.H. Spinal cord syndromes with physiological and anatomic correlations. In Principles of Spinal Surger; Menezes, A.H., Sonntag, V.K.H., Eds.; McGraw-Hill: New York, NY, USA, 1996; pp. 785–799. [Google Scholar]
  5. Guha, A.; Tator, C.H. Acute cardiovascular effects of experimental spinal cord injury. J. Trauma 1988, 28, 481–490. [Google Scholar] [CrossRef] [PubMed]
  6. Kiss, Z.H.T.; Tator, C.H. Neurogenic shock. In Shock and Resuscitation; Geller, E.R., Ed.; McGraw-Hill: New York, NY, USA, 1993; pp. 421–440. [Google Scholar]
  7. Nemecek, S. Morphological evidence of microcirculatory disturbances in experimental spinal cord trauma. Adv. Neurol. 1978, 20, 395–405. [Google Scholar] [PubMed]
  8. Tator, C.H.; Fehlings, M.G. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J. Neurosurg. 1991, 75, 15–26. [Google Scholar] [CrossRef] [PubMed]
  9. Faden, A.I.; Chan, P.H.; Longar, S. Alterations in lipid metabolism, Na, K-ATPase activity and tissue water content of spinal cord after experimental traumatic injury. J. Neurochem. 1987, 48, 1809–1816. [Google Scholar] [CrossRef] [PubMed]
  10. Hall, E.D.; Wolf, D.L. A pharmacological analysis of the pathophysiological mechanisms of posttraumatic spinal cord ischemia. J. Neurosurg. 1986, 64, 951–961. [Google Scholar] [CrossRef] [PubMed]
  11. Hsu, C.Y.; Halushka, P.V.; Hogan, E.L.; Banik, N.L.; Lee, W.A.; Perot, P.L., Jr. Alteration of thromboxane and prostacyclin levels in experimental spinal cord injury. Neurology 1985, 35, 1003–1009. [Google Scholar] [CrossRef] [PubMed]
  12. Haldor, T.J., Jr.; Herman, B.D. Altered levels of PGF in cat spinal cord tissue after traumatic injury. Prostaglandins 1976, 11, 51–59. [Google Scholar]
  13. Shields, D.C.; Schaecher, K.E.; Hogan, E.L.; Banik, N.L. Calpain activity and expression increased in activated glial and inflammatory cells in penumbra of spinal cord injury lesion. J. Neurosci. Res. 2000, 61, 146–150. [Google Scholar] [CrossRef]
  14. Lewen, A.; Matz, P.; Chan, P.H. Free radical pathways in CNS injury. J. Neurotrauma 2000, 17, 871–890. [Google Scholar] [CrossRef] [PubMed]
  15. Faden, A.I.; Lemke, M.; Simon, R.P.; Noble, L.J. N-methyl-D-aspartate antagonist MK801 improves outcome after traumatic spinal cord injury in rats: Behavioral, anatomic, and neurochemical studies. J. Neurotrauma 1988, 5, 33–45. [Google Scholar] [CrossRef] [PubMed]
  16. Faden, A.I.; Simon, R.P. A potential role for excitotoxins in the pathophysiology of spinal cord injury. Ann. Neurol. 1988, 23, 623–627. [Google Scholar] [CrossRef] [PubMed]
  17. Emery, E.; Aldana, P.; Bunge, M.B.; Puckett, W.; Srinivasan, A.; Keane, R.W.; Bethea, J.; Levi, A.D. Apoptosis after traumatic human spinal cord injury. J. Neurosurg. 1998, 89, 911–920. [Google Scholar] [CrossRef] [PubMed]
  18. Li, G.L.; Farooque, M.; Holtz, A.; Olsson, Y. Apoptosis of oligodendrocytes occurs for long distances away from the primary injury after compression trauma to rat spinal cord. Acta Neuropathol. 1999, 98, 473–480. [Google Scholar] [CrossRef] [PubMed]
  19. Shuman, S.L.; Bresnahan, J.C.; Beattie, M.S. Apoptosis of microglia and oligodendrocytes after spinal cord contusion in rats. J. Neurosci. Res. 1997, 50, 798–808. [Google Scholar] [CrossRef]
  20. Schwab, M.E.; Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 1996, 76, 319–370. [Google Scholar] [PubMed]
  21. Bethea, J.R.; Nagashima, H.; Acosta, M.C.; Briceno, C.; Gomez, F.; Marcillo, A.E.; Loor, K.; Green, J.; Dietrich, W.D. Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats. J. Neurotrauma 1999, 16, 851–863. [Google Scholar] [CrossRef] [PubMed]
  22. Horn, K.P.; Busch, S.A.; Hawthorne, A.L.; van Rooijen, N.; Silver, J. Another barrier to regeneration in the CNS: Activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J. Neurosci. 2008, 28, 9330–9341. [Google Scholar] [CrossRef] [PubMed]
  23. Isaksson, J.; Farooque, M.; Olsson, Y. Spinal cord injury in ICAM-1-deficient mice: Assessment of functional and histopathological outcome. J. Neurotrauma 2000, 17, 333–344. [Google Scholar] [CrossRef] [PubMed]
  24. Leskovar, A.; Moriarty, L.J.; Turek, J.J.; Schoenlein, I.A.; Borgens, R.B. The macrophage in acute neural injury: Changes in cell numbers over time and levels of cytokineproduction in mammalian central and peripheral nervous systems. J. Exp. Biol. 2000, 203, 1783–1795. [Google Scholar] [PubMed]
  25. Wu, J.; Pajoohesh-Ganji, A.; Stoica, B.A.; Dinizo, M.; Guanciale, K.; Faden, A.I. Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion. J. Neuroinflamm. 2012, 9, 169. [Google Scholar] [CrossRef] [PubMed]
  26. Fugate, J.E.; Moore, S.A.; Knopman, D.S.; Claassen, D.O.; Wijdicks, E.F.; White, R.D.; Rabinstein, A.A. Cognitive outcomes of patients undergoing therapeutic hypothermia after cardiac arrest. Neurology 2013, 81, 40–45. [Google Scholar] [CrossRef] [PubMed]
  27. Hollenbeck, R.D.; Wells, Q.; Pollock, J.; Kelley, M.B.; Wagner, C.E.; Cash, M.E.; Scott, C.; Burns, K.; Jones, I.; Fredi, J.L.; et al. Implementation of a standardized pathway for the treatment of cardiac arrest patients using therapeutic hypothermia: “CODE ICE”. Crit. Pathw. Cardiol. 2012, 11, 91–98. [Google Scholar] [CrossRef] [PubMed]
  28. Dehaes, M.; Aggarwal, A.; Lin, P.Y.; Rosa Fortuno, C.; Fenoglio, A.; Roche-Labarbe, N.; Soul, J.S.; Franceschini, M.A.; Grant, P.E. Cerebral oxygen metabolism in neonatal hypoxic ischemic encephalopathy during and after therapeutic hypothermia. J. Cereb. Blood Flow Metab. 2014, 34, 87–94. [Google Scholar] [CrossRef] [PubMed]
  29. Soll, R.F. Cooling for newborns with hypoxic ischemic encephalopathy. Neonatology 2013, 104, 260–262. [Google Scholar] [CrossRef]
  30. Stravitz, R.T.; Larsen, F.S. Therapeutic hypothermia for acute liver failure. Crit. Care Med. 2009, 37 (Suppl. 7), 258–264. [Google Scholar] [CrossRef] [PubMed]
  31. Varon, J.; Marik, P.E.; Einav, S. Therapeutic hypothermia: A state-of-the-art emergency medicine perspective. Am. J. Emerg. Med. 2012, 30, 800–810. [Google Scholar] [CrossRef] [PubMed]
  32. Karibe, H.; Sato, K.; Shimizu, H.; Tominaga, T.; Koshu, K.; Yoshimoto, T. Intraoperative mild hypothermia ameliorates postoperative cerebral blood flow impairment in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 2000, 47, 594–599. [Google Scholar] [PubMed]
  33. Lusczek, E.R.; Lexcen, D.R.; Witowski, N.E.; Determan, C., Jr.; Mulier, K.E.; Beilman, G. Prolonged induced hypothermia in hemorrhagic shock is associated with decreased muscle metabolism: An NMR-based metabolomics study. Shock 2014, 41, 79–84. [Google Scholar] [CrossRef] [PubMed]
  34. Morrison, J.J.; Ross, J.D.; Poon, H.; Midwinter, M.J.; Jansen, J.O. Intra-operative correction of acidosis, coagulopathy and hypothermia in combat casualties with severe haemorrhagic shock. Anaesthesia 2013, 68, 846–850. [Google Scholar] [CrossRef] [PubMed]
  35. Adelson, P.D.; Wisniewski, S.R.; Beca, J.; Brown, S.D.; Bell, M.; Muizelaar, J.P.; Okada, P.; Beers, S.R.; Balasubramani, G.K.; Hirtz, D. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): A phase 3, randomised controlled trial. Lancet Neurol. 2013, 12, 546–553. [Google Scholar] [CrossRef]
  36. Bramlett, H.M.; Dietrich, W.D. The effects of posttraumatic hypothermia on diffuse axonal injury following parasaggital fluid percussion brian injury in rats. Ther. Hypoth. Temp. Manag. 2012, 2, 14–23. [Google Scholar] [CrossRef] [PubMed]
  37. Fujita, M.; Wei, E.P.; Povlishock, J.T. Effects of hypothermia on cerebral autoregulatory vascular responses in two rodent models of traumatic brain injury. J. Neurotrauma 2012, 29, 1491–1498. [Google Scholar] [CrossRef] [PubMed]
  38. Gao, G.; Oda, Y.; Wei, E.P.; Povlishock, J.T. The adverse pial arteriolar and axonal consequences of traumatic brain injury complicated by hypoxia and their therapeutic modulation with hypothermia in rat. J. Cereb. Blood Flow Metab. 2010, 30, 628–637. [Google Scholar] [CrossRef] [PubMed]
  39. Ahmad, F.; Wang, M.Y.; Levi, A.D. Hypothermia for acute spinal cord injury—A review. World Neurosurg. 2014, 82, 207–214. [Google Scholar] [CrossRef] [PubMed]
  40. Dididze, M.; Green, B.A.; Dietrich, W.D.; Vanni, S.; Wang, M.Y.; Levi, A.D. Systemic hypothermia in acute cervical spinal cord injury: A case-controlled study. Spinal Cord 2013, 51, 395–400. [Google Scholar] [CrossRef] [PubMed]
  41. Grulova, I.; Slovinska, L.; Nagyova, M.; Cizek, M.; Cizkova, D. The effect of hypothermia on sensory-motor function and tissue sparing after spinal cord injury. Spine J. 2013, 13, 1881–1891. [Google Scholar] [CrossRef] [PubMed]
  42. Lo, T.P., Jr.; Cho, K.S.; Garg, M.S.; Lynch, M.P.; Marcillo, A.E.; Koivisto, D.L.; Stagg, M.; Abril, R.M.; Patel, S.; Dietrich, W.D.; et al. Systemic hypothermia improves histological and functional outcome after cervical spinal cord contusion in rats. J. Comp. Neurol. 2009, 514, 433–448. [Google Scholar] [CrossRef] [PubMed]
  43. Cooley, D.A.; Ott, D.A.; Frazier, O.H.; Walker, W.E. Surgical treatment of aneurysms of the transverse aortic arch: Experience with 25 patients using hypothermic techniques. Ann. Thorac. Surg. 1981, 32, 260–272. [Google Scholar] [CrossRef]
  44. Lucas, J.H.; Wang, G.F.; Gross, G.W. NMDA antagonists prevent hypothermic injury and death of mammalian spinal neurons. J. Neurotrauma 1990, 7, 229–236. [Google Scholar] [CrossRef] [PubMed]
  45. Alonso-Alconada, D.; Broad, K.D.; Bainbridge, A.; Chandrasekaran, M.; Faulkner, S.D.; Kerenyi, Á.; Hassell, J.; Rocha-Ferreira, E.; Hristova, M.; Fleiss, B.; et al. Brain cell death is reduced with cooling by 3.5 to 5 °C but increased with cooling by 8.5 °C in a piglet asphyxia model. Stroke 2015, 46, 275–278. [Google Scholar] [CrossRef] [PubMed]
  46. Albin, M.S.; White, R.J.; Locke, G.S.; Massopust, L.C., Jr.; Kretchmer, H.E. Localized spinal cord hypothermia:-anesthetic effects and application to spinal cord injury. Anesth. Analg. 1967, 46, 8–16. [Google Scholar] [CrossRef] [PubMed]
  47. Albin, M.S.; White, R.J.; Acosta-Rua, G.; Yashon, D. Study of functional recovery produced by delayed localized cooling after spinal cord injury in primates. J. Neurosurg. 1968, 29, 113–120. [Google Scholar] [CrossRef] [PubMed]
  48. Ducker, T.B.; Hamit, H.F. Experimental treatments of acute spinal cord injury. J. Neurosurg. 1969, 30, 693–697. [Google Scholar] [CrossRef] [PubMed]
  49. Salzano, R.P., Jr.; Ellison, L.H.; Altonji, P.F.; Richter, J.; Deckers, P.J. Regional deep hypothermia of the spinal cord protects against ischemic injury during thoracic aortic cross-clamping. Ann. Thorac. Surg. 1994, 57, 65–70. [Google Scholar] [CrossRef]
  50. Tabayashi, K.; Niibori, K.; Konno, H.; Mohri, H. Protection from postischemic spinal cord injury by perfusion cooling of the epidural space. Ann. Thorac. Surg. 1993, 56, 494–498. [Google Scholar] [CrossRef]
  51. Rokkas, C.K.; Cronin, C.S.; Nitta, T.; Helfrich, L.R., Jr.; Lobner, D.C.; Choi, D.W.; Kouchoukos, N.T. Profound systemic hypothermia inhibits the release of neurotransmitter amino acids in spinal cord ischemia. J. Thorac. Cardiovasc. Surg. 1995, 110, 27–35. [Google Scholar] [CrossRef]
  52. Rose, W.W.; Reddy, D.J.; Ernst, C.B.; Reickert, C.A.; Patterson, J.S. Protective effect of hypothermia and left heart bypass on spinalischemia in the dog. Arch. Surg. 1997, 132, 633–639. [Google Scholar] [CrossRef] [PubMed]
  53. Ueno, T.; Furukawa, K.; Katayama, Y.; Itoh, T. Protection against ischemic spinal cord injury: One-shot perfusion cooling and percutaneous topical cooling. J. Vasc. Surg. 1994, 19, 882–887. [Google Scholar] [CrossRef]
  54. Yu, C.G.; Jimenez, O.; Marcillo, A.E.; Weider, B.; Bangerter, K.; Dietrich, W.D.; Castro, S.; Yezierski, R.P. Beneficial effects of modest systemic hypothermia on locomotor function and histopathological damage following contusion-induced spinal cord injury in rats. J. Neurosurg. 2000, 93 (Suppl. 1), 85–93. [Google Scholar] [CrossRef] [PubMed]
  55. Batchelor, P.E.; Kerr, N.F.; Gatt, A.M.; Cox, S.F.; Ghasem-Zadeh, A.; Wills, T.E.; Sidon, T.K.; Howells, D.W. Intracanal pressure in compressive spinal cord injury: Reduction with hypothermia. J. Neurotrauma 2011, 28, 809–820. [Google Scholar] [CrossRef] [PubMed]
  56. Maybhate, A.; Hu, C.; Bazley, F.A.; Yu, Q.; Thakor, N.V.; Kerr, C.L.; All, A.H. Potential long-term benefits of acute hypothermia after spinal cord injury: Assessments with somatosensory-evoked potentials. Crit. Care Med. 2012, 40, 573–579. [Google Scholar] [CrossRef] [PubMed]
  57. Saito, T.; Saito, S.; Yamamoto, H.; Tsuchida, M. Neuroprotection following mild hypothermia after spinal cord ischemia in rats. J. Vasc. Surg. 2013, 57, 173–181. [Google Scholar] [CrossRef] [PubMed]
  58. Jackson, F.; Assam, S. Extensive spinal epidural abscess treated by laminectomy and hypothermia. Case report. J. Neurosurg. 1964, 21, 237–239. [Google Scholar] [CrossRef] [PubMed]
  59. Demian, Y.K.; White, R.J.; Yashon, D.; Kretchmer, H.E. Anaesthesia for laminectomy and localized cord cooling in acute cervical spine injury. Report of three cases. Br. J. Anaesth. 1971, 43, 973–979. [Google Scholar] [CrossRef] [PubMed]
  60. Bricolo, A.; Ore, G.D.; Da Pian, R.; Faccioli, F. Local cooling in spinal cord injury. Surg. Neurol. 1976, 6, 101–106. [Google Scholar] [PubMed]
  61. Koons, D.D.; Gildenberg, P.L.; Dohn, D.F.; Henoch, M. Local hypothermia in the treatment of spinal cord injuries. Report of seven cases. Clevel. Clin. Q. 1972, 39, 109–117. [Google Scholar] [CrossRef]
  62. Romodanov, A.P.; Mikhaĭlovskiĭ, V.S.; Andreĭko, R.L. Spinal cord hypothermia in neurosurgical practice. Zh Vopr Neirokhir Im N N Burdenko 1979, 2, 9–13. (In Russian) [Google Scholar] [PubMed]
  63. Iumashev, G.S.; Cherkashina, Z.A.; Kostin, V.A.; Lysikov, A.V.; El’kina, I.A. Method of using local hypothermia of the spinal cord in spinalized patients during the postoperative period. Zh Vopr Neirokhir Im N N Burdenko 1983, 6, 34–36. (In Russian) [Google Scholar] [PubMed]
  64. Cherkashina, Z.A. Effectiveness of local hypothermia in the complex treatment of patients with complicated injuries of the spine. Ortop. Travmatol. protež. 1989, 5, 12–16. (In Russian) [Google Scholar] [PubMed]
  65. Kouchoukos, N.T.; Kulik, A.; Castner, C.F. Outcomes after thoracoabdominal aortic aneurysm repair using hypothermic circulatory arrest. J. Thorac. Cardiovasc. Surg. 2013, 145 (Suppl. 3), 139–141. [Google Scholar] [CrossRef] [PubMed]
  66. Cambria, R.P.; Davison, J.K.; Zannetti, S.; L’Italien, G.; Brewster, D.C.; Gertler, J.P.; Moncure, A.C.; LaMuraglia, G.M.; Abbott, W.M. Clinical experience with epidural cooling for spinal cord protection during thoracic and thoracoabdominal aneurysm repair. J. Vasc. Surg. 1997, 25, 234–241. [Google Scholar] [CrossRef]
  67. Rokkas, C.K.; Kouchoukos, N.T. Profound hypothermia for spinal cord protection in operations on the descending thoracic and thoracoabdominal aorta. Semin. Thorac. Cardiovasc. Surg. 1998, 10, 57–60. [Google Scholar] [CrossRef]
  68. Svensson, L.G.; Hess, K.R.; D’Agostino, R.S.; Entrup, M.H.; Hreib, K.; Kimmel, W.A.; Nadolny, E.; Shahian, D.M. Reduction of neurologic injury after high-risk thoracoabdominal aortic operation. Ann. Thorac. Surg. 1998, 66, 132–138. [Google Scholar] [CrossRef]
  69. Hayes, K.C.; Hsieh, J.T.; Potter, P.J.; Wolfe, D.L.; Delaney, G.A.; Blight, A.R. Effects of induced hypothermia on somatosensory evoked potentials in patients with chronic spinal cord injury. Paraplegia 1993, 31, 730–741. [Google Scholar] [CrossRef] [PubMed]
  70. Cappuccino, A.; Bisson, L.J.; Carpenter, B.; Marzo, J.; Dietrich, W.D.; Cappuccino, H. The use of systemic hypothermia for the treatment of an acute cervical spinal cord injury in a professional football player. Spine 2010, 35, E57–E62. [Google Scholar] [CrossRef] [PubMed]
  71. Dietrich, W.D.; Levi, A.D.; Wang, M.; Green, B.A. Hypothermic treatment for acute spinal cord injury. Neurotherapeutics 2011, 8, 229–239. [Google Scholar] [CrossRef] [PubMed]
  72. Levi, A.D.; Casella, G.; Green, B.A.; Dietrich, W.D.; Vanni, S.; Jagid, J.; Wang, M.Y. Clinical outcomes using modest intravascular hypothermia after acute cervical spinal cord injury. Neurosurgery 2010, 66, 670–677. [Google Scholar] [CrossRef] [PubMed]
  73. Levi, A.D.; Green, B.A.; Wang, M.Y.; Dietrich, W.D.; Brindle, T.; Vanni, S.; Casella, G.; Elhammady, G.; Jagid, J. Clinical application of modest hypothermia after spinal cord injury. J. Neurotrauma 2009, 26, 407–415. [Google Scholar] [CrossRef] [PubMed]
  74. Madhavan, K.; Benglis, D.M.; Wang, M.Y.; Vanni, S.; Lebwohl, N.; Green, B.A.; Levi, A.D. The use of modest systemic hypothermia after iatrogenic spinal cord injury during surgery. Ther. Hypoth. Temp. Manag. 2012, 2, 183–192. [Google Scholar] [CrossRef] [PubMed]
  75. Tripathy, S.; Whitehead, C.F. Endovascular cooling for severe hyperthermia in cervical spine injury. Neurocrit. Care 2011, 15, 525–528. [Google Scholar] [CrossRef] [PubMed]
  76. Chatzipanteli, K.; Yanagawa, Y.; Marcillo, A.E.; Kraydieh, S.; Yezierski, R.P.; Dietrich, W.D. Posttraumatic hypothermia reduces polymorphonuclear leukocyte accumulation following spinal cord injury in rats. J. Neurotrauma 2000, 17, 321–332. [Google Scholar] [CrossRef] [PubMed]
  77. González-Ibarra, F.P.; Varon, J.; López-Meza, E.G. Therapeutic hypothermia: Critical review of the molecular mechanisms of action. Front. Neurol. 2011, 2, 4. [Google Scholar] [CrossRef] [PubMed]
  78. Morino, T.; Ogata, T.; Takeba, J.; Yamamoto, H. Microglia inhibition is a target of mild hypothermic treatment after the spinal cord injury. Spinal Cord 2008, 46, 425–431. [Google Scholar] [CrossRef] [PubMed]
  79. Dzsinich, C.; Nagy, G.; Selmeci, L.; Sepa, G.; Fazekas, L.; Kékesi, V.; Juhász-Nagy, S. Effect of regional hypothermia on cerebrospinal fluid parameters during thoracoabdominal aorta clamping in dogs. Magy. Seb. 2000, 53, 79–84. (In Hungarian) [Google Scholar] [PubMed]
  80. Allen, B.T.; Davis, C.G.; Osborne, D.; Karl, I. Spinal cord ischemia and reperfusion metabolism: The effect of hypothermia. J. Vasc. Surg. 1994, 19, 332–339. [Google Scholar] [CrossRef]
  81. Drenger, B.; Parker, S.D.; Frank, S.M.; Beattie, C. Changes in cerebrospinal fluid pressure and lactate concentrations during thoracoabdominal aortic aneurysm surgery. Anesthesiology 1997, 86, 41–47. [Google Scholar] [CrossRef] [PubMed]
  82. Luo, J.; Li, N.; Robinson, J.P.; Shi, R. The increase of reactive oxygen species and their inhibition in an isolated guinea pig spinal cord compression model. Spinal Cord 2002, 40, 656–665. [Google Scholar] [CrossRef] [PubMed]
  83. Tüzgen, S.; Kaynar, M.Y.; Güner, A.; Gümüştaş, K.; Belce, A.; Etuş, V.; Ozyurt, E. The effect of epidural cooling on lipid peroxidation after experimentalspinal cord injury. Spinal Cord 1998, 36, 654–657. [Google Scholar] [CrossRef] [PubMed]
  84. Park, E.; Velumian, A.A.; Fehlings, M.G. The role of excitotoxicity in secondary mechanisms of spinal cord injury: A review with an emphasis on the implications for white matter degeneration. J. Neurotrauma 2004, 21, 754–774. [Google Scholar] [CrossRef] [PubMed]
  85. Mazzone, G.L.; Nistri, A. Electrochemical detection of endogenous glutamate release from rat spinal cord organotypic slices as a real-time method to monitor excitotoxicity. J. Neurosci. Methods 2011, 197, 128–132. [Google Scholar] [CrossRef] [PubMed]
  86. Ishikawa, T.; Marsala, M. Hypothermia prevents biphasic glutamate release and corresponding neuronal degeneration after transient spinal cord ischemia in the rat. Cell Mol. Neurobiol. 1999, 19, 199–208. [Google Scholar] [PubMed]
  87. Wakamatsu, H.; Matsumoto, M.; Nakakimura, K.; Sakabe, T. The effects of moderate hypothermia and intrathecal tetracaine on glutamate concentrations of intrathecal dialysate and neurologic and histopathologic outcome in transient spinal cord ischemia in rabbits. Anesth. Analg. 1999, 88, 56–62. [Google Scholar] [PubMed]
  88. Nishi, H.; Nakatsuka, T.; Takeda, D.; Miyazaki, N.; Sakanaka, J.; Yamada, H.; Yoshida, M. Hypothermia suppresses excitatory synaptic transmission and neuronal death induced by experimental ischemia in spinal ventral horn neurons. Spine 2007, 32, E741–E747. [Google Scholar] [CrossRef] [PubMed]
  89. Kotipatruni, RR1.; Dasari, V.R.; Veeravalli, K.K.; Dinh, D.H.; Fassett, D.; Rao, J.S. p53- and Bax-mediated apoptosis in injured rat spinal cord. Neurochem. Res. 2011, 36, 2063–2074. [Google Scholar]
  90. Springer, J.E.; Azbill, R.D.; Knapp, P.E. Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat. Med. 1999, 5, 943–946. [Google Scholar] [CrossRef] [PubMed]
  91. Takagi, T.; Takayasu, M.; Mizuno, M.; Yoshimoto, M.; Yoshida, J. Caspase activation in neuronal and glial apoptosis following spinal cord injury in mice. Neurol. Med. Chir. 2003, 43, 20–29. [Google Scholar] [CrossRef]
  92. Zhang, J.; Cui, Z.; Feng, G.; Bao, G.; Xu, G.; Sun, Y.; Wang, L.; Chen, J.; Jin, H.; Liu, J.; et al. RBM5 and p53 expression after rat spinal cord injury: Implications for neuronal apoptosis. Int. J. Biochem. Cell Biol. 2015, 60, 43–52. [Google Scholar] [CrossRef] [PubMed]
  93. Ok, J.H.; Kim, Y.H.; Ha, K.Y. Neuroprotective effects of hypothermia after spinal cord injury in rats: Comparative study between epidural hypothermia and systemic hypothermia. Spine 2012, 37, E1551–E1559. [Google Scholar] [CrossRef] [PubMed]
  94. Wang, L.M.; Yan, Y.; Zou, L.J.; Jing, N.H.; Xu, Z.Y. Moderate hypothermia prevents neural cell apoptosis following spinal cord ischemia in rabbits. Cell Res. 2005, 15, 387–393. [Google Scholar] [CrossRef] [PubMed]
  95. Sato, A.; Ohtaki, H.; Tsumuraya, T.; Song, D.; Ohara, K.; Asano, M.; Iwakura, Y.; Atsumi, T.; Shioda, S. Interleukin-1 participates in the classical and alternative activation of microglia/macrophages after spinal cord injury. J. Neuroinflamm. 2012, 9, 65. [Google Scholar] [CrossRef] [PubMed]
  96. Kigerl, K.A.; Gensel, J.C.; Ankeny, D.P.; Alexander, J.K.; Donnelly, D.J.; Popovich, P.G. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 2009, 29, 13435–13444. [Google Scholar] [CrossRef] [PubMed]
  97. Busch, S.A.; Horn, K.P.; Silver, D.J.; Silver, J. Overcoming macrophage-mediated axonal dieback following CNS injury. J. Neurosci. 2009, 29, 9967–9976. [Google Scholar] [CrossRef] [PubMed]
  98. Ashwell, J.D. The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat. Rev. Immunol. 2006, 6, 532–540. [Google Scholar] [CrossRef] [PubMed]
  99. Boyle, D.L.; Jones, T.L.; Hammaker, D.; Svensson, C.I.; Rosengren, S.; Albani, S.; Sorkin, L.; Firestein, G.S. Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med. 2006, 3, e338. [Google Scholar] [CrossRef] [PubMed]
  100. Bartanusz, V.; Jezova, D.; Alajajian, B.; Digicaylioglu, M. The blood-spinal cord barrier: Morphology and clinical implications. Ann. Neurol. 2011, 70, 194–206. [Google Scholar] [CrossRef] [PubMed]
  101. Cohen, D.M.; Patel, C.B.; Ahobila-Vajjula, P.; Sundberg, L.M.; Chacko, T.; Liu, S.J.; Narayana, P.A. Blood-spinal cord barrier permeability in experimental spinal cord injury: Dynamic contrast-enhanced MRI. NMR Biomed. 2009, 22, 332–341. [Google Scholar] [CrossRef] [PubMed]
  102. Sharma, H.S. Pathophysiology of blood-spinal cord barrier in traumatic injury and repair. Curr. Pharm. Des. 2005, 11, 1353–1389. [Google Scholar] [CrossRef] [PubMed]
  103. Yu, W.R.; Westergren, H.; Farooque, M.; Holtz, A.; Olsson, Y. Systemic hypothermia following compression injury of rat spinal cord: Reduction of plasma protein extravasation demonstrated by immunohistochemistry. Acta Neuropathol. 1999, 98, 15–21. [Google Scholar] [CrossRef] [PubMed]
  104. Wang, D.; Yang, Z.; Zhang, J. Treatment of spinal cord injury by mild hypothermia combined with bonemarrow mesenchymal stem cells transplantation in rats. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2010, 24, 801–805. (In Chinese) [Google Scholar] [PubMed]
  105. Wilcox, J.T.; Satkunendrarajah, K.; Zuccato, J.A.; Nassiri, F.; Fehlings, M.G. Neural precursor cell transplantation enhances functional recovery and reduces astrogliosis in bilateral compressive/contusive cervical spinal cord injury. Stem Cells Transl. Med. 2014, 3, 1148–1159. [Google Scholar] [CrossRef] [PubMed]
  106. Dubory, A.; Laemmel, E.; Badner, A.; Duranteau, J.; Vicaut, E.; Court, C.; Soubeyrand, M. Contrast enhanced ultrasound imaging for assessment of spinal cord blood flow in experimental spinal cord injury. J. Vis. Exp. 2015, 99. [Google Scholar] [CrossRef] [PubMed]
  107. Hu, J.; Cao, Y.; Wu, T.; Li, D.; Lu, H. 3D angioarchitecture changes after spinal cord injury in rats using synchrotron radiation phase-contrast tomography. Spinal Cord 2015. [Google Scholar] [CrossRef] [PubMed]
  108. Salkov, M.; Tsymbaliuk, V.; Dzyak, L.; Rodinsky, A.; Cherednichenko, Y.; Titov, G. New concept of pathogenesis of impaired circulation in traumatic cervical spinal cord injury and its impact on disease severity: Case series of four patients. Eur. Spine J. 2015. [Google Scholar] [CrossRef] [PubMed]
  109. Kao, C.H.; Chio, C.C.; Lin, M.T.; Yeh, C.H. Body cooling ameliorating spinal cord injury may be neurogenesis-, anti-inflammation- and angiogenesis-associated in rats. J. Trauma 2011, 70, 885–893. [Google Scholar] [CrossRef] [PubMed]
  110. Del Mar, N.; von Buttlar, X.; Yu, A.S.; Guley, N.H.; Reiner, A.; Honig, M. A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments. Exp. Neurol. 2015, 271, 53–71. [Google Scholar] [CrossRef] [PubMed]
  111. Ward, R.E.; Huang, W.; Kostusiak, M.; Pallier, P.N.; Michael-Titus, A.T.; Priestley, J.V. A characterization of white matter pathology following spinal cord compression injury in the rat. Neuroscience 2014, 260, 227–239. [Google Scholar] [CrossRef] [PubMed]
  112. Wu, W.; Wu, W.; Zou, J.; Shi, F.; Yang, S.; Liu, Y.; Lu, P.; Ma, Z.; Zhu, H.; Xu, X.M. Axonal and glial responses to a mid-thoracic spinal cord hemisection in the Macaca fascicularis monkey. J. Neurotrauma 2013, 30, 826–839. [Google Scholar] [CrossRef] [PubMed]
  113. Westergren, H.; Yu, W.R.; Farooque, M.; Holtz, A.; Olsson, Y. Systemic hypothermia following spinal cord compression injury in the rat: Axonal changes studied by beta-APP, ubiquitin, and PGP 9.5 immunohistochemistry. Spinal Cord 1999, 37, 696–704. [Google Scholar] [CrossRef] [PubMed]
  114. Park, K.W.; Lin, C.Y.; Lee, Y.S. Expression of suppressor of cytokine signaling-3 (SOCS3) and its role in neuronal death after complete spinal cord injury. Exp. Neurol. 2014, 261, 65–75. [Google Scholar] [CrossRef] [PubMed]
  115. Herlambang, B.; Orihashi, K.; Mizukami, T.; Takahashi, S.; Uchida, N.; Hiyama, E.; Sueda, T. New method for absolute spinal cord ischemia protection in rabbits. J. Vasc. Surg. 2011, 54, 1109–1116. [Google Scholar] [CrossRef] [PubMed]
  116. Topuz, K.; Colak, A.; Cemil, B.; Kutlay, M.; Demircan, M.N.; Simsek, H.; Ipcioglu, O.; Kucukodaci, Z.; Uzun, G. Combined hyperbaric oxygen and hypothermia treatment on oxidative stress parameters after spinal cord injury: An experimental study. Arch. Med. Res. 2010, 41, 506–512. [Google Scholar] [CrossRef] [PubMed]
  117. Alipour, M.; Buonocore, C.; Omri, A.; Szabo, M.; Pucaj, K.; Suntres, Z.E. Therapeutic effect of liposomal-N-acetylcysteine against acetaminophen-induced hepatotoxicity. J Drug Target. 2013, 21, 466–473. [Google Scholar] [CrossRef] [PubMed]
  118. Vecchiarelli, A.; Dottorini, M.; Pietrella, D.; Cociani, C.; Eslami, A.; Todisco, T.; Bistoni, F. Macrophage activation by N-acetyl-cysteine in COPD patients. Chest 1994, 105, 806–811. [Google Scholar] [CrossRef] [PubMed]
  119. Cuzzocrea, S.; Mazzon, E.; Costantino, G.; Serraino, I.; Dugo, L.; Calabrò, G.; Cucinotta, G.; De Sarro, A.; Caputi, A.P. Beneficial effects of N-acetylcysteine on ischaemic brain injury. Br. J. Pharmacol. 2000, 130, 1219–1226. [Google Scholar] [CrossRef] [PubMed]
  120. Cakir, O.; Erdem, K.; Oruc, A.; Kilinc, N.; Eren, N. Neuroprotective effect of N-acetylcysteine and hypothermia on the spinal cord ischemia-reperfusion injury. Cardiovasc. Surg. 2003, 11, 375–379. [Google Scholar] [CrossRef]
  121. Chen, W.F.; Sung, C.S.; Jean, Y.H.; Su, T.M.; Wang, H.C.; Ho, J.T.; Huang, S.Y.; Lin, C.S.; Wen, Z.H. Suppressive effects of intrathecal granulocyte colony-stimulating factor on excessive release of excitatory amino acids in the spinal cerebrospinal fluid of rats with cord ischemia: Role of glutamate transporters. Neuroscience 2010, 165, 1217–1232. [Google Scholar] [CrossRef] [PubMed]
  122. Umebayashi, D.; Natsume, A.; Takeuchi, H.; Hara, M.; Nishimura, Y.; Fukuyama, R.; Sumiyoshi, N.; Wakabayashi, T. Blockade of gap junction hemichannel protects secondary spinal cord injury from activated microglia-mediated glutamate exitoneurotoxicity. J. Neurotrauma 2014, 31, 1967–1974. [Google Scholar] [CrossRef] [PubMed]
  123. Goss, S.L.; Lemons, K.A.; Kerstetter, J.E.; Bogner, R.H. Determination of calcium salt solubility with changes in pH and P(CO(2)), simulating varying gastrointestinal environments. J. Pharm. Pharmacol. 2007, 59, 1485–1492. [Google Scholar] [CrossRef] [PubMed]
  124. Cruz, O.; Kuffler, D.P. Neuroprotection of adult rat dorsal root ganglion neurons by combined hypothermia and alkalinization against prolonged ischemia. Neuroscience 2005, 132, 115–122. [Google Scholar] [CrossRef] [PubMed]
  125. Reyes, O.; Sosa, I.; Kuffler, D.P. Neuroprotection of adult human neurons against ischemia by hypothermia and alkalinization. P. R. Health Sci. J. 2006, 25, 43–50. [Google Scholar] [PubMed]
  126. Kuffler, D.P. Neuroprotection by hypothermia plus alkalinization of dorsal root ganglia neurons through ischemia. Ann. N. Y. Acad. Sci. 2010, 1199, 158–163. [Google Scholar] [CrossRef] [PubMed]
  127. Kuffler, D.P. Combinatorial techniques for enhancing neuroprotection: Hypothermia and alkalinization. Ann. N. Y. Acad. Sci. 2010, 1199, 164–174. [Google Scholar] [CrossRef] [PubMed]
  128. Tang, S.H.; Yu, J.G.; Li, J.J.; Sun, J.Y. Neuroprotective effect of ketamine on acute spinal cord injury in rats. Genet. Mol. Res. 2015, 14, 3551–3556. [Google Scholar] [CrossRef] [PubMed]
  129. Niiyama, S.; Tanaka, E.; Yamamoto, S.; Yasumoto, S.; Kano, T.; Higashi, H. Bupivacaine, but not tetracaine, protects against the in vitro ischemic insult of rat hippocampal CA1 neurons. Neurosci. Res. 2002, 42, 231–241. [Google Scholar] [CrossRef]
  130. Lee, J.R.; Han, S.M.; Leem, J.G.; Hwang, S.J. Effects of intrathecal bupivacaine in conjunction with hypothermia on neuronal protection against transient spinal cord ischemia in rats. Acta Anaesthesiol. Scand. 2007, 51, 60–67. [Google Scholar] [CrossRef] [PubMed]
  131. Horiuchi, T.; Kawaguchi, M.; Kurita, N.; Inoue, S.; Sakamoto, T.; Nakamura, M.; Konishi, N.; Furuya, H. Effects of delta-opioid agonist SNC80 on white matter injury following spinal cord ischemia in normothermic and mildly hypothermic rats. J. Anesth. 2008, 22, 32–37. [Google Scholar] [CrossRef] [PubMed]
  132. Wang, D.; Zhang, J. Effects of hypothermia combined with neural stem cell transplantation on recovery of neurological function in rats with spinal cord injury. Mol. Med. Rep. 2015, 11, 1759–1767. [Google Scholar] [CrossRef] [PubMed]
  133. Colak, A.; Kaya, M.; Karaoğlan, A.; Sağmanligil, A.; Akdemir, O.; Sahan, E.; Celik, O. Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats. Neurocirugia 2009, 20, 245–254. [Google Scholar] [CrossRef]
  134. Sonmez, E.; Kabatas, S.; Ozen, O.; Karabay, G.; Turkoglu, S.; Ogus, E.; Yilmaz, C.; Caner, H.; Altinors, N. Minocycline treatment inhibits lipid peroxidation, preservesspinal cord ultrastructure, and improves functional outcome after traumatic spinal cord injury in the rat. Spine 2013, 38, 1253–1259. [Google Scholar] [CrossRef] [PubMed]
  135. Impellizzeri, D.; Mazzon, E.; Paterniti, I.; Esposito, E.; Cuzzocrea, S. Effect of fasudil, a selective inhibitor of Rho kinase activity, in the secondaryinjury associated with the experimental model of spinal cord trauma. J. Pharmacol. Exp. Ther. 2012, 343, 21–33. [Google Scholar] [CrossRef] [PubMed]
  136. White, R.J.; Albin, M.S.; Harris, S.; Yashon, D. Spinal cord injury: Sequential morphology and hypothermic stabilization. Surg. Fonon 1969, 20, 432–434. [Google Scholar]
  137. Batchelor, P.E.; Skeers, P.; Antonic, A.; Wills, T.E.; Howells, D.W.; Macleod, M.R.; Sena, E.S. Systematic review and meta-analysis of therapeutic hypothermia in animal models of spinal cord injury. PLoS ONE 2013, 8, e71317. [Google Scholar] [CrossRef] [PubMed]
  138. Inoue, S.; Mori, A.; Shimizu, H.; Yoshitake, A.; Tashiro, R.; Kabei, N.; Yozu, R. Combined use of an epidural cooling catheter and systemic moderatehypothermia enhances spinal cord protection against ischemic injury in rabbits. J. Thorac. Cardiovasc. Surg. 2013, 146, 696–701. [Google Scholar] [CrossRef] [PubMed]
  139. Bazley, F.A.; Pashai, N.; Kerr, C.L.; All, A.H. The effects of local and general hypothermia on temperature profiles of the central nervous system following spinal cord injury in rats. Ther. Hypoth. Temp. Manag. 2014, 4, 115–124. [Google Scholar] [CrossRef] [PubMed]
  140. Tsutsumi, K.; Ueda, T.; Shimizu, H.; Hashizume, K.; Yozu, R. Effect of delayed induction of postischemic hypothermia on spinal cord damage induced by transient ischemic insult in rabbits. Jpn. J. Thorac. Cardiovasc. Surg. 2004, 52, 411–418. [Google Scholar] [CrossRef] [PubMed]
  141. Kabon, B.; Bacher, A.; Spiss, C.K. Therapeutic hypothermia. Best Pract. Res. Clin. Anaesthesiol. 2003, 17, 551–568. [Google Scholar] [CrossRef]
  142. Che, D.; Li, L.; Kopil, C.M.; Liu, Z.; Guo, W.; Neumar, R.W. Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Crit. Care Med. 2011, 39, 1423–1430. [Google Scholar] [CrossRef] [PubMed]
  143. Karamouzian, S.; Akhtarshomar, S.; Saied, A.; Gholamhoseinian, A. Effects of methylprednisolone on neuroprotective effects of delay hypothermia on spinal cord injury in rat. Asian Spine J. 2015, 9, 1–6. [Google Scholar] [CrossRef] [PubMed]
  144. Wells, J.D.; Hansebout, R.R. Local hypothermia in experimental spinal cord trauma. Surg. Neurol. 1978, 10, 200–204. [Google Scholar] [PubMed]
  145. Duz, B.; Kaplan, M.; Bilgic, S.; Korkmaz, A.; Kahraman, S. Does hypothermic treatment provide an advantage after spinal cord injury until surgery? An experimental study. Neurochem. Res. 2009, 34, 407–410. [Google Scholar] [CrossRef] [PubMed]
  146. Horiuchi, T.; Kawaguchi, M.; Kurita, N.; Inoue, S.; Nakamura, M.; Konishi, N.; Furuya, H. The long-term effects of mild to moderate hypothermia on gray and white matter injury after spinal cord ischemia in rats. Anesth. Analg. 2009, 109, 559–566. [Google Scholar] [CrossRef] [PubMed]
  147. Maeda, T.; Mori, K.; Shiraishi, Y.; Tatebayashi, K.; Kawai, Y. Selective occlusion of lumbar arteries as a spinal cord ischemia model in rabbits. Jpn. J. Physiol. 2003, 53, 9–15. [Google Scholar] [CrossRef] [PubMed]
  148. Shibuya, S.; Miyamoto, O.; Janjua, N.A.; Itano, T.; Mori, S.; Norimatsu, H. Post-traumatic moderate systemic hypothermia reduces TUNEL positive cells following spinal cord injury in rat. Spinal Cord 2004, 42, 29–34. [Google Scholar] [CrossRef] [PubMed]
  149. Strauch, J.T.; Lauten, A.; Spielvogel, D.; Rinke, S.; Zhang, N.; Weisz, D.; Bodian, C.A.; Griepp, R.B. Mild hypothermia protects the spinal cord from ischemic injury in a chronic porcine model. Eur. J. Cardiothorac. Surg. 2004, 25, 708–715. [Google Scholar] [CrossRef] [PubMed]
  150. Vipin, A.; Kortelainen, J.; Al-Nashash, H.; Chua, S.M.; Thow, X.; Manivannan, J.; Astrid Thakor, N.V.; Kerr, C.L.; All, A.H. Prolonged local hypothermia has no long-term adverse effect on the spinal cord. Ther. Hypoth. Temp. Manag. 2015. [Google Scholar] [CrossRef] [PubMed]
  151. Mclntyre, L.A.; Fergusson, D.A.; Hébert, P.C.; Moher, D.; Hutchison, J.S. Prolonged therapeutic hypothermia after traumatic brain injury in adults: A systematic review. JAMA 2003, 289, 2992–2999. [Google Scholar] [CrossRef] [PubMed]
  152. Povlishock, J.T.; Wei, E.P. Posthypothermic rewarming considerations following traumatic brain injury. J. Neurotrauma 2009, 26, 333–340. [Google Scholar] [CrossRef] [PubMed]
  153. Suehiro, E.; Povlishock, J.T. Exacerbation of traumatically induced axonal injury by rapid posthypothermic rewarming and attenuation of axonal change by cyclosporin A. J. Neurosurg. 2001, 94, 493–498. [Google Scholar] [CrossRef] [PubMed]
  154. Suehiro, E.; Ueda, Y.; Wei, E.P.; Kontos, H.A.; Povlishock, J.T. Posttraumatic hypothermia followed by slow rewarming protects the cerebral microcirculation. J. Neurotrauma 2003, 20, 381–390. [Google Scholar] [CrossRef] [PubMed]
  155. Ueda, Y.; Suehiro, E.; Wei, E.P.; Kontos, H.A.; Povlishock, J.T. Uncomplicated rapid posthypothermic rewarming alters cerebrovascular responsiveness. Stroke 2004, 35, 601–606. [Google Scholar] [CrossRef] [PubMed]
  156. Thompson, H.J.; Kirkness, C.J.; Mitchell, P.H. Hypothermia and rapid rewarming is associated with worse outcome following traumatic brain injury. J. Trauma Nurs. 2010, 17, 173–177. [Google Scholar] [CrossRef] [PubMed]
  157. Lavinio, A.; Timofeev, I.; Nortje, J.; Outtrim, J.; Smielewski, P.; Gupta, A.; Hutchinson, P.J.; Matta, B.F.; Pickard, J.D.; Menon, D.; et al. Cerebrovascular reactivity during hypothermia and rewarming. Br. J. Anaesth. 2007, 99, 237–244. [Google Scholar] [CrossRef] [PubMed]
  158. Yu, C.G.; Jagid, J.; Ruenes, G.; Dietrich, W.D.; Marcillo, A.E.; Yezierski, R.P. Detrimental effects of systemic hyperthermia on locomotor function and histopathological outcome after traumatic spinal cord injury in the rat. Neurosurgery 2001, 49, 152–159. [Google Scholar] [PubMed]

Share and Cite

MDPI and ACS Style

Wang, J.; Pearse, D.D. Therapeutic Hypothermia in Spinal Cord Injury: The Status of Its Use and Open Questions. Int. J. Mol. Sci. 2015, 16, 16848-16879. https://doi.org/10.3390/ijms160816848

AMA Style

Wang J, Pearse DD. Therapeutic Hypothermia in Spinal Cord Injury: The Status of Its Use and Open Questions. International Journal of Molecular Sciences. 2015; 16(8):16848-16879. https://doi.org/10.3390/ijms160816848

Chicago/Turabian Style

Wang, Jiaqiong, and Damien D. Pearse. 2015. "Therapeutic Hypothermia in Spinal Cord Injury: The Status of Its Use and Open Questions" International Journal of Molecular Sciences 16, no. 8: 16848-16879. https://doi.org/10.3390/ijms160816848

Article Metrics

Back to TopTop