Role of Induced Hypothermia in Thoracoabdominal Aortic Aneurysm Surgery

Abstract

For more than 50 years, hypothermia has been used in aortic surgery as a tool for neuroprotection. Hypothermia has been introduced into thoracoabdominal aortic aneurysm (TAAA) surgery by many cardiovascular centers to protect the body's organs, including the spinal cord. Numerous publications have shown that hypothermia can prevent immediate and delayed motor dysfunction after aortic cross-clamping. Here, we reviewed the historical application of hypothermia in aortic surgery, role of hypothermia in preclinical studies, cellular and molecular mechanisms by which hypothermia confers neuroprotection, and the role of systemic and regional hypothermia in clinical protocols to reduce and/or eliminate the devastating consequences of ischemic spinal cord injury after TAAA repair.

Introduction

Paraplegia, one of the most feared complications of thoracoabdominal aortic aneurysm (TAAA) surgery, causes physical disability and shortens long-term survival after surgery. Unfortunately, this is not a rare complication of TAAA surgery, with incidence rate ranging from 1% to 23% (Cambria et al., 1997; Coselli et al., 2008; Greenberg et al., 2008; Sundt et al., 2011). Neuronal dysfunction that occurs subsequent to aortic aneurysm repair (even after successful surgeries) is a consequence of several factors, such as interruption of blood flow, increased cerebrospinal fluid (CSF) pressure, reperfusion injury, and postoperative hypotension. The increase in CSF pressure during aortic cross-clamping is secondary to increased CSF production and venous pressure, which impairs the already-reduced cord perfusion (Piano and Gewertz, 1990; Gelman, 1995).

There are two main approaches to protecting the spinal cord during TAAA repair surgery. The first involves preservation of regional blood supply and increasing the ischemic tolerance of the spinal cord during aortic cross-clamping. This approach focuses on maximizing effective collateral perfusion by reimplantation of intercostal arteries, left heart bypass grafting, or CSF drainage (Coselli and LeMaire, 1999; Coselli et al., 2002; Griepp and Griepp, 2007). The second approach involves induced hypothermia (systemic and regional) and/or use of neuroprotective agents (Acher et al., 1994; Kouchoukos et al., 1995; Safi et al., 1998).

The induction of systemic hypothermia is a reliable method for conferring neuroprotection and is used by many cardiovascular surgeons. It acts by decreasing oxygen consumption, reducing tissue metabolism, inhibiting the synthesis and release of excitatory neurotransmitters, and eventually restraining the inflammatory response caused by ischemia (Fig. 1) (Busto et al., 1989; Martelli et al., 2002). However, systemic hypothermia also can be associated with adverse events such as impairment of coagulation, increased risk of infection, electrolyte imbalance, cardiac arrhythmia, and pulmonary dysfunction (Rohrer and Natale, 1992; Kurz et al., 1996).

FIG. 1.

Hypothermia affects several mechanisms of ischemic neuronal injury and repair, including (1) maintenance of cell membrane homeostasis; (2) excitotoxicity; (3) oxidative stress subsequent to reperfusion; (4) increasing expression of neurotrophic genes and genes associated with cell survival (e.g., Bcl-2) while also downregulating proinflammatory and apoptotic genes. (5) Blocking apoptosis by altering cellular levels of p53 and Bcl-2, increase signaling via ERK and Akt and increase secretion of neurotrophins. (6) Attenuating microglial activation and parallel inflammatory cascades.

Conversely, regional hypothermia has fewer side effects, providing neuroprotection without systemic complications (Cambria et al., 1997). It can be applied by infusion of iced saline into the epidural space. However, epidural cooling can cause a sharp increase in CSF pressure, which may attenuate spinal cord perfusion (Meylaerts et al., 2000; Yoshitake et al., 2007). Although systemic or regional hypothermia has some drawbacks, it is still the most frequently used neuroprotective intervention against ischemic spinal cord injury (ISCI) after TAAA surgery.

In this article, we review the history of induced hypothermia in aortic surgery, mechanism of hypothermia-mediated neuroprotection, experimental animal studies, and clinical reports regarding hypothermia application in TAAA surgery. We conducted a PubMed search using keywords such as hypothermia, therapeutic hypothermia, systemic hypothermia, regional hypothermia, spinal cord ischemia, neuroprotection, TAAA surgery, aortic arch, and endovascular repair. We summarized the gathered information and presented in this article to reflect the current state of induced hypothermia in TAAA repair surgery.

History

Induced hypothermia has been the mainstay of spinal cord protection since the inception of aortic aneurysm surgery. Hypothermia has been shown to protect spinal cord function during periods of aortic occlusion in other experimental studies (Pontius et al., 1954; Owens et al., 1955; Parkins et al., 1955). Thereafter, regional hypothermia was proposed as a technique to prevent ISCI. In the early 1960s, Negrin and Klauber used iced saline perfusion through an epidural catheter to protect motor neurons during thoracic aorta cross-clamping (Negrin and Klauber, 1960). In 1975, Hansebout et al. used regional hypothermia to minimize damage and promote recovery after experimental spinal cord compression injury (Hansebout et al., 1975). In the early 1990s, several publications documented success with regional spinal cord cooling in animal models (Allen et al., 1994; Salzano et al., 1994). In 1993, Tabayashi et al. and Marsala et al. reported that epidural cooling was neuroprotective in a canine model of ISCI (Tabayashi et al., 1993; Marsala et al., 1993). Davison et al. evaluated this technique in a clinical study in 1994 and found that epidural cooling was effective in preventing ISCI in eight patients undergoing thoracic or TAAA repair (Davison et al., 1994). In 1995, Kouchoukos applied hypothermic bypass with circulatory arrest during descending thoracic and TAAA surgery (Kouchoukos et al., 1995).

Deep hypothermia was also used to protect the brain during aortic arch surgery (Griepp et al., 1975). In the 1980s, in addition to using systemic hypothermia, anterograde or retrograde cerebral perfusion was added as a supplement to the hypothermia brain protection strategy (Soma et al., 1982). Over the last 15 years in the clinic, many adjuncts have been introduced into the spinal cord protection protocols during TAAA repair, including CSF drainage, distal aortic perfusion, evaluation of motor-evoked potentials (MEPs) and sensory-evoked potentials (Safi et al., 1996; de Haan et al., 1997; Coselli and LeMaire, 1999; van Dongen et al., 2001; Coselli et al., 2002), sequential clamping, prevention of retrograde bleeding from segmental arteries, cardiovascular stability (Shimizu and Yozu, 2011), and imaging of the spinal cord blood supply (Nijenhuis et al., 2007). Still, systemic and/or regional induced hypothermia remains one of the most effective methods of neuroprotection in most cardiovascular surgery centers.

Mechanisms of Neuroprotection

Hypothermia interrupts several mechanisms of neuronal ischemic injury (Fig. 1), which include, but are not limited to, excitotoxicity, oxidative stress, gene expression, microRNA response, apoptosis, and inflammation.

Effects of hypothermia on metabolism

The relationship between cerebral metabolic rate and temperature was investigated in a number of experimental studies by Michenfelder (Michenfelder and Theye, 1968; Michenfelder and Milde, 1991, 1992). He found that hypothermia could affect the neurological functions through alteration of biochemical reactions in the neurons, in a complex relationship. On the other hand, Rosomoff and Holaday (1954) showed a linear relationship between cerebral oxygen consumption and a decrease in body temperature. Hypothermia slows the cellular metabolic rate by 5%–7% for every 1°C drop in body temperature (Michenfelder and Milde, 1992; Svyatets et al., 2010). It decreases glucose and oxygen consumption after reperfusion and maintains high levels of oxygen in the blood (Erecinska et al., 2003). Although high oxygen levels may pose a risk during reperfusion (Lin et al., 2008), oxygen is needed to maintain oxidative metabolism in neurons. Hypothermia also helps maintain cell membrane biophysics. This is accomplished by (1) minimizing or reducing intracellular Ca⁺⁺ influx, which in turn limits mitochondrial dysfunction (Eguchi et al., 1997); (2) re-establishing K⁺ gradients (Sick et al., 1999); and (3) recovering Ca⁺⁺/calmodulin-dependent protein kinase activity (Hu et al., 1995).

Effects of hypothermia on excitotoxicity

Because the synthesis and uptake of neurotransmitters are temperature-dependent processes, glutamate excitotoxicity could be mitigated by hypothermia (Kataoka and Yanase, 1998). Various animal studies have shown that key processes of excitotoxicity (e.g., accumulation of glutamate or its coagonist glycine) can be interrupted or blocked by hypothermia (Busto et al., 1989; Baker et al., 1991; Rokkas et al., 1995; Globus et al., 1995a; Winfree et al., 1996). On the other hand, Yamamoto et al. (1999) showed, in an experimental study, that neuroprotection effect induced by mild hypothermia cannot be linked to reduction of glutamate release. More research is needed to clarify this controversy.

Effects of hypothermia on oxidative stress

The inflammatory reactions that occur secondary to reperfusion injury are associated with enhanced generation of free radicals, such as reactive oxygen species, which cause DNA damage and induce apoptosis. Globus et al. (1995b) were the first group to show that free radical-induced neuronal injury can be interrupted by hypothermia. In fact, a linear correlation exists between reactive oxygen species production and temperature changes (Novack et al., 1996). Several studies have shown that hypothermia attenuates reactive oxygen species formation and protects cells from oxidative stress (Maier et al., 2002; Horiguchi et al., 2003).

Effects of hypothermia on gene expression

The neuroprotective mechanisms of hypothermia extend to modification of neuronal gene expression. Under hypothermic conditions, beneficial genes (cell survival and trophic genes) are upregulated (Boris-Moller et al., 1998; Vosler et al., 2005; Zhao et al., 2005), while proinflammatory and pro-apoptotic genes are downregulated or repressed (Xu et al., 2002; Van Hemelrijck et al., 2005). Such changes in gene expression could be linked to upregulation of cold shock proteins (Han and Yenari, 2007), or to specific transcription factors that are temperature sensitive (Hicks et al., 2000; Han et al., 2003). Temperature-dependent regulation of gene expression also has been documented in inflammatory cells. Sonna et al. (2006) found that several heat shock proteins (Hsps) were decreased in leukocytes exposed to moderate hypothermia (32°C for 24 hours). This could limit the function and survival of inflammatory cells responding to ischemia/reperfusion injury.

In our experience, ischemia reperfusion injury of spinal cord is associated with a significant increase in the Hsp70 level in the CSF of dogs after aortic cross-clamping (Awad et al., 2008). Whether hypothermia can reduce Hsp70 after spinal cord ischemia has not been tested in ISCI; however, according to data from a recent experiment in a model of cerebral ischemia, hypothermia was able to decrease Hsp70 protein and gene expression (Tirapelli et al., 2010).

Recently, the triangular relationship between microRNA, target gene expression, and hypothermia has been explored in a number of studies (Dresios et al., 2005; Pilotte et al., 2011; Truettner et al., 2011). Dresios et al. (2005) studied the effect of Rbm 3 expression (member of a small, highly conserved family of RNA) on global protein expression by changing the microRNA levels under normal and hypothermic conditions. In addition, Pilotte et al. (2011) found that alteration of microRNA expression by Rbm3 is a temperature-dependent process that can be added to the scope of hypothermia effect on cellular events. Truettner et al. (2011) showed that mild hypothermia (33°C) alters the microRNA response in a rat model of traumatic brain injury. These findings point to other underlying mechanisms of hypothermia-mediated neurprotection though microRNA. This will open a new field of research to further address the possibility of manipulating harmful microRNA expression by induced hypothermia.

Effects of hypothermia on apoptosis

Hypothermia can interrupt the apoptotic pathway, thereby preventing programmed cell death (Inamasu et al., 2000). In a rabbit model of spinal cord ischemia, hypothermia was shown to inhibit nerve cell apoptosis by altering expression of p53 (tumor suppressor protein) and Bcl-2 (apoptosis regulatory protein) (Wang et al., 2005). Hypothermia may also augment cell survival pathways mediated by ERK (extracellular signal regulated kinase) (D'Cruz et al., 2005), Akt (protein kinase B) (Zhao et al., 2005), and upregulation of the anti-apoptotic protein Bcl-2 (Prakasa et al., 2000; Zhang et al., 2001). Hypothermia can also increase expression of trophic factors (Boris-Moller et al., 1998; Schmidt et al., 2004). In experimental models of cardiac arrest, induction of hypothermia was associated with increased secretion of neutrophins, including glial-derived neurotrophic factor and brain-derived neurotrophic factor (Boris-Moller et al., 1998; D'Cruz et al., 2002; Vosler et al., 2005). Hypothermia may also inhibit other aspects of apoptosis, including cytochrome c release (Yenari et al., 2002), Fas (Phanithi et al., 2000), and activation of caspases (e.g., caspases 3 and 8) (Wang et al., 2000; Fukuda et al., 2001).

Effects of hypothermia on inflammation

Several studies have tested the ability of hypothermia to attenuate postischemic inflammation (Aibiki et al., 1999; Kimura et al., 2002; Dietrich et al., 2004). Hypothermia can delay neutrophil influx, suppress activation of microglia, and inhibit release of inflammatory mediators (e.g., cytokines) (Si et al., 1997; Ishikawa et al., 1999; Zheng and Yenari, 2004). In a recent in vitro study, hypothermia was shown to reduce microglial proliferation and downregulate expression of tumor necrosis factor-alpha and monocyte chemotactic protein-1, two proinflammatory mediators. Mild hypothermia was shown to inhibit IκB kinase, an enzyme responsible for phosphorylating IκBα, and an inhibitor of NFκB. Phosphorylated IκBα dissociates from nuclear localization sequences on NFκB, resulting in NFκB-dependent transcription and the onset of inflammatory gene transcription (Han et al., 2003). In addition, degradation of IκBα was reduced and delayed by hypothermia (Diestel et al., 2010).

Conversely, hypothermia can activate microglia, increasing their phagocytic capabilities and their ability to synthesize and release anti-inflammatory cytokines, including interleukin (IL)-1ra and IL-10 (Diestel et al., 2010). Previous studies have shown that IL-10 can protect neurons against glutamate excitotoxicity or ischemic/hypoxic injury (Dietrich et al., 1999; Bachis et al., 2001), and that the neurotoxic effects of IL-1 can be blocked by IL-1ra (Dinarello, 1997). Thus, hypothermia may actively induce neuroprotection via anti-inflammatory mechanisms (Hsieh et al., 2009).

Endothelial cells play a pivotal role in inflammation, acting as gatekeepers for circulating leukocytes. Moreover, maintenance of endothelial cell integrity is critical for minimizing blood–brain barrier injury, hemorrhage, and edema. Hypothermia has cytoprotective effects on endothelial cells. Six hours of mild hypothermia upregulates Bcl-2, a survival protein, and increases IL-6 secretion by endothelial cells (Diestel et al., 2008). Hypothermia also blocks the pro-apoptotic effects of tumor necrosis factor-alpha on human endothelia (Yang et al., 2010).

Induced Hypothermia in Experimental Studies of ISCI

We have recently reviewed the available data on various animal models that have been used for ISCI experimental studies in a book chapter “Animal Models of Spinal Cord Ischemia” (Animal Models in Spinal Cord Repair, edited by Hakan Aldskogius, M.D., Ph.D.). A consistent feature of most models is aortic cross-clamping that simulates the ischemic events that occur during TAAA repair. Different approaches and degrees of hypothermia were applied in some ISCI models to test the feasibility and efficacy of induced hypothermia as a tool of neuroprotection (Table 1).

Table 1.

Application of Hypothermia in Animal Models of Ischemic Spinal Cord Injury

Study	Model of ISCI	Hypothermia approach	Effect of hypothermia on the neurological outcomes
Awad et al. (2010)	Mouse model ACC (different intervals)	Systemic hypothermia Core temp (33°C) Temperature-controlled surgical platform was used to induce hypothermia	Delayed hind limb paralysis and better survival in the hypothermic group compared to normothermic mice
Kang et al. (2010)	Mouse model ACC (8 min)	Systemic hypothermia Mice were cooled passively to 34°C (hypothermic group) Normothermic group (38°C)	Normothermic group: severe neurologic deficit Hypothermic group: Transient, mild neurologic deficit
Ishikawa et al. (2009)	Pig model ACC (45 min)	Regional hypothermia Perfusion of cold saline (4°C) into the epidural space Rectal temp: 36°C Epidural temp: 24°C–26°C Subarachnoid temp: 26°C–28°C	↑ Tarlov scores Normal appearing motor neurons ↑ Expression of inducible nitric oxide synthase (iNOS) in spinal cord
Yoshitake et al. (2007)	Pig model ACC (45 min)	Regional hypothermia Perfusion of cold saline (4°C) into the epidural space Rectal temp: 36°C Epidural temp: 21.5°C–2.5°C	↑ Tarlov scores ↓ Duration of total loss of SSEPs ↑ Number of intact motor neurons
Isaka et al. (2006)	Rabbit model ACC (12 min)	Regional hypothermia G I: Normothermia (cord temp: 38°C) G II: Perfusion of cold saline (3°C) into the isolated aortic segment (Cord temp: 36°C) G III: As G II+a cooling pad placed longitudinally along the vertebral column (cord temp: 33°C–34°C)	Tarlov scores and histopathologic analysis in G III were significantly superior to those of G I and II The rabbits in G III were protected from paraplegia
Wang et al. (2005)	Rabbit model ACC (30 min)	Regional hypothermia Perfusion of iced saline into the epidural space Cord temp: 26°C–28°C	↓ Nerve cell apoptosis and necrosis ↓ p53 expression and ↑ bcl-2 expression→neuroprotection
Mori et al. (2005)	Pig model ACC (30 min)	Regional hypothermia Perfusion of cold water (4°C) into the epidural space	↓ Duration of postischemic loss of SSEPs Better neurologic function and histologic characteristics in cooling group No↑of intrathecal pressure
Strauch et al. (2004)	Pig model ACC (different intervals)	Systemic hypothermia Mild hypothermia (32°C) induced by covering animals with cold packs made from artificial refrigerants	Animals tolerated 50 min of ischemia without evidence of neurologic injury Recovery of normal motor function after 60 min of ischemia, but developed paraplegia 36 h later
Maeda et al. (2003)	Rabbit model Selective occlusion of lumbar arteries (different intervals)	Systemic hypothermia Mild hypothermia (35°C) Used cooling pad under chest and abdomen of the animals	Preserved hind limb motor function Preserved large number of motor neurons in the anterior horns
Martelli et al. (2002)	Rabbit model ACC (40 min)	Regional hypothermia Pidural infusion of iced saline solution at 17°C (G 1); 24°C (G 2); 32°C (G 3); 39°C (G 4)	Rabbits in G 1, 2, and 3 were neurologically intact Minimal histopathology in G 1 and 2 Low-grade ischemic changes in G 3 in the low-lumbar and mid-lumbar segments; severe ischemic injury occurred at the same segments in G 4
Ross et al. (2000)	Pig model ACC (30 min)	Regional hypothermia G I: Normothermia G II: Retrograde perfusion of the paravertebral veins with hypothermic (4°C) saline solution G III: Hypothermic adenosine solution in a similar fashion	↑ Tarlov scores SSEPs returned to 85% of baseline in G III and 90% of baseline in G II compared with only 10% of baseline in G I Preserved neurological function in: 5/6 animals in G III, 1/6 animal in G II, and 0/6 in G I
Gonzalez-Fajardo et al. (1996)	Rabbit model ACC (30 min)	Regional hypothermia Epidural perfusion of iced normal saline solution (4°C) Rectal temp: 35.1°C±0.8 °C	No paraplegia after 24 h After 48 h: 1/10 animal had weakness of hind limb, while all normothermic animals had irreversible paraplegia at 24 and 48 h Transient↑in CSF pressure
Rokkas et al. (1995)	Pig model ACC (60 min)	Systemic hypothermia Profound hypothermia induced with CPB Rectal temp: 20°C	↓ Release of glutamate, aspartate, glycine and H-aminobutyric in the ischemic spinal cord
Salzano et al. (1994)	Pig model ACC (30 min)	Regional hypothermia Perfusion of subarachnoid space with cold saline (4°C) Cord temperature: <20°C Rectal temp: 35°C–38°C	All animals (n=8) in control group had paraplegia after the procedure. 1/8 animal in the hypothermic group had paraplegia after the procedure.
Marsala et al. (1993)	Dog model ACC (40 min)	Regional hypothermia Epidural perfusion of iced normal saline solution (5°C) Cord temp: 28.5°C±1.3°C Core temp: 35.7°C±1.1°C	Two days after the procedure: 4/8 dogs in the normothermic group had complete paraplegia, 1/8 dog had partial recovery in the hypothermic group. Histological analysis was correlated with neurological outcomes
Tabayashi et al. (1993)	Dog model G 1 and G 2: ACC (60 min) G 3: ACC (120 min)	Regional hypothermia G 1: Normothermia G 2 and 3: Epidural perfusion of chilled saline solution (10.5°C±1.9 °C) Cord temp: 26°C–31°C Esophageal temp: G 1 (33.5°C±1.2°C), G 2 (32.6°C±1.l °C), and G 3 (32.1°C±1.O°C)	Seven days after the procedure: 4 dogs in G 1 had spastic paraplegia, 1 dog was unable to walk normally in G 2, and all dogs were normal in G 3 Histological analysis was correlated with neurological outcomes
Vanicky et al. (1993)	Rabbit model ACC (different intervals)	Regional hypothermia Epidural perfusion of iced saline (5°C) Cord temp: (<15°C)	After 60 min of ischemia: Hypothermic group showed full neurological recovery, while all normothermic animals had paraplegia Electrophysiological and histological observations were correlated with the neurological findings
Rokkas et al. (1993)	Baboon model ACC (60 min)	Systemic hypothermia G 1: Normothermia (rectal temp 37°C) G 2: Profound hypothermia induced by CPB–Rectal temp: (15°C)	G I: Six animals were paraplegic and two were paraparetic G II: All six animals that survived were neurologically intact (p=0.0002)
Naslund et al. (1992)	Rabbit model Aortic ligation (21 min)	Systemic hypothermia Submersion in iced bath Rectal temp: (20°C) Animals treated with anesthetic drugs with or without systemic hypothermia	Hypothermia with any anesthetic drug was completely protective and reduced neurologic deficits to 0% compared with 91% in controls (p<0.05)
Colon et al. (1987)	Pig model Control G: ACC (30 min) Cooling G: ACC (30 min or 45 min)	Regional hypothermia Perfusion cooling of isolated segment of the thoracic aorta with cold blood (25.5°C±3.75°C) Cord temp: (30.8°C±0.76°C)	Control G: 4/5 had complete paraplegia–1/5 had severe spastic paraplegia Cooling G: Preserved hind limb motor function in all animals (n=10) Postmortem pathological analysis of spinal cords was correlated with the neurological findings
Vacanti and Ames (1984)	Rabbit model Aortic ligation (different intervals)	Systemic hypothermia Reducing ambient temp under general anesthesia Core temp: (34°C–36.8°C) A group of animals was treated with intravenous administration of Mg⁺⁺ prior to ischemia	Cooler animals showed uniformly better recovery than warmer ones Combination of hypothermia and Mg⁺⁺ extended the survivable period of ischemia ∼3-fold
Coles et al. (1983)	Dog model ACC (30 min)	Regional hypothermia Perfusion cooling of isolated segment of the thoracic aorta with cold lactated Ringer's solution (50 cc/kg at 5°C)	Significant reduction in the incidence of neurological dysfunction at 24 h and 7 days (p<0.05)

ACC, aortic cross-clamping; CPB, cardiopulmonary bypass; G, group; iNOS, inducible nitric oxide synthase; SSEPs, somatosensory-evoked potentials;. Temp, temperature; Tarlov scores, scale for assessment of neurological motor function; CSF, cerebrospinal fluid; ISCI, ischemic spinal cord injury.

Mild systemic hypothermia

In a study in pigs, Strauch et al. (2004) were able to double the ischemic tolerance of the spinal cord by performing aortic cross-clamping with mild hypothermia (32°C). Neurological functions were intact in animals that underwent aortic cross-clamping for 50 minutes under mild hypothermia, while animals subjected to the same procedure under normothermic conditions developed paraplegia after 30 minutes of aortic cross-clamping. Interestingly, animals that were neurologically intact after 60 minutes of aortic cross-clamping with mild hypothermia did develop delayed onset paraplegia, suggesting that hypothermia slows rather than inhibits mechanisms of tissue injury.

Profound systemic hypothermia

Rokkas et al. (1993) studied the effect of profound hypothermia (15°C) on the neurological outcomes of a primate model of ISCI, in which systemic hypothermia was accomplished through cardiopulmonary bypass (CPB). They found that motor function was preserved in all animals subjected to 60 minutes of experimental ischemia with hypothermia. Animals that were subjected to the same ischemic insult under normothermic (37°C) conditions became paraplegic or paraparetic. Two years later, the same group used profound hypothermia (20°C) in an experimental study of ISCI in pigs to evaluate the effects of hypothermia on changing extracellular levels of excitatory neurotransmitters (Rokkas et al., 1995). Within 60 minutes of ischemia, the concentration of excitatory amino acids was significantly reduced compared to basal (nonischemic) levels in pigs that were hypothermic. In normothermic animals (37°C), excitatory amino acid concentrations remained high in the extracellular space even after reperfusion.

Systemic hypothermia and delayed paralysis

Recently, we developed a mouse model of ISCI in which aortic cross-clamping was performed under conditions of normothermia or systemic hypothermia (33°C). Using this approach, normothermic mice developed immediate paralysis after reperfusion, whereas mice maintained at 33°C during cross-clamping and reperfusion developed paralysis only after a delay of 40–48 hours (Awad et al., 2010). A similar model developed in an independent lab confirmed that aortic cross-clamping performed under normothermia (37.0°C±0.5°C) causes rapid (within 1 hour) hind limb dysfunction (Wang et al., 2010).

In a third model, Kang et al. (2010) studied the effect of hypothermia (34°C) on ischemia-perfusion injury in a mouse model of ISCI. At 24 hours before reperfusion, only mild and transient neurological deficit took place in mice subjected to ischemia under hypothermic conditions. However, at 48 hours, reperfusion delayed onset ISCI developed in half of the mice in the hypothermic group. In addition, they measured markers of systemic inflammation in various organs at 24 and 48 hours of reperfusion. There was no correlation between the neurological deficits and the inflammatory markers in other organs. The authors concluded that the delayed onset ISCI is due to a local event, not as a part of systemic inflammatory response to ischemia.

From these data in preclinical models, we conclude that hypothermia prevents or slows the early phase of ischemic injury through one or more of the mechanisms described above; however, it does not completely prevent delayed neuronal damage. Whether modification of the degree and duration of hypothermia can prevent delayed ischemic injury requires further investigation.

Regional hypothermia

On the topic of regional hypothermia in preclinical studies, Negrin and Klauber applied epidural cooling experimentally for the first time in 1960 to prevent ISCI during aortic cross-clamping (Negrin and Klauber, 1960). Thereafter, regional hypothermia was applied in different experimental studies by perfusion of cold blood or crystalloids into the segmental vessels supplying the spinal cord (Coles et al., 1983; Colon et al., 1987; Allen et al., 1994), or by infusion of iced saline into the subarachnoid (Berguer et al., 1992; Wisselink et al., 1994), or epidural space (Marsala et al., 1993; Tabayashi et al., 1993; Vanicky et al., 1993; Gonzalez-Fajardo et al., 1996). To identify the optimal temperature for spinal cord protection, Martelli et al. (2002) cooled rabbit spinal cords to different degrees via epidural infusion of cold saline. Cooling the spinal cord to 17°C, 24°C or 32°C prevented neurological deficits after 40 minutes of induced ischemia, while infusion of saline at 39°C resulted in paralysis. Histological examination revealed complete necrosis of the anterior horn cells in the spinal cord with epidural cooling at 39°C and incomplete necrosis at 34°C. No histophatologic changes were observed with EC at 17°C and 24°C.

Clearly, additional work is needed in preclinical models to optimize protocols for neuroprotective hypothermia. For example, comparative studies are needed in clinically relevant (large animal) models in order to compare the efficacy of systemic (mild, moderate, and profound) versus regional (infusion of cold blood into vessels supplying spinal cord, or infusion of iced saline into the epidural space or the subarachnoid space) hypothermia with and without mechanical support. In summary, studies of this type should reveal the safest and most efficacious induced hypothermia protocols and should lead to newer institutional strategies to prevent paralysis after TAAA repair surgery.

Induced Hypothermia in TAAA Repair Surgery

The trend of paraplegia incidence after TAAA has significantly declined over the last 25 years, especially after incorporating hypothermic perfusion with CSF drainage along with increasing arterial perfusion and use of neurochemical protection (Shimizu and Yozu, 2011). The observed/expected (O/E) ratios of paraplegia decreased in most clinical reports from ∼1 to 0.25 or less in the last decade (Acher and Wynn, 2010). Over the past 40 years, the Baylor Vascular Center in Houston has reported a progressive decline in the paraplegia rate from 16% (O/E 1.0; ∼1960–1970s) to ∼3.8% (O/E 0.22) (Svensson et al., 1993; de Haan et al., 1997; Coselli et al., 2008). A similar reduction also has been reported in other vascular surgery centers. For example, since the introduction of these strategies in the mid-1980s, the paraplegia rate at University of Wisconsin decreased from 25% (O/E 1.04) to 3.3% (O/E 0.18) (Acher and Wynn, 2010).

Despite these advances, ∼22% of patients undergoing type II repair (type II includes aneurysms involving most of the descending thoracic and most of the abdominal aorta) still become paraplegic (Greenberg et al., 2008). Those patients suffer from severe long-term physical disability and have a shorter lifespan (Svensson et al., 1993). Since 1956 when DeBakey first completed a successful TAAA repair with an aortic homograft, many adjunct therapies have been used to minimize ISCI (Creech et al., 1956). The basic approach to protect the spinal cord has been to facilitate distal aortic perfusion during aortic cross-clamping with a temporary shunt. This passive perfusion approach has since been replaced with active CPB. Other adjuncts include the use of (1) preoperative spinal angiography, (2) reattachment of the intercostal artery, (3) CSF drainage, (4) increasing ischemic tolerance with pharmacological adjuncts (e.g., naloxane, steroids, and barbiturates), (5) monitoring of somatosensory and MEPs, and (6) hypothermia. The remainder of this review will focus on using hypothermia as a critical component of the spinal cord protection protocol. There are two approaches for spinal cord cooling during TAAA surgery, regional and systemic cooling.

Systemic Hypothermia

Technique and approach

Systemic hypothermia can be induced through CPB and temperature can be mild (32°C–35°C), moderate (28°C–32°C), deep (20°C–28°C), or profound (15°C–20°C). With regard to organ protection during aortic surgery, two methods are commonly used: hypothermic circulatory arrest and left heart bypass. For hypothermic circulatory arrest, after induction of anesthesia, femoral vessels are exposed and systemic heparinization is achieved. A long catheter is introduced through the femoral vein and advanced to settle in the right atrium for venous blood drainage under transesophageal echocardiography guidance. The femoral or external iliac artery is the route for the arterial inflow cannula. Other sites for arterial cannulation can be used, such as aortic arch or subclavian artery, in case of extensive atherosclerosis of the femoral or iliac arteries. Once femoral vessels are cannulated and connected to the CPB machine, cooling of the blood starts by indirect contact with cold water (Safi et al., 1998; Kouchoukos et al., 2001). Once the target temperature is reached, the CPB is suspended and the aortic replacement will be done in a bloodless field.

To avoid the systemic drawbacks of deep hypothermia, the surgeon can use the left heart bypass technique. This technique includes using a centrifugal pump to circulate the blood in a closed circuit without using an oxygenator or a warming device. A cannula is introduced into the left atrium via inferior pulmonary vein for draining the blood, and blood is then returned to the distal thoracic aorta or the femoral artery through another cannula (Coselli et al., 1996; Coselli et al., 2004). Using the left heart bypass technique, patient core temperatures fluctuate between 32°C to 34°C (Wong et al., 2011). This approach does not require full heparinization, which avoids the synergism between hypothermia and anticoagulation.

Complications and limitations of systemic hypothermia

Despite the protective effects of systemic hypothermia, the procedure has side effects, including pulmonary dysfunction, generalized edema, and cardiac arrhythmia (Schubert, 1995; Ogino, 2010). Hypothermia causes coagulopathy through reversible platelet dysfunction, enhanced fibrinolytic activity, and slow enzymatic activity required for clotting (Rohrer and Natale, 1992). Moreover, using CPB for induced hypothermia requires full heparinization, which increases the risk of bleeding along with the coagulopathy caused by hypothermia (Okita, 2011). In addition, an increase in the incidence of infection at wound sites has been reported with systemic hypothermia application (Beltramini et al., 2011). This likelihood of infection can be attributed to impaired leucocytes migration, phagocytosis, and bactericidal oxidative burst activity (van Oss et al., 1980; Wenisch et al., 1996).

Regional Cooling

Technique and approach

Regional cooling was introduced as a way to avoid the complications associated with systemic cooling. The day before the surgery, an epidural catheter is inserted at the level of T11–T12 and advanced cranially under radiological guidance. Therefore, regional cooling of the spinal cord is usually accomplished via infusion of iced saline (4°C) into the epidural space through the catheter connected to a transfusion pump. Infusion is started 30 minutes before cross-clamping at a rate of 3–5 mL/min. This interval is important to reach the target temperature of CSF (25°C–28°C). Initial increase of CSF pressure occurs with starting the epidural infusion. Thereby, a gradient of (≈40 mmHg) is kept between the mean arterial pressure and the CSF pressure to maintain the cord blood perfusion. During the cross-clamp procedure, iced saline infusion rate is maintained at 0–7 mL/min then is discontinued at the end of the procedure. During cooling, CSF temperatures range from 25°C to 28°C with no significant change in body temperature and infusion of mean volume 489 mL (range 80–1700 mL) of iced saline solution. Another catheter is introduced into the subarachnoid space for CSF drainage and pressure measurement (checked every 5 minutes by a medical engineer). Epidural cooling is discontinued after re-anastomosis of critical arterial supply to the cord is achieved (Davison et al., 1994; Motoyoshi et al., 2004).

Complications and limitations of regional cooling

Although effective, regional cooling can increase CSF pressure, which can impair spinal cord perfusion (Meylaerts et al., 2000; Yoshitake et al., 2007). In a large cohort of patients (n=102) undergoing TAAA repair surgery, Tabayashi et al. (2010) reported that high CSF pressure during EC epidural cooling was associated with proximal center cord syndrome in two out of four patients who developed ISCI. However, the authors were not able to determine a mechanism of increased CSF pressure in these four patients whether it was due to a mechanical issue related to the catheter insertion, rate of infusion or anatomical variations within the epidural space among these four patients.

This potential drawback of regional cooling can be controlled by CSF drainage or epidural fluid drainage (Cambria et al., 1997, 2000). However, insertion of a second epidural catheter for drainage might be difficult with the high flow rate of saline infusion that is required to reach the targeted spinal cord temperature. In such clinical situations, the mean spinal cord perfusion (mean arterial pressure−mean CSF pressure) can be improved by manipulating the cold saline infusion rate or increasing the systemic pressure (Black et al., 2003). Figure 2 shows techniques of the epidural cooling system used by Massachusetts General Hospital.

FIG. 2.

Equipment setup for epidural cold infusion and measurement of CSF temperature and pressure. Syringe A: local anesthesia; syringe B: blousing and removing infusate; and syringe C: CSF drainage. CSF, cerebrospinal fluid. Reprinted from Dennison et al. (1994), with permission from Elsevier.

CSF temperature is measured during epidural cooling as an indicator of temperature within the spinal cord parenchyma. This makes it difficult to take an accurate measurement of spinal cord temperature (Ogino, 2010). This makes homogeneous cooling uncertain and could affect the clinical outcome.

The Effects of Induced Hypothermia on Electrophysiological Monitoring

Induced hypothermia affects the reliability of evoked potentials monitoring in detecting ISCI during aortic cross-clamping. MEPs and somatosensory evoked potentials (SSEPs) are used in some aortic surgery centers for monitoring spinal cord function during TAAA repair surgery (Shine et al., 2008; Keyhani et al., 2009). MEPs are recorded from limb muscles after trans-cranial electrical stimulation of the motor cortex with electrodes placed on the scalp. SSEPs are recorded from the scalp after stimulating the peripheral nerves. The function of spinal cord anterior columns can be assessed with MEPs while SSEPs can be used to evaluate posterior column function.

Recently, the reliability of neurophysiologic monitoring during TAAA surgery was debated (Coselli and Tsai, 2010; Koeppel et al., 2010). Because hypothermia can decrease nerve conduction velocity that will slow transmission of nerve impulses across synapses, an increase in the latency of cortical-evoked potentials is expected (Katz and Miledi, 1965; Benita and Conde, 1972; Ludin and Beyeler, 1977; van Rheineck et al., 1986). In addition, decreasing spinal cord temperature could diminish signal amplitude, which would require an increase in the stimulation threshold. Collectively, the adverse effects of hypothermia on these physiological variables could conceivably make MEPs/SSEPs monitoring difficult if not unreliable (Seyal and Mull, 2002; Wang et al., 2009; Coselli and Tsai, 2010).

However, the monitoring of MEPs was shown to be useful for alerting the surgical team about impending spinal cord damage. Using MEPs along with other adjunct therapies (e.g., CSF drainage and bypass grafting), one group was able to reduce the risk of paralysis after TAAA surgery to <3% (Jacobs et al., 2002). This same group also found no adverse affect of moderate hypothermia (28°C) on monitoring MEPs in a pig model of ISCI (Jacobs et al., 2002). However, profound cooling (14°C) markedly reduced the amplitude of MEPs and increased the latency. From these data, it was concluded that MEP monitoring becomes unreliable when CSF temperatures are below 25°C (Meylaerts et al., 1999).

In a preclinical cat model of ISCI, Browning et al. (1992) also noted an effect of temperature on evoked potentials. Specifically, the amplitude of MEPs increased at 28°C, while a significant increase in SSEP amplitude occurred at 34°C. The latency of both evoked potentials increased at 28°C. This group also recommends that, in addition to temperature, anesthetics and arterial CO₂ partial pressure should be considered when monitoring-evoked potentials. The need for expert individuals to monitor each of these physiological variables, in addition to monitoring and interpreting evoked potentials, likely explains why monitoring of evoked potentials is not a common practice in all aortic surgery centers.

In a clinical series reported from Mayo Clinic, Shine et al. (2008) evaluated the sensitivity and specificity of evoked potential monitoring in predicting the neurological outcomes of 58 patients who underwent TAAA repair surgery. Epidural cooling was applied to reach CSF temperature 26°C–28°C. Ten patients developed paraplegia after surgery. By conducting comparative analysis of the 10 paraplegic patients' data and the remaining data from the 48 patients without paraplegia, the investigators found that the sensitivity of MEPs monitoring in predicting ISCI was 88%, while the specificity was 65%. The negative predictive value of MEPS at 20 minutes after aortic cross-clamping was 96%. Also, they reported that during aortic cross-clamping, the signal was lost after 10 minutes in patients with paraplegia and 31 minutes in patients without paraplegia. They concluded that the chances of developing paraplegia are low when an MEP signal is present and that loss of an MEP shortly after aortic cross-clamping is a sign of impending paraplegia (Shine et al., 2008).

MEP monitoring may also be useful for revealing the hemodynamic significance of collateral blood supply to the spinal cord. Takahashi et al. showed that segmental cold blood infusion, which accelerates a decline in MEPs, is useful for determining when specific arteries need to be reconstructed (e.g., artery of Adamkiewicz). This technique was found to minimize reconstruction time and limit spinal cord damage (Takahashi et al., 2011).

Neurological Outcomes of TAAA Surgery with Hypothermia Application

Systemic hypothermia

Several clinical studies have reported the effectiveness of hypothermia in decreasing the risk of spinal cord injury during TAAA repair over the last 20 years (Table 2). A linear correlation seems to exist between temperature reduction and ischemic tolerance of the spinal cord (Hollier, 1987). Von Segesser et al. (2001) studied the direct impact of systemic hypothermia on the clinical outcomes in 100 patients undergoing TAAA repair surgery. Partial CPB with normothermic perfusion (36°C) was applied in 52 patients, and hypothermic perfusion (28°C) was applied in 48 patients. Application of hypothermia allowed more cross-clamping time, which enabled the surgical team to perform more complex repairs. Mortality, paraplegia, and surgical revision were all significantly reduced in the hypothermic group.

Table 2.

Application of Hypothermia in Thoracoabdominal Aortic Aneurysm Surgery

Study	Clinical series	Hypothermia approach	Neurological outcomes
Sundt et al. (2011)	TAA (n=37) TAA+Arch (n=25) TAAA (n=37) (2001–2010)	Systemic hypothermia Hypothermic CPB circulatory arrest Nasopharyngeal temp: (20°C–22°C)	Postoperative paraplegia developed in one patient (1%)
Kulik et al. (2011)	TAAA (n=218) (1986–2008)	Systemic hypothermia Hypothermic CPB circulatory arrest Nasopharyngeal temp: (20°C–22°C)	ISCI occurred in 10 (4.6%) patients (eight with paraplegia and two with paraparesis)
Tabayashi et al. (2010)	TAAA (n=102) (1998–2007)	Systemic and regional hypothermia EC and CSF drainage CSF lowest mean temp: (23.3°C) Nasopharyngeal temp: (28.0°C–33.6°C)	ISCI was 3.9% (4/102)
Acher and Wynn (2009)	TAAA (n=15,000) (1985–2008)	Systemic and regional hypothermia They reviewed the protective role of HA, EC, SFD, assisted circulation and MAP The O/E ratios were calculated for each series Results were grouped into Era 1 (1985–1997) to Era 2 (1997–2008)	The mean O/E ratio for paraplegia for all patients declined from 1.13 in Era 1 to 0.26 in Era 2 O/E for HA declined from 0.42 to 0.14 with SFD Hypothermia, SFD, ↑ MAP→reducing O/E deficit ratios from 1.03 to 0.16
Tabayashi et al. (2008)	TAAA (n=116) (1988–2007)	Systemic and regional hypothermia Group A: 38 patients with mild hypothermia Group B: 78 patients with EC, mild hypothermia and CSF drainage Lowest nasopharyngeal temp: Group A (31.3°C±1.6°C) and Group B (31.5°C±0.9°C)	ISCI incidence: Group A: 16.2% Group B: 3.8% p=0.03
Coselli et al. (2008)	TAA (n=83) TAAA (n=28) (1986–2008)	Systemic hypothermia Hypothermic CPB circulatory arrest Nasopharyngeal temp: (15°C–18°C)	Postoperative paraplegia developed in one patient (1%)
Grabenwöger et al. (1994)	TAA (n=63) TAAA (n=110) (1995–2005)	Systemic hypothermia Hypothermic CPB circulatory arrest Tympanic membrane temp: (15°C)	Paraplegia incidence: 2.4% (four patients/169 survivors) Paraparesis incidence: 2.4% (four patients) Six immediate deficits and four delayed deficits Five patients with permanent ISCI (3%)
Conrad et al. (2007)	TAAA (n=455) (1987–2005)	Regional hypothermia EC was used in 240 patients (68%) Cord temp: (25°C–27°C)	Overall ISCI in type I/II>in III/IV (33/190 [17%] vs. 22/265 [8%]; p=0.002) Application of epidural cooling in type I to type III TAAA repairs was associated with a significant decrease in ISCI (29/211 [13.7%] vs. 25/86 [29%]; p=0.01)
Motoyoshi et al. (2004)	TAAA (n=24) (1998–2002)	Systemic and regional hypothermia Moderate hypothermia (31°C–32°C) and EC CSF temp: (22°C–28.5°C)	Paraplegia incidence: one patient (4%)
Kouchoukos et al. (2002)	TAA (n=78) TAAA (n=114) (1986–2002)	Systemic hypothermia Hypothermic CPB circulatory arrest Nasopharyngeal temp: (12°C–15°C) Bladder temp: (15°C–19°C)	Paraplegia incidence: 4/186 survivor patients Paraparesis incidence: 1/186 survivor patients Total ISCI incidence: 2.7%
Cambria et al. (2002)	TAAA (n=337) (1987–2001)	Regional hypothermia EC has been used since July 1993 in types I III TAAA (n=194) Mean CSF temp: (25.2°C–27.6°C)	Use of EC was associated with a significant decrease in ISCI (19/180 [10.6%] vs. 18/91 [19.8%], P=.04)
von Segesser et al. (2001)	TAAA (n=100) (Prospective study)	Systemic hypothermia Partial CPB with normothermia (35°C–37°C) or hypothermia (28°C–30°C) according to surgeon preference 52/100 patients received normothermic perfusion 48/100 patients received hypothermic perfusion	Paraparesis/paraplegia occurred in 4/52 patients (8%) with normothermia vs. 4/48 (8%) with hypothermia Freedom from death, paraplegia, and surgical revision was 89.9% with normothermia vs. 94.8% with hypothermia (p=0.04; odds ratio 2.0) Active cooling during repair of TAAA allows for longer cross-clamp times, more complex repairs and improves outcome
Black et al. (2003)	TAA (n=14) TAAA (n=156)	Regional hypothermia EC was used in 97% of cases CSF mean temp: (26.4°C±3°C)	ISCI: 12/170 patients (7%) versus a predicted incidence of (18.5%) for this cohort (P=.003) Half the deficits were minor, with good functional recovery Devastating paraplegia occurred in three patients (2.0%)
Carrel et al. (2000)	TAA (n=61) TAAA (n=67) (1982–1998)	Systemic hypothermia Group 1: 90 patients operated with moderate hypothermic left heart bypass (lowest tympanic temp: 33.5°C) Group 2: 38 patients operated using deep hypothermic CPB and a period of circulatory arrest (lowest tympanic temp: 18°C)	Paraplegia incidence: Group 1: eight patients (8.8%) Group 2: one patient (2.6%)
Kouchoukos and Rokkas (1999)	TAA/TAAA (n=114) (1986–1998)	Systemic hypothermia Elective hypothermic CPB with a period of circulatory arrest Nasopharyngeal temp: (12°C–14°C) Bladder temp: (15°C–19°C)	Paraplegia occurred in two, and paraparesis in one of the 108 patients whose lower limb function was assessed postoperatively (2.8%) No delayed ISCI
Cambria et al. (1997)	TAA (n=9) TAAA (n=61) (1993–1995)	Regional hypothermia EC: CSF temperature was reduced to a mean of (24°C±3°C) during ACC with core temp of (34°C±0.8°C) Neurologic outcome was compared with a control group (n=55) who underwent TAAA repair in the period 1990–1993 before use of EC	Lower extremity neurologic deficits: two patients (2.9%) in EC group, 13 patients (23%) in control group (p<0.0001) Observed and predicted deficits: In the EC patients were 2.9% and 20.0% (p=0.001), and for the control group 23% and 17.8% (p=0.48)
Kouchoukos et al. (1995)	TAA (n=19) TAAA (n=32) (1986–1994)	Systemic hypothermia Elective hypothermic CPB with a period of circulatory arrest Lowest nasopharyngeal temp: (10.8°C–16.1°C) Lowest rectal/bladder temp: (6.8°C–22.0°C)	ISCI: 3/46 survivor patients (6.5%) Paraplegia in two patients Paraparesis in one patient
Frank et al. (1994)	TAA (n=4) TAAA (n=14) (1992–1993)	Systemic hypothermia Moderate hypothermia (30°C) with partial CPB	No neurological deficit in 16 surviving patients
Davison et al. (1994)	TAA/TAAA (n=8) (7/1993–10/1993)	Regional hypothermia Mean CSF temp: (26.7°C±0.9°C) Mean core temp: (34.3°C±0.7°C)	No postoperative neurologic deficits were observed
Grabenwöger et al. (1994)	TAA (n=7) TAAA (n=7) (1991–1993)	Systemic hypothermia Hypothermic CPB circulatory arrest Nasopharyngeal temp: (11°C)	None of the surviving 11/14 patients developed a permanent neurological deficit
Pokrovsky et al. (1991)	TAA (n=53) (1983–1988)	Systemic hypothermia Moderate hypothermia (30°C–31°C) used in 47/50 patients	Paraplegia incidence: One of three normothermic patients One of 47 hypothermic patients
Kouchoukos et al. (1990)	TAAA (n=5)	Systemic hypothermia Hypothermic CPB with periods of circulatory arrest Rectal/bladder temp: (15°C–19°C)	None of the four survivor patients had neurologic deficits

EC, epidural cooling; HA, hypothermic arrest; MAP, mean arterial pressure; O/E, observed/expected; SFD, spinal fluid drainage; TAA, thoracic aortic aneurysm; TAAA, thoracoabdominal aortic aneurysm.

Carrel et al. (2000) compared the effects of deep hypothermia (18°C) with a period of circulatory arrest and moderate hypothermia (33°C) with left heart bypass during TAAA repair. Paraplegia incidence was 8.8% in the moderate hypothermia group, while it was 2.6% in those individuals provided with deep hypothermia. With deep hypothermic circulatory arrest, it was also easier to identify the dissection tear site in the proximal aorta with a bloodless field and without an aortic clamp. They attributed the differences in the outcomes to the easier surgical access to all segments of the aorta, the biochemical effect of deep hypothermia on the extracellular excitatory amino acids release, and reduction of CSF lactate production.

These two studies examined the effect of normothermia versus hypothermia and which degree of hypothermia has a better outcome with regard to ISCI and paralysis. However, the optimal temperature management strategy is not clearly defined, and there is no agreement among different surgical teams about the ideal range of induced hypothermia to balance the risk–benefit ratio. Clinical trials should be directed to further investigate the optimum temperature management.

Regional cooling

Epidural cooling was introduced for the first time in TAAA repair surgery by Davison et al. (1994) at Massachusetts General Hospital in Boston. They successfully applied epidural cooling in eight patients undergoing TAAA repair with no incidence of postoperative neurological dysfunction. Since then, this same group reviewed the clinical outcomes of 445 cases of TAAA repair between 1998 and 2007 with epidural cooling applied in 240 TAAA surgeries for spinal cord protection. The overall incidence of ISCI was 13.2%, with 9.5% patients developing major paraplegia. They reported that when epidural cooling was applied during TAAA repair, the risk of ISCI was significantly reduced compared to cases without epidural cooling (13.2% with epidural cooling vs. 29% without epidural cooling; p=0.01) (Conrad et al., 2007).

The epidural cooling technique was also used at the Mayo Clinic in a consecutive series of 58 patients who underwent TAAA repair surgery between 1998 and 2000 (Shine et al., 2008). MEPs and SSEPs also were used to monitor spinal cord function during aortic cross-clamping. The ISCI incidence after surgery was 17.2% in this clinical series.

In Japan, a leading surgical team compared the ISCI incidence in 38 patients who had TAAA repair with mild hypothermia alone (33°C) and 78 patients with mild systemic hypothermia, epidural cooling, and CSF drainage. The incidence of ISCI was 16.2% in patients receiving only mild hypothermia; however, it was reduced to 3.8% in those receiving mild hypothermia with epidural cooling and CSF drainage (Tabayashi et al., 2008).

In 2008, the epidural cooling technique was applied for the first time in Germany in a small group of patients (Tschop et al., 2008). They reported no paraplegia in all seven patients after TAAA repair surgery; however, three patients died from other comorbidities.

Clinical considerations (systemic vs. regional cooling)

The application of induced hypothermia for spinal cord protection in TAAA repair varies between major aortic surgery centers. Some surgeons recommended profound hypothermia with circulatory arrest, while others prefer moderate hypothermia with left heart bypass (Borst et al., 1994; Okita et al., 1997; Carrel et al., 2000; Kouchoukos et al., 2001). The choice of approach and technique is based mainly on the preference and experience of the operating team as well as the extent of the aneurysm. Although deep hypothermic circulatory arrest is used in many aortic surgery centers (Grabenwöger et al., 1994; Kouchoukos and Rokkas, 1999; Carrel et al., 2000; Fehrenbacher et al., 2007), some surgeons recommend using this technique only in the following situations: aneurismal involvement of the aortic arch, extensive atherosclerosis of the aorta which makes aortic cross-clamping hazardous, and catastrophic bleeding intraoperatively due to the side effects of deep hypothermic circulatory arrest on the whole body (Coselli et al., 1996; Safi et al., 1998; Wong et al., 2011).

Epidural cooling is a newer and more complex approach requiring insertion of an epidural cooling catheter, constant monitoring of CSF pressure and maintenance of a gradient between the nasopharyngeal temperature and the CSF temperature. Accordingly, it is not as widely used as systemic hypothermia for multiple reasons. It is technically demanding, requiring additional skilled personnel and the rate of paralysis is not lowered compared to centers using systemic hypothermia. The incidence of ISCI is high in centers that are attempting to adopt this technique (Shine et al., 2008; Tschop et al., 2008). On the other hand, in centers that routinely use epidural cooling, it has been shown to effectively reduce ISCI incidence with fewer complications associated with systemic hypothermia (Conrad et al., 2007; Tabayashi et al., 2008; Tabayashi et al., 2010).

In general, induced hypothermia, systemic or regional, plays a beneficial role in protecting the spinal cord during ischemic injury. However, clinical application of either systemic or regional hypothermia was not successful in eliminating the ischemic injury.

Induced Hypothermia in Aortic Arch Surgery

There is an ongoing debate about whether deep hypothermia or moderate hypothermia with selective antegrade cerebral perfusion should be used for brain and spinal cord protection during aortic arch surgery. A recent editorial argues that prolonged selective antegrade cerebral perfusion with moderate hypothermia might not be enough to protect the spinal cord during aortic arch repair surgery (Ranasinghe and Bonser, 2009). The authors suggest performing a multi-center study with appropriate stratification for aortic pathology and extent of repair instead of relying on retrospective reports with missing data, era effects, learning curves or animal studies (Ranasinghe and Bonser, 2009). We agree with this position of the editorial.

Endovascular Repair

Recent advances in endovascular repair are being applied to the treatment of aortic aneurysm diseases. Initially, endovascular repair was limited to infra-renal or descending thoracic aortic aneurysm (TAA) patients, that is, those patients at high risk for open surgery (Greenberg and Lytle, 2008). However, the development of fenestrated and branched aortic endografts has allowed endovascular therapies to be used in more extensive TAAA surgeries. Still, even with this less invasive approach, spinal cord injury remains a risk. The incidence of spinal cord injury after endovascular repair of TAA is 2%–10% (Dake et al., 1998; Greenberg et al., 2005; Makaroun et al., 2005; Eagleton and Greenberg, 2010). In a clinical report from the Cleveland Clinic, the incidence of ISCI was found to decrease after endovascular repair by ∼3% compared to open surgical repair (4.3% endovascular repair vs. 7.5% surgical repair, p=0.08) (Eagleton and Greenberg, 2010).

The ISCI during endovascular repair could be attributed to several factors, such as immediate ischemic injury from occlusion of critical intercostal arteries, episodes of hypotension, or loss of collaterals needed for maintaining spinal cord perfusion. Coverage of critical intercostal arteries by the stent does not result in immediate occlusion because these arteries can maintain blood flow through collaterals, which is sometimes evident as an endoleak. Delayed thrombosis of these intercostal arteries due to low blood flow with resolution of the endoleak could be another mechanism of delayed ischemic injury. Visceral ischemia also can develop during endoaortic abdominal repair and could increase the release of inflammatory mediators with subsequent secondary spinal cord ischemia (Carroccio et al., 2003).

Endovascular techniques seem to be a promising alternative for the conventional open TAAA repair; however, the prospect of causing spinal cord injury is still of great concern. Identification of critical intercostal vessels, maintenance of interoperative arterial blood pressure, CSF drainage, and neuroprotective drugs have been incorporated as protective measures to minimize ISCI during endovascular repair (Greenberg and Lytle, 2008; Eagleton and Greenberg, 2010). To date, regional hypothermia has not been tested before as an adjunct to endovascular therapy in a systematic way.

As we have described above, several reports have used induced hypothermia to prevent spinal cord dysfunction in animal models and/or in patients undergoing open surgery repair. Application of systemic or regional hypothermia in endovascular repair should be evaluated in further experimental and clinical studies so that ISCI incidence will be markedly reduced in this minimally invasive technique.

In a recent study, the performance of the prosthetic grafts used in endovascular repair was tested under hypothermic conditions (in vitro) (Robich et al., 2012). These grafts showed significant reduction in the radial expansion and deployed diameter at or below 30°C. Failure of full expansion of the endografts may lead to serious complications such as migration or endoleak. Special attention should be given to cases undergoing endovascular repair of TAA or TAAA by using these prosthetic grafts under hypothermic conditions.

Conclusions and Future Directions

Despite marked advances in the surgical treatment of TAAA and a general decline in rates of paraplegia across most vascular surgery centers (Acher and Wynn, 2010), paraplegia and paraparesis remain devastating postsurgical complications. Hypothermia is an effective neuroprotective therapy capable of limiting histological and neurological deficits caused by ISCI in diverse experimental models and clinical settings. Hypothermia not only reduces the metabolism and energy requirements of neurons, it also interrupts the ischemic injury cascade at the cellular and molecular levels through alteration of gene expression and protein synthesis in neurons, glia and inflammatory leukocytes. Still, more research is needed to fully understand the cellular and molecular mechanisms of neuroprotection afforded by hypothermia. This increased knowledge will help researchers and clinicians to develop more effective interventions against ISCI.

Regarding the area of endovascular repair, there are no randomized controlled clinical trials that targeted the temperature management for spinal cord protection. Furthermore, the relationship between temperature management, synthetic grafts durability, and endoleak needs further research.

Recently, drug therapeutics such as cannabinoids were shown to induce hypothermia and have organ protection effects which could synergize with or potentially replace systemic and regional hypothermia (Tisherman, 2010). Looking to the future, it might be feasible to simulate the effects of hypothermia using pharmacological agents that induce a poikilothermic state in the nervous tissue and avoid the side effects of physical hypothermia.

Footnotes

Disclosure Statement

All authors declared that no competing financial interests exist.

References

Acher

, Wynn

. Outcomes in open repair of the thoracic and thoracoabdominal aorta. J Vasc Surg, 2010; 52:3S–9S.

Acher

, Wynn

. A modern theory of paraplegia in the treatment of aneurysms of the thoracoabdominal aorta: an analysis of technique specific observed/expected ratios for paralysis. J Vasc Surg, 2009; 49:1117–1124discussion 1124.

Acher

, Wynn

, Hoch

, Popic

, Archibald

, Turnipseed

. Combined use of cerebral spinal fluid drainage and naloxone reduces the risk of paraplegia in thoracoabdominal aneurysm repair. J Vasc Surg, 1994; 19:236–246discussion 47–48.

Aibiki

, Maekawa

, Ogura

, Kinoshita

, Kawai

, Yokono

. Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic brain injury in humans. J Neurotrauma, 1999; 16:225–232.

Allen

, Davis

, Osborne

, Karl

. Spinal cord ischemia and reperfusion metabolism: the effect of hypothermia. J Vasc Surg, 1994; 19:332–339discussion 9–40.

Awad

, Ankeny

, Guan

, Wei

, McTigue

, Popovich

. A mouse model of ischemic spinal cord injury with delayed paralysis caused by aortic cross-clamping. Anesthesiology, 2010; 113:880–891.

Awad

, Suntres

, Heijmans

, Smeak

, Bergdall-Costell

, Christofi

, Magro

, Oglesbee

. Intracellular and extracellular expression of the major inducible 70 kDa heat shock protein in experimental ischemia-reperfusion injury of the spinal cord. Exp Neurol, 2008; 212:275–284.

Bachis

, Colangelo

, Vicini

, Doe

, De Bernardi

, Brooker

, Mocchetti

. Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci, 2001; 21:3104–3112.

Baker

, Zornow

, Grafe

, Scheller

, Skilling

, Smullin

, Larson

. Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits. Stroke, 1991; 22:666–673.

10.

Beltramini

, Salata

, Ray

. Thermoregulation and risk of surgical site infection. Infect Control Hosp Epidemiol, 2011; 32:603–610.

11.

Benita

, Conde

. Effects of local cooling upon conduction and synaptic transmission. Brain Res, 1972; 36:133–151.

12.

Berguer

, Porto

, Fedoronko

, Dragovic

. Selective deep hypothermia of the spinal cord prevents paraplegia after aortic cross-clamping in the dog model. J Vasc Surg, 1992; 15:62–71discussion 71–72.

13.

Black

, Davison

, Cambria

. Regional hypothermia with epidural cooling for prevention of spinal cord ischemic complications after thoracoabdominal aortic surgery. Semin Thorac Cardiovasc Surg, 2003; 15:345–352.

14.

Boris-Moller

, Kamme

, Wieloch

. The effect of hypothermia on the expression of neurotrophin mRNA in the hippocampus following transient cerebral ischemia in the rat. Brain Res Mol Brain Res, 1998; 63:163–173.

15.

Borst

, Jurmann

, Buhner

, Laas

. Risk of replacement of descending aorta with a standardized left heart bypass technique. J Thorac Cardiovasc Surg, 1994; 107:126–132discussion 132–133.

16.

Browning

, Heizer

, Baskin

. Variations in corticomotor and somatosensory evoked potentials: effects of temperature, halothane anesthesia, and arterial partial pressure of CO₂. Anesth Analg, 1992; 74:643–648.

17.

Busto

, Globus

, Dietrich

, Martinez

, Valdés

, Ginsberg

. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke, 1989; 20:904–910.

18.

Cambria

, Clouse

, Davison

, Dunn

, Corey

, Dorer

. Thoracoabdominal aneurysm repair: results with 337 operations performed over a 15-year interval. Ann Surg, 2002; 236:471–479discussion 479.

19.

Cambria

, Davison

, Carter

, Brewster

, Chang

, Clark

, Atamian

. Epidural cooling for spinal cord protection during thoracoabdominal aneurysm repair: a five-year experience. J Vasc Surg, 2000; 31:1093–1102.

20.

Cambria

, Davison

, Zannetti

, L'Italien

, Brewster

, Gertler

, Moncure

, LaMuraglia

, Abbott

. Clinical experience with epidural cooling for spinal cord protection during thoracic and thoracoabdominal aneurysm repair. J Vasc Surg, 1997; 25:234–241discussion 41–43.

21.

Carrel

, Berdat

, Robe

, Gysi

, Nguyen

, Kipfer

, Althaus

. Outcome of thoracoabdominal aortic operations using deep hypothermia and distal exsanguination. Ann Thorac Surg, 2000; 69:692–695.

22.

Carroccio

, Marin

, Ellozy

, Hollier

. Pathophysiology of paraplegia following endovascular thoracic aortic aneurysm repair. J Card Surg, 2003; 18:359–366.

23.

Coles

, Wilson

, Sima

, Klement

, Tait

, Williams

, Baird

. Intraoperative management of thoracic aortic aneurysm. Experimental evaluation of perfusion cooling of the spinal cord. J Thorac Cardiovasc Surg, 1983; 85:292–299.

24.

Colon

, Frazier

, Cooley

, McAllister

. Hypothermic regional perfusion for protection of the spinal cord during periods of ischemia. Ann Thorac Surg, 1987; 43:639–643.

25.

Conrad

, Crawford

, Davison

, Cambria

. Thoracoabdominal aneurysm repair: a 20-year perspective. Ann Thorac Surg, 2007; 83:S856–S861discussion S890–S892.

26.

Coselli

, Bozinovski

, Cheung

. Hypothermic circulatory arrest: safety and efficacy in the operative treatment of descending and thoracoabdominal aortic aneurysms. Ann Thorac Surg, 2008; 85:956–963discussion 964.

27.

Coselli

, LeMaire

, Conklin

, Adams

. Left heart bypass during descending thoracic aortic aneurysm repair does not reduce the incidence of paraplegia. Ann Thorac Surg, 2004; 77:1298–1303discussion 1303.

28.

Coselli

, Lemaire

, Köksoy

, Schmittling

, Curling

. Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: results of a randomized clinical trial. J Vasc Surg, 2002; 35:631–639.

29.

Coselli

, LeMaire

. Left heart bypass reduces paraplegia rates after thoracoabdominal aortic aneurysm repair. Ann Thorac Surg, 1999; 67:1931–1934discussion 53–58.

30.

Coselli

, Plestis

, La Francesca

, Cohen

. Results of contemporary surgical treatment of descending thoracic aortic aneurysms: experience in 198 patients. Ann Vasc Surg, 1996; 10:131–137.

31.

Coselli

, Tsai

. Motor evoked potentials in thoracoabdominal aortic surgery: CON. Cardiol Clin, 2010; 28:361–368.

32.

Creech

Jr. , Debakey

, Morris

Jr.

Aneurysm of thoracoabdominal aorta involving the celiac, superior mesenteric, and renal arteries; report of four cases treated by resection and homograft replacement. Ann Surg, 1956; 144:549–573.

33.

Dake

, Miller

, Mitchell

, Semba

, Moore

, Sakai

. The “first generation” of endovascular stent-grafts for patients with aneurysms of the descending thoracic aorta. J Thorac Cardiovasc Surg, 1998; 116:689–703discussion 703–704.

34.

Davison

, Cambria

, Vierra

, Columbia

, Koustas

. Epidural cooling for regional spinal cord hypothermia during thoracoabdominal aneurysm repair. J Vasc Surg, 1994; 20:304–310.

35.

D'Cruz

, Fertig

, Filiano

, Hicks

, DeFranco

, Callaway

. Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation. J Cereb Blood Flow Metab, 2002; 22:843–851.

36.

D'Cruz

, Logue

, Falke

, DeFranco

, Callaway

. Hypothermia and ERK activation after cardiac arrest. Brain Res, 2005; 1064:108–118.

37.

de Haan

, Kalkman

, de Mol

, Ubags

, Veldman

, Jacobs

. Efficacy of transcranial motor-evoked myogenic potentials to detect spinal cord ischemia during operations for thoracoabdominal aneurysms. J Thorac Cardiovasc Surg, 1997; 113:87–100discussion 100–101.

38.

Dennison

, Cambria

, Vierra

, Columbus

, Koustas

. Epidural cooling for regional spinal cord hypothermia during thoracoabdominal aneurysm repair. J Vasc Surg, 1994; 20:304–310.

39.

Diestel

, Roessler

, Berger

, Schmitt

. Hypothermia downregulates inflammation but enhances IL-6 secretion by stimulated endothelial cells. Cryobiology, 2008; 57:216–222.

40.

Diestel

, Troeller

, Billecke

, Sauer

, Berger

, Schmitt

. Mechanisms of hypothermia-induced cell protection mediated by microglial cells in vitro. Eur J Neurosci, 2010; 31:779–787.

41.

Dietrich

, Busto

, Bethea

. Postischemic hypothermia and IL-10 treatment provide long-lasting neuroprotection of CA1 hippocampus following transient global ischemia in rats. Exp Neurol, 1999; 158:444–450.

42.

Dietrich

, Chatzipanteli

, Vitarbo

, Wada

, Kinoshita

. The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma. Acta Neurochir Suppl, 2004; 89:69–74.

43.

Dinarello

. Induction of interleukin-1 and interleukin-1 receptor antagonist. Semin Oncol, 1997; 24:S9–81–S9–93.

44.

Dresios

, Aschrafi

, Owens

, Vanderklish

, Edelman

, Mauro

. Cold stress-induced protein Rbm3 binds 60S ribosomal subunits, alters microRNA levels, and enhances global protein synthesis. Proc Natl Acad Sci U S A, 2005; 102:1865–1870.

45.

Eagleton

, Greenberg

. Spinal and visceral ischemia after endovascular aortic repair. J Cardiovasc Surg (Torino), 2010; 51:71–83.

46.

Eguchi

, Yamashita

, Iwamoto

, Ito

. Effects of brain temperature on calmodulin and microtubule-associated protein 2 immunoreactivity in the gerbil hippocampus following transient forebrain ischemia. J Neurotrauma, 1997; 14:109–118.

47.

Erecinska

, Thoresen

, Silver

. Effects of hypothermia on energy metabolism in mammalian central nervous system. J Cereb Blood Flow Metab, 2003; 23:513–530.

48.

Fehrenbacher

, Hart

, Huddleston

, Siderys

, Rice

. Optimal end-organ protection for thoracic and thoracoabdominal aortic aneurysm repair using deep hypothermic circulatory arrest. Ann Thorac Surg, 2007; 83:1041–1046.

49.

Frank

, Parker

, Rock

, Gorman

, Kelly

, Beattie

, Williams

. Moderate hypothermia, with partial bypass and segmental sequential repair for thoracoabdominal aortic aneurysm. J Vasc Surg, 1994; 19:687–697.

50.

Fukuda

, Tomimatsu

, Watanabe

, Mu

, Kohzuki

, Endo

, Fujii

, Kanzaki

, Murata

. Post-ischemic hypothermia blocks caspase-3 activation in the newborn rat brain after hypoxia-ischemia. Brain Res, 2001; 910:187–191.

51.

Gelman

. The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology, 1995; 82:1026–1060.

52.

Globus

, Alonso

, Dietrich

, Busto

, Ginsberg

. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem, 1995a. 65:1704–1711.

53.

Globus

, Busto

, Lin

, Schnippering

, Ginsberg

. Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. J Neurochem, 1995b. 65:1250–1256.

54.

Gonzalez-Fajardo

, Beatriz

, Perez-Burkhardt

, Alvarez

, Fernandez

, Ramos

, Vaquero

. Epidural regional hypothermia for prevention of paraplegia after aortic occlusion: experimental evaluation in a rabbit model. J Vasc Surg, 1996; 23:446–452.

55.

Grabenwöger

, Ehrlich

, Simon

, Grimm

, Laufer

, Wollenek

, Mares

, Wolner

, Havel

. Thoracoabdominalaneurysm repair: spinal cord protection using profound hypothermia and circulatory arrest. J Card Surg, 1994; 9:679–684.

56.

Greenberg

, Lu

, Roselli

, Svensson

, Moon

, Hernandez

, Dowdall

, Cury

, Francis

, Pfaff

, Clair

, Ouriel

, Lytle

. Contemporary analysis of descending thoracic and thoracoabdominal aneurysm repair: a comparison of endovascular and open techniques. Circulation, 2008; 118:808–817.

57.

Greenberg

, Lytle

. Endovascular repair of thoracoabdominal aneurysms. Circulation, 2008; 117:2288–2296.

58.

Greenberg

, O'Neill

, Walker

, Haddad

, Lyden

, Svensson

, Lytle

, Clair

, Ouriel

. Endovascular repair of thoracic aortic lesions with the Zenith TX1 and TX2 thoracic grafts: intermediate-term results. J Vasc Surg, 2005; 41:589–596.

59.

Griepp

, Griepp

. Spinal cord perfusion and protection during descending thoracic and thoracoabdominal aortic surgery: the collateral network concept. Ann Thorac Surg, 2007; 83:S865–S869discussion S90–S92.

60.

Griepp

, Stinson

, Hollingsworth

, Buehler

. Prosthetic replacement of the aortic arch. J Thorac Cardiovasc Surg, 1975; 70:1051–1063.

61.

Han

, Karabiyikoglu

, Kelly

, Sobel

, Yenari

. Mild hypothermia inhibits nuclear factor-kappaB translocation in experimental stroke. J Cereb Blood Flow Metab, 2003; 23:589–598.

62.

Han

, Yenari

. Effect on gene expression by therapeutic hypothermia in cerebral ischemia. Future Neurol, 2007; 2:435–440.

63.

Hansebout

, Kuchner

, Romero-Sierra

. Effects of local hypothermia and of steroids upon recovery from experimental spinal cord compression injury. Surg Neurol, 1975; 4:531–536.

64.

Hicks

, Parmele

, DeFranco

, Klann

, Callaway

. Hypothermia differentially increases extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun terminal kinase activation in the hippocampus during reperfusion after asphyxial cardiac arrest. Neuroscience, 2000; 98:677–685.

65.

Hollier

. Protecting the brain and spinal cord. J Vasc Surg, 1987; 5:524–528.

66.

Horiguchi

, Shimizu

, Ogino

, Suga

, Inamasu

, Kawase

. Postischemic hypothermia inhibits the generation of hydroxyl radical following transient forebrain ischemia in rats. J Neurotrauma, 2003; 20:511–520.

67.

Hsieh

, Koike

, Spusta

, Niemi

, Yenari

, Nakamura

, Seaman

. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem, 2009; 109:1144–1156.

68.

, Kamme

, Wieloch

. Alterations of Ca2⁺/calmodulin-dependent protein kinase II and its messenger RNA in the rat hippocampus following normo- and hypothermic ischemia. Neuroscience, 1995; 68:1003–1016.

69.

Inamasu

, Suga

, Sato

, Horiguchi

, Akaji

, Mayanagi

, Kawase

. Postischemic hypothermia attenuates apoptotic cell death in transient focal ischemia in rats. Acta Neurochir Suppl, 2000; 76:525–527.

70.

Isaka

, Kumagai

, Sugawara

, Okada

, Orihashi

, Ohtaki

, Sueda

. Cold spinoplegia and transvertebral cooling pad reduce spinal cord injury during thoracoabdominal aortic surgery. J Vasc Surg, 2006; 43:1257–1262.

71.

Ishikawa

, Mori

, Kabei

, Yoshitake

, Suzuki

, Katori

, Morisaki

, Yozu

, Takeda

. Epidural cooling minimizes spinal cord injury after aortic cross-clamping through induction of nitric oxide synthase. Anesthesiology, 2009; 111:818–825.

72.

Ishikawa

, Sekizuka

, Sato

, Yamaguchi

, Inamasu

, Bertalanffy

, Kawase

, Iadecola

. Effects of moderate hypothermia on leukocyte- endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke, 1999; 30:1679–1686.

73.

Jacobs

, de Mol

, Elenbaas

, Mess

, Kalkman

, Schurink

, Mochtar

. Spinal cord blood supply in patients with thoracoabdominal aortic aneurysms. J Vasc Surg, 2002; 35:30–37.

74.

Kang

, Albadawi

, Casey

, Abbruzzese

, Patel

, Yoo

, Cambria

, Watkins

. The effects of systemic hypothermia on a murine model of thoracic aortic ischemia reperfusion. J Vasc Surg, 2010; 52:435–443.

75.

Kataoka

, Yanase

. Mild hypothermia—a revived countermeasure against ischemic neuronal damages. Neurosci Res, 1998; 32:103–117.

76.

Katz

, Miledi

. The effect of temperature on the synaptic delay at the neuromuscular junction. J Physiol, 1965; 181:656–670.

77.

Keyhani

, Miller

3rd , Estrera

, Wegryn

, Sheinbaum

, Safi

. Analysis of motor and somatosensory evoked potentials during thoracic and thoracoabdominal aortic aneurysm repair. J Vasc Surg, 2009; 49:36–41.

78.

Kimura

, Sakurada

, Ohkuni

, Todome

, Kurata

. Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells. Crit Care Med, 2002; 30:1499–1502.

79.

Koeppel

, Mess

, Jacobs

. Motor evoked potentials in thoracoabdominal aortic surgery: PRO. Cardiol Clin, 2010; 28:351–360.

80.

Kouchoukos

, Daily

, Rokkas

, Murphy

, Bauer

, Abboud

. Hypothermic bypass and circulatory arrest for operations on the descending thoracic and thoracoabdominal aorta. Ann Thorac Surg, 1995; 60:67–76discussion 76–77.

81.

Kouchoukos

, Masetti

, Rokkas

, Murphy

. Hypothermic cardiopulmonary bypass and circulatory arrest for operations on the descending thoracic and thoracoabdominal aorta. Ann Thorac Surg, 2002; 74:S1885–S1887discussion S1892–S1898.

82.

Kouchoukos

, Masetti

, Rokkas

, Murphy

, Blackstone

. Safety and efficacy of hypothermic cardiopulmonary bypass and circulatory arrest for operations on the descending thoracic and thoracoabdominal aorta. Ann Thorac Surg, 2001; 72:699–707discussion 707–708.

83.

Kouchoukos

, Rokkas

. Hypothermic cardiopulmonary bypass for spinal cord protection: rationale and clinical results. Ann Thorac Surg, 1999; 67:1940–1942discussion 1953–1958.

84.

Kouchoukos

, Wareing

, Izumoto

, Klausing

, Abboud

. Elective hypothermic cardiopulmonary bypass and circulatory arrest for spinal cord protection during operations on the thoracoabdominal aorta. J Thorac Cardiovasc Surg, 1990; 99:659–664.

85.

Kulik

, Castner

, Kouchoukos

. Outcomes after thoracoabdominal aortic aneurysm repair with hypothermic circulatory arrest. J Thorac Cardiovasc Surg, 2011; 141:953–960.

86.

Kurz

, Sessler

, Lenhardt

. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med, 1996; 334:1209–1215.

87.

Lin

, Chen

, Chiang

, Ma

. Hypoxic preconditioning protects rat hearts against ischaemia-reperfusion injury: role of erythropoietin on progenitor cell mobilization. J Physiol, 2008; 586:5757–5769.

88.

Ludin

, Beyeler

. Temperature dependence of normal sensory nerve action potentials. J Neurol, 1977; 216:173–180.

89.

Maeda

, Mori

, Shiraishi

, Tatebayashi

, Kawai

. Selective occlusion of lumbar arteries as a spinal cord ischemia model in rabbits. Jpn J Physiol, 2003; 53:9–15.

90.

Maier

, Sun

, Cheng

, Yenari

, Chan

, Steinberg

. Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. Neurobiol Dis, 2002; 11:28–42.

91.

Makaroun

, Dillavou

, Kee

, Sicard

, Chaikof

, Bavaria

, Williams

, Cambria

, Mitchell

. Endovascular treatment of thoracic aortic aneurysms: results of the phase II multicenter trial of the GORE TAG thoracic endoprosthesis. J Vasc Surg, 2005; 41:1–9.

92.

Marsala

, Vanicky

, Galik

, Radonak

, Kundrat

, Marsala

. Panmyelic epidural cooling protects against ischemic spinal cord damage. J Surg Res, 1993; 55:21–31.

93.

Martelli

, Cho

, Mozes

, Gloviczki

. Epidural cooling for the prevention of ischemic injury to the spinal cord during aortic occlusion in a rabbit model: determination of the optimal temperature. J Vasc Surg, 2002; 35:547–553.

94.

Meylaerts

, De Haan

, Kalkman

, Lips

, De Mol

, Jacobs

. The influence of regional spinal cord hypothermia on transcranial myogenic motor-evoked potential monitoring and the efficacy of spinal cord ischemia detection. J Thorac Cardiovasc Surg, 1999; 118:1038–1045.

95.

Meylaerts

, Kalkman

, de Haan

, Porsius

, Jacobs

. Epidural versus subdural spinal cord cooling: cerebrospinal fluid temperature and pressure changes. Ann Thorac Surg, 2000; 70:222–227discussion 228.

96.

Michenfelder

, Milde

. The effect of profound levels of hypothermia (below 14 degrees C) on canine cerebral metabolism. J Cereb Blood Flow Metab, 1992; 12:877–880.

97.

Michenfelder

, Milde

. The relationship among canine brain temperature, metabolism, and function during hypothermia. Anesthesiology, 1991; 75:130–136.

98.

Michenfelder

, Theye

. Hypothermia: effect on canine brain and whole-body metabolism. Anesthesiology, 1968; 29:1107–1112.

99.

Mori

, Ueda

, Hachiya

, Kabei

, Okano

, Yozu

, Sasaki

. An epidural cooling catheter protects the spinal cord against ischemic injury in pigs. Ann Thorac Surg, 2005; 80:1829–1833.

100.

Motoyoshi

, Takahashi

, Sakurai

, Tabayashi

. Safety and efficacy of epidural cooling for regional spinal cord hypothermia during thoracoabdominal aneurysm repair. Eur J Cardiothorac Surg, 2004; 25:139–141.

101.

Naslund

, Hollier

, Money

, Facundus

, Skenderis

2nd . Protecting the ischemic spinal cord during aortic clamping. The influence of anesthetics and hypothermia. Ann Surg, 1992; 215:409–415discussion 415–416.

102.

Negrin

Jr. , Klauber

. Direct regional hypothermia of the central nervous system: a preliminary report of a pilot project on experimental hypothermia. Arch Neurol, 1960; 3:100–104.

103.

Nijenhuis

, Jacobs

, Jaspers

, Reinders

, van Engelshoven

, Leiner

, Backes

. Comparison of magnetic resonance with computed tomography angiography for preoperative localization of the Adamkiewicz artery in thoracoabdominal aortic aneurysm patients. J Vasc Surg, 2007; 45:677–685.

104.

Novack

, Dillon

, Jackson

. Neurochemical mechanisms in brain injury and treatment: a review. J Clin Exp Neuropsychol, 1996; 18:685–706.

105.

Ogino

. Is hypothermia a reliable adjunct for spinal cord protection in descending and thoracoabdominal aortic repair with regional or systemic cooling? Gen Thorac Cardiovasc Surg, 2010; 58:220–222.

106.

Okita

. Fighting spinal cord complication during surgery for thoracoabdominal aortic disease. Gen Thorac Cardiovasc Surg, 2011; 59:79–90.

107.

Okita

, Takamoto

, Ando

, Morota

, Yamaki

, Matsukawa

, Kawashima

. Repair for aneurysms of the entire descending thoracic aorta or thoracoabdominal aorta using a deep hypothermia. Eur J Cardiothorac Surg, 1997; 12:120–126.

108.

Owens

, Prevedel

, Swan

. Prolonged experimental occlusion of thoracic aorta during hypothermia. AMA Arch Surg, 1955; 70:95–97.

109.

Parkins

, Ben

, Vars

. Tolerance of temporary occlusion of the thoracic aorta in normothermic and hypothermic dogs. Surgery, 1955; 38:38–47.

110.

Phanithi

, Yoshida

, Santana

, Su

, Kawamura

, Yasui

. Mild hypothermia mitigates post-ischemic neuronal death following focal cerebral ischemia in rat brain: immunohistochemical study of Fas, caspase-3 and TUNEL. Neuropathology, 2000; 20:273–282.

111.

Piano

, Gewertz

. Mechanism of increased cerebrospinal fluid pressure with thoracic aortic occlusion. J Vasc Surg, 1990; 11:695–701.

112.

Pilotte

, Dupont-Versteegden

, Vanderklish

. Widespread regulation of miRNA biogenesis at the Dicer step by the cold-inducible RNA-binding protein, RBM3. PLoS One, 2011; 6:e28446.

113.

Pokrovsky

, Yermoljuk

, Sultanalijev

, Smolnikoff

, Zhutchkov

. General moderate hypothermia in the surgical treatment of descending thoracic aortic aneurysms. J Cardiovasc Surg (Torino), 1991; 32:436–442.

114.

Pontius

, Brockman

, Hardy

, Cooley

, Debakey

. The use of hypothermia in the prevention of paraplegia following temporary aortic occlusion: experimental observations. Surgery, 1954; 36:33–38.

115.

Prakasa Babu

, Yoshida

, Su

, Segura

, Kawamura

, Yasui

. Immunohistochemical expression of Bcl-2, Bax and cytochrome c following focal cerebral ischemia and effect of hypothermia in rat. Neurosci Lett, 2000; 291:196–200.

116.

Ranasinghe

, Bonser

. The brain, the spinal cord, selective antegrade cerebral perfusion and corporeal arrest temperature—are we reducing the margin of patient safety in aortic arch surgery? Eur J Cardiothorac Surg, 2009; 36:943–945.

117.

Robich

, Hagberg

, Schermerhorn

, Pomposelli

, Nilson

, Gendron

, Sellke

, Rodriguez

. Hypothermia severely effects performance of nitinol-based endovascular grafts in vitro. Ann Thorac Surg, 2012; 93:1223–1227.

118.

Rohrer

, Natale

. Effect of hypothermia on the coagulation cascade. Crit Care Med, 1992; 20:1402–1405.

119.

Rokkas

, Cronin

, Nitta

, Helfrich

Jr. , Lobner

, Choi

, Kouchoukos

. Profound systemic hypothermia inhibits the release of neurotransmitter amino acids in spinal cord ischemia. J Thorac Cardiovasc Surg, 1995; 110:27–35.

120.

Rokkas

, Sundaresan

, Shuman

, Palazzo

, Nitta

, Despotis

, Burns

, Wareing

, Kouchoukos

. Profound systemic hypothermia protects the spinal cord in a primate model of spinal cord ischemia. J Thorac Cardiovasc Surg, 1993; 106:1024–1035.

121.

Rosomoff

, Holaday

. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol, 1954; 179:85–88.

122.

Ross

, Kern

, Gangemi

St . Laurent CR, Shockey KS, Kron IL, Tribble CG. Hypothermic retrograde venous perfusion with adenosine cools the spinal cord and reduces the risk of paraplegia after thoracic aortic clamping. J Thorac Cardiovasc Surg, 2000; 119:588–595.

123.

Safi

, Hess

, Randel

, Iliopoulos

, Baldwin

, Mootha

, Shenaq

, Sheinbaum

, Greene

. Cerebrospinal fluid drainage and distal aortic perfusion: reducing neurologic complications in repair of thoracoabdominal aortic aneurysm types I and II. J Vasc Surg, 1996; 23:223–228discussion 229.

124.

Safi

, Miller

3rd , Subramaniam

, Campbell

, Iliopoulos

, O'Donnell

, Reardon

, Letsou

, Espada

. Thoracic and thoracoabdominal aortic aneurysm repair using cardiopulmonary bypass, profound hypothermia, and circulatory arrest via left side of the chest incision. J Vasc Surg, 1998; 28:591–598.

125.

Salzano

Jr. , Ellison

, Altonji

, Richter

, Deckers

. Regional deep hypothermia of the spinal cord protects against ischemic injury during thoracic aortic cross-clamping. Ann Thorac Surg, 1994; 57:65–70discussion 71.

126.

Schmidt

, Repine

, Hicks

, DeFranco

, Callaway

. Regional changes in glial cell line-derived neurotrophic factor after cardiac arrest and hypothermia in rats. Neurosci Lett, 2004; 368:135–139.

127.

Schubert

. Side effects of mild hypothermia. J Neurosurg Anesthesiol, 1995; 7:139–147.

128.

Seyal

, Mull

. Mechanisms of signal change during intraoperative somatosensory evoked potential monitoring of the spinal cord. J Clin Neurophysiol, 2002; 19:409–415.

129.

Shimizu

, Yozu

. Current strategies for spinal cord protection during thoracic and thoracoabdominal aortic aneurysm repair. Gen Thorac Cardiovasc Surg, 2011; 59:155–163.

130.

Shine

, Harrison

, De Ruyter

, Crook

, Heckman

, Daube

, Stapelfeldt

, Cherry

, Gloviczki

, Bower

, Murray

. Motor and somatosensory evoked potentials: their role in predicting spinal cord ischemia in patients undergoing thoracoabdominal aortic aneurysm repair with regional lumbar epidural cooling. Anesthesiology, 2008; 108:580–587.

131.

, Nakamura

, Kataoka

. Hypothermic suppression of microglial activation in culture: inhibition of cell proliferation and production of nitric oxide and superoxide. Neuroscience, 1997; 81:223–229.

132.

Sick

, Tang

, Perez-Pinzon

. Cerebral blood flow does not mediate the effect of brain temperature on recovery of extracellular potassium ion activity after transient focal ischemia in the rat. Brain Res, 1999; 821:400–406.

133.

Soma

, Kawada

, Kono

, Imamura

, Yotsu

, Odagiri

, Inoue

. Clinical results of cardiopulmonary bypass with selective cerebral perfusion for aneurysm of the ascending aorta and the aortic arch. Ann Thorac Surg, 1982; 34:659–663.

134.

Sonna

, Kuhlmeier

, Carter

, Hasday

, Lilly

, Fairchild

. Effect of moderate hypothermia on gene expression by THP-1 cells: a DNA microarray study. Physiol Genomics, 2006; 26:91–98.

135.

Strauch

, Lauten

, Spielvogel

, Rinke

, Zhang

, Weisz

, Bodian

, Griepp

. Mild hypothermia protects the spinal cord from ischemic injury in a chronic porcine model. Eur J Cardiothorac Surg, 2004; 25:708–715.

136.

Sundt

, Flemming

, Oderich

, Torres

, Li

, Lenoch

, Kalra

. Spinal cord protection during open repair of thoracic and thoracoabdominal aortic aneurysms using profound hypothermia and circulatory arrest. J Am Coll Surg, 2011; 212:678–683discussion 684–685.

137.

Svensson

, Crawford

, Hess

, Coselli

, Safi

. Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg, 1993; 17:357–368discussion 68–70.

138.

Svyatets

, Tolani

, Zhang

, Tulman

, Charchaflieh

. Perioperative management of deep hypothermic circulatory arrest. J Cardiothorac Vasc Anesth, 2010; 24:644–655.

139.

Tabayashi

, Motoyoshi

, Saiki

, Kokubo

, Takahashi

, Masuda

, Shibuya

, Akasaka

, Oda

, Kamata

, Iguti

. Efficacy of perfusion cooling of the epidural space and cerebrospinal fluid drainage during repair of extent I and II thoracoabdominal aneurysm. J Cardiovasc Surg (Torino), 2008; 49:749–755.

140.

Tabayashi

, Niibori

, Konno

, Mohri

. Protection from postischemic spinal cord injury by perfusion cooling of the epidural space. Ann Thorac Surg, 1993; 56:494–498.

141.

Tabayashi

, Saiki

, Kokubo

, Takahashi

, Akasaka

, Yoshida

, Hata

, Niibori

, Miura

, Konnai

. Protection from postischemic spinal cord injury by perfusion cooling of the epidural space during most or all of a descending thoracic or thoracoabdominal aneurysm repair. Gen Thorac Cardiovasc Surg, 2010; 58:228–234.

142.

Takahashi

, Orihashi

, Imai

, Mizukami

, Takasaki

, Sueda

. Cold blood spinoplegia under motor-evoked potential monitoring during thoracic aortic surgery. J Thorac Cardiovasc Surg, 2011; 141:755–761.

143.

Tirapelli

, Carlotti

Jr. , Leite

, Tirapelli

, Colli

. Expression of HSP70 in cerebral ischemia and neuroprotetive action of hypothermia and ketoprofen. Arq Neuropsiquiatr, 2010; 68:592–596.

144.

Tisherman

. Cannabinoids after cardiac arrest: should your brain be on drugs? Crit Care Med, 2010; 38:2409–2410.

145.

Truettner

, Alonso

, Bramlett

, Dietrich

. Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats. J Cereb Blood Flow Metab, 2011; 31:1897–1907.

146.

Tschop

, Czerner

, Nuscheler

, Thiel

. Epiduralcooling. Neuroprotective treatment of thoracoabdominal aortic aneurysms. Anaesthesist, 2008; 57:988–997.

147.

Vacanti

, Ames

3rd . Mild hypothermia and Mg⁺⁺ protect against irreversible damage during CNS ischemia. Stroke, 1984; 15:695–698.

148.

Van Dongen

, Schepens

, Morshuis

, ter Beek

, Aarts

, de Boer

, Boezeman

. Thoracic and thoracoabdominal aortic aneurysm repair: use of evoked potential monitoring in 118 patients. J Vasc Surg, 2001; 34:1035–1040.

149.

Van Hemelrijck

, Hachimi-Idrissi

, Sarre

, Ebinger

, Michotte

. Post-ischaemic mild hypothermia inhibits apoptosis in the penumbral region by reducing neuronal nitric oxide synthase activity and thereby preventing endothelin-1-induced hydroxyl radical formation. Eur J Neurosci, 2005; 22:1327–1337.

150.

Van Oss

, Absolom

, Moore

, Park

, Humbert

. Effect of temperature on the chemotaxis, phagocytic engulfment, digestion and O₂ consumption of human polymorphonuclear leukocytes. J Reticuloendothel Soc, 1980; 27:561–565.

151.

Van Rheineck Leyssius

, Kalkman

, Bovill

. Influence of moderate hypothermia on posterior tibial nerve somatosensory evoked potentials. Anesth Analg, 1986; 65:475–480.

152.

Vanicky

, Marsala

, Galik

, Marsala

. Epidural perfusion cooling protection against protracted spinal cord ischemia in rabbits. J Neurosurg, 1993; 79:736–741.

153.

Von Segesser

, Marty

, Mueller

, Ruchat

, Gersbach

, Stumpe

, Fischer

. Active cooling during open repair of thoraco-abdominal aortic aneurysms improves outcome. Eur J Cardiothorac Surg, 2001; 19:411–415discussion 415–416.

154.

Vosler

, Logue

, Repine

, Callaway

. Delayed hypothermia preferentially increases expression of brain-derivedneurotrophic factor exon III in rat hippocampus after asphyxial cardiac arrest. Brain Res Mol Brain Res, 2005; 135:21–29.

155.

Wang

, Than

, Etame

, La Marca

, Park

. Impact of anesthesia on transcranial electric motor evoked potential monitoring during spine surgery: a review of the literature. Neurosurg Focus, 2009; 27:E7.

156.

Wang

, Yan

, Zou

, Jing

, Xu

. Moderate hypothermia prevents neural cell apoptosis following spinal cord ischemia in rabbits. Cell Res, 2005; 15:387–393.

157.

Wang

, Jung

, Asahi

, Chwang

, Russo

, Moskowitz

, Dixon

, Fini

, Lo

. Effects of matrix metalloproteinase-9 gene knock-out on morphological and motor outcomes after traumatic brain injury. J Neurosci, 2000; 20:7037–7042.

158.

Wang

, Yang

, Britz

, Lombard

, Warner

, Sheng

. Development of a simplified spinal cord ischemia model in mice. J Neurosci Methods, 2010; 189:246–251.

159.

Wenisch

, Narzt

, Sessler

, Parschalk

, Lenhardt

, Kurz

, Graninger

. Mild intraoperative hypothermia reduces production of reactive oxygen intermediates by polymorphonuclear leukocytes. Anesth Analg, 1996; 82:810–816.

160.

Winfree

, Baker

, Connolly

Jr. , Fiore

, Solomon

. Mild hypothermia reduces penumbral glutamate levels in the rat permanent focal cerebral ischemia model. Neurosurgery, 1996; 38:1216–1222.

161.

Wisselink

, Becker

, Nguyen

, Money

, Hollier

. Protecting the ischemic spinal cord during aortic clamping:the influence of selective hypothermia and spinal cord perfusion pressure. J Vasc Surg, 1994; 19:788–795discussion 95–96.

162.

Wong

, Parenti

, Green

, Chowdhary

, Liao

, Zarda

, Huh

, LeMaire

, Coselli

. Open repair of thoracoabdominal aortic aneurysm in the modern surgical era: contemporary outcomes in 509 patients. J Am Coll Surg, 2011; 212:569–579discussion 79–81.

163.

, Yenari

, Steinberg

, Giffard

. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb Blood Flow Metab, 2002; 22:21–28.

164.

Yamamoto

, Mitani

, Cui

, Takechi

, Irita

, Suga

, Arai

, Kataoka

. Neuroprotective effect of mild hypothermia cannot be explained in terms of a reduction of glutamate release during ischemia. Neuroscience, 1999; 91:501–509.

165.

Yang

, Xie

, Guo

, Li

. Induction of MAPK phosphatase-1 by hypothermia inhibits TNF-alpha-induced endothelial barrier dysfunction and apoptosis. Cardiovasc Res, 2010; 85:520–529.

166.

Yenari

, Iwayama

, Cheng

, Sun

, Fujimura

, Morita-Fujimura

, Chan

, Steinberg

. Mild hypothermia attenuates cytochrome c release but does not alter Bcl-2 expression or caspase activation after experimental stroke. J Cereb Blood Flow Metab, 2002; 22:29–38.

167.

Yoshitake

, Mori

, Shimizu

, Ueda

, Kabei

, Hachiya

, Okano

, Yozu

. Use of an epidural cooling catheter with a closed countercurrent lumen to protect against ischemic spinal cord injury in pigs. J Thorac Cardiovasc Surg, 2007; 134:1220–1226.

168.

Zhang

, Sobel

, Cheng

, Steinberg

, Yenari

. Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia. Brain Res Mol Brain Res, 2001; 95:75–85.

169.

Zhao

, Shimohata

, Wang

, Sun

, Schaal

, Sapolsky

, Steinberg

. Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J Neurosci, 2005; 25:9794–9806.

170.

Zheng

, Yenari

. Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res, 2004; 26:884–892.