Do we have a novel, clinically applicable approach to spinal cord protection?

Paraplegia remains the most devastating complication related to thoracoabdominal aortic surgery. The early and late presentations may have disparate mechanisms, but nevertheless the outcome is the same, with a profoundly life-changing impact on the patient. Through the years, numerous strategies have been introduced with the hope of preventing paraplegia, including the use of profound hypothermic circulatory arrest, lumbar drains, intercostal artery reimplantation, and various pharmacologic adjuncts. Indeed, these efforts have shown success, and in modern high-volume aortic surgical centers the incidence of paraplegia has dropped below 5%. This devastating complication still looms large, however, for patients undergoing thoracoabdominal aortic surgery. Recently, various researchers have discovered the ability to “precondition” neurons against damage with pharmacologic agents, some of which seem quite idiosyncratic. The classic example of this is the use of erythropoietin.1 Another fascinating and somewhat surprising neuroprotective strategy seems to involve α2 adrenergic receptor stimulation. Previously, Bell and colleagues2 showed that the α2 adrenergic agonist dexmedetomidine, when given postoperatively, attenuates neuronal injury in a murine model of spinal cord ischemia and reperfusion causing delayed paraplegia. The mechanism of action is unclear but may involve increased phosphorylation of protein kinase B and subsequent phosphorylation of cyclic adenosine monophosphate response element–binding protein (CREB), a transcription factor found in previous studies to be critical for neuronal protection and survival. Cyclic adenosine monophosphate response element–binding protein has been shown to upregulate antiapoptotic factor B-cell lymphoma 2 and brain-derived factors such as glial cell line–derived neurotrophic factor (GDNF), produced by astrocytes. A criticism of the in vivo spinal cord injury models used for these studies, however, is that one can only study interventions on the entire spinal cord, making it difficult to separate the effects of various cells within the spinal cord, such as astrocytes and motor or sensory neurons. In the current issue of the Journal, Freeman and colleagues3 have reported an eloquent series of experiments designed to increase the granularity of these findings. On the basis of the hypothesis that the astrocyte plays a critical role in neuroprotection through the release of GDNF, Freeman and colleagues3 tested the role of α2 adrenergic receptor agonism with dexmedetomidine on development of GDNF in cultures of perinatal spinal cord astrocytes and neurons. Freeman and colleagues3 found that astrocytes treated with dexmedetomidine had significantly increased GDNF production relative to control levels. Neurons subjected to oxygen and glucose deprivation had significant preservation of viability with the use of dexmedetomidine-treated astrocyte media. Finally, GDNF-neutralizing antibody eliminated the protective effects of the dexmedetomidine-treated astrocyte media. Freeman and colleagues3 concluded that the α2 adrenergic agonist efficacy of dexmedetomidine in providing neuroprotection is therefore related to stimulation of GDNF from astrocytes. There are certain limitations associated with the study. First, adult neuron cell cultures are extremely difficult to obtain, and studies that use them are therefore very difficult to interpret. Only pediatric or perinatal neurons could be used for these experiments, limiting to some extent the ability to translate these results to adults. In addition, because it was not possible to separate sensory and motor neurons in culture, it cannot be known from this study whether the protective effect is skewed toward either cell type. Finally, the use of the oxygen and glucose deprivation model is intended to simulate the conditions of ischemia–reperfusion; however, this model clearly may not be entirely translatable to the clinical realm. The study of Freeman and colleagues3 also gives some insights into the potential applicability of α2 adrenergic agonism in thoracoabdominal aortic surgery. The data from this laboratory suggest that the highest concentration of GDNF is seen 24 hours after treatment with dexmedetomidine. Clinically, it would therefore be necessary to treat patients 24 to 36 hours before surgery to maximize GDNF concentration in the spinal cord at the time of ischemia–reperfusion injury. The studies of Freeman and colleagues3 are particularly intriguing because dexmedetomidine (Precedex) is already used in surgical settings as a highly effective short-acting sedative. There would therefore be few barriers to incorporating this agent into a neuroprotective protocol, potentially supplementing the largely but not entirely successful strategies that aortic surgeons use on a daily basis to prevent spinal cord injury in their patients undergoing complex thoracoabdominal aortic replacement.