Comparison of systemic and retrograde delivery of adenosine A2A agonist for attenuation of spinal cord injury after thoracic aortic cross-clamping

T. Brett Reece; David O. Okonkwo; Peter I. Ellman; Thomas S. Maxey; Carlos Tache-Leon; Patrick S. Warren; Jeffrey J. Laurent; Joel Linden; Irving L. Kron; Curtis G. Tribble; John A. Kern

doi:10.1016/j.athoracsur.2005.09.023

Comparison of systemic and retrograde delivery of adenosine A_2A agonist for attenuation of spinal cord injury after thoracic aortic cross-clamping

T. Brett Reece, David O. Okonkwo, Peter I. Ellman, Thomas S. Maxey, Carlos Tache-Leon, Patrick S. Warren, Jeffrey J. Laurent, Joel Linden, Irving L. Kron, Curtis G. Tribble, John A. Kern

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Abstract

Background. Paraplegia remains a devastating complication of thoracic aortic surgery, which has been attenuated by retrograde adenosine and systemic adenosine A_2A receptor activation. We hypothesized that despite retrograde spinal perfusion of an adenosine A_2A agonist (ATL-146e), systemic therapy produces superior spinal cord protection with reduced inflammation. Methods. Forty pigs underwent 30-minute thoracic aortic cross-clamping. Pigs received: no therapy (control); retrograde saline (retrograde control); retrograde ATL-146e; systemic ATL-146e; systemic ATL-146e with retrograde saline; or systemic and retrograde ATL-146e. Retrograde therapies were given during ischemia. Systemic ATL-146e (0.06 μg·kg^-1·min^-1) was given intravenously for 3 hours at reperfusion. At 24 hours, motor function was assessed using the Tarlov scale. Tissue was analyzed for neuronal viability, microtubule-associated protein-2 expression, and neutrophil sequestration (myeloperoxidase activity). Results. Four pigs received retrograde barium showing both radiographic and histologic spinal cord perfusion. Tarlov scores at 24 hours were significantly improved versus both control groups in all ATL groups except the combined ATL-146e group (all p < 0.05). Neuronal viability by hematoxylin and eosin stain was significantly preserved in systemic ATL groups compared with both control groups (all p < 0.05). Microtubule-associated protein-2 expression was significantly preserved compared with both control groups in all systemic ATL groups. Systemic ATL significantly lowered myeloperoxidase activity versus both control groups (p < 0.01). Conclusions. Both retrograde and systemic ATL-146e therapies attenuate ischemic spinal cord injury, but combining the two routes was less effective. Given comparable results between the two routes and the simplicity of systemic delivery, peripheral venous ATL-146e at reperfusion should be preferred for spinal cord protection in thoracic aortic surgery.

Original language	English (US)
Pages (from-to)	902-909
Number of pages	8
Journal	Annals of Thoracic Surgery
Volume	81
Issue number	3
DOIs	https://doi.org/10.1016/j.athoracsur.2005.09.023
State	Published - Mar 2006

ASJC Scopus subject areas

Surgery
Pulmonary and Respiratory Medicine
Cardiology and Cardiovascular Medicine

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10.1016/j.athoracsur.2005.09.023

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Reece, T. B., Okonkwo, D. O., Ellman, P. I., Maxey, T. S., Tache-Leon, C., Warren, P. S., Laurent, J. J., Linden, J., Kron, I. L., Tribble, C. G., & Kern, J. A. (2006). Comparison of systemic and retrograde delivery of adenosine A_2A agonist for attenuation of spinal cord injury after thoracic aortic cross-clamping. Annals of Thoracic Surgery, 81(3), 902-909. https://doi.org/10.1016/j.athoracsur.2005.09.023

Reece, TB, Okonkwo, DO, Ellman, PI, Maxey, TS, Tache-Leon, C, Warren, PS, Laurent, JJ, Linden, J, Kron, IL, Tribble, CG & Kern, JA 2006, 'Comparison of systemic and retrograde delivery of adenosine A_2A agonist for attenuation of spinal cord injury after thoracic aortic cross-clamping', Annals of Thoracic Surgery, vol. 81, no. 3, pp. 902-909. https://doi.org/10.1016/j.athoracsur.2005.09.023

@article{a12c47a8c9644977a95bde640d832a20,

title = "Comparison of systemic and retrograde delivery of adenosine A2A agonist for attenuation of spinal cord injury after thoracic aortic cross-clamping",

abstract = "Background. Paraplegia remains a devastating complication of thoracic aortic surgery, which has been attenuated by retrograde adenosine and systemic adenosine A2A receptor activation. We hypothesized that despite retrograde spinal perfusion of an adenosine A2A agonist (ATL-146e), systemic therapy produces superior spinal cord protection with reduced inflammation. Methods. Forty pigs underwent 30-minute thoracic aortic cross-clamping. Pigs received: no therapy (control); retrograde saline (retrograde control); retrograde ATL-146e; systemic ATL-146e; systemic ATL-146e with retrograde saline; or systemic and retrograde ATL-146e. Retrograde therapies were given during ischemia. Systemic ATL-146e (0.06 μg·kg-1·min-1) was given intravenously for 3 hours at reperfusion. At 24 hours, motor function was assessed using the Tarlov scale. Tissue was analyzed for neuronal viability, microtubule-associated protein-2 expression, and neutrophil sequestration (myeloperoxidase activity). Results. Four pigs received retrograde barium showing both radiographic and histologic spinal cord perfusion. Tarlov scores at 24 hours were significantly improved versus both control groups in all ATL groups except the combined ATL-146e group (all p < 0.05). Neuronal viability by hematoxylin and eosin stain was significantly preserved in systemic ATL groups compared with both control groups (all p < 0.05). Microtubule-associated protein-2 expression was significantly preserved compared with both control groups in all systemic ATL groups. Systemic ATL significantly lowered myeloperoxidase activity versus both control groups (p < 0.01). Conclusions. Both retrograde and systemic ATL-146e therapies attenuate ischemic spinal cord injury, but combining the two routes was less effective. Given comparable results between the two routes and the simplicity of systemic delivery, peripheral venous ATL-146e at reperfusion should be preferred for spinal cord protection in thoracic aortic surgery.",

author = "Reece, {T. Brett} and Okonkwo, {David O.} and Ellman, {Peter I.} and Maxey, {Thomas S.} and Carlos Tache-Leon and Warren, {Patrick S.} and Laurent, {Jeffrey J.} and Joel Linden and Kron, {Irving L.} and Tribble, {Curtis G.} and Kern, {John A.}",

note = "Funding Information: Furthermore, retrograde delivery has instigated some controversy over the local effects of various therapies [ 22 ]. Although the regional delivery of the adenosine was supported by the filling of the epidural veins, there was no direct evidence of delivery to the spinal cord vasculature. Venous stasis from aortic cross-clamping should increase retrograde perfusion of the spinal cord. The current study was able to show that retrograde venous delivery would fill both the epidural veins and that this would penetrate the parenchymal vessels. Although these findings imply that the retrograde route does reach the spinal cord parenchyma, the barium is large to extravasate into the spinal parenchyma. Despite the lack of extravasation into the tissue, this is evidence for the local vascular delivery of therapies to the spinal cord through the accessory hemiazygous vein. ",

year = "2006",

month = mar,

doi = "10.1016/j.athoracsur.2005.09.023",

language = "English (US)",

volume = "81",

pages = "902--909",

journal = "Annals of Thoracic Surgery",

issn = "0003-4975",

publisher = "Elsevier USA",

number = "3",

}

TY - JOUR

T1 - Comparison of systemic and retrograde delivery of adenosine A2A agonist for attenuation of spinal cord injury after thoracic aortic cross-clamping

AU - Reece, T. Brett

AU - Okonkwo, David O.

AU - Ellman, Peter I.

AU - Maxey, Thomas S.

AU - Tache-Leon, Carlos

AU - Warren, Patrick S.

AU - Laurent, Jeffrey J.

AU - Linden, Joel

AU - Kron, Irving L.

AU - Tribble, Curtis G.

AU - Kern, John A.

N1 - Funding Information: Furthermore, retrograde delivery has instigated some controversy over the local effects of various therapies [ 22 ]. Although the regional delivery of the adenosine was supported by the filling of the epidural veins, there was no direct evidence of delivery to the spinal cord vasculature. Venous stasis from aortic cross-clamping should increase retrograde perfusion of the spinal cord. The current study was able to show that retrograde venous delivery would fill both the epidural veins and that this would penetrate the parenchymal vessels. Although these findings imply that the retrograde route does reach the spinal cord parenchyma, the barium is large to extravasate into the spinal parenchyma. Despite the lack of extravasation into the tissue, this is evidence for the local vascular delivery of therapies to the spinal cord through the accessory hemiazygous vein.

PY - 2006/3

Y1 - 2006/3

N2 - Background. Paraplegia remains a devastating complication of thoracic aortic surgery, which has been attenuated by retrograde adenosine and systemic adenosine A2A receptor activation. We hypothesized that despite retrograde spinal perfusion of an adenosine A2A agonist (ATL-146e), systemic therapy produces superior spinal cord protection with reduced inflammation. Methods. Forty pigs underwent 30-minute thoracic aortic cross-clamping. Pigs received: no therapy (control); retrograde saline (retrograde control); retrograde ATL-146e; systemic ATL-146e; systemic ATL-146e with retrograde saline; or systemic and retrograde ATL-146e. Retrograde therapies were given during ischemia. Systemic ATL-146e (0.06 μg·kg-1·min-1) was given intravenously for 3 hours at reperfusion. At 24 hours, motor function was assessed using the Tarlov scale. Tissue was analyzed for neuronal viability, microtubule-associated protein-2 expression, and neutrophil sequestration (myeloperoxidase activity). Results. Four pigs received retrograde barium showing both radiographic and histologic spinal cord perfusion. Tarlov scores at 24 hours were significantly improved versus both control groups in all ATL groups except the combined ATL-146e group (all p < 0.05). Neuronal viability by hematoxylin and eosin stain was significantly preserved in systemic ATL groups compared with both control groups (all p < 0.05). Microtubule-associated protein-2 expression was significantly preserved compared with both control groups in all systemic ATL groups. Systemic ATL significantly lowered myeloperoxidase activity versus both control groups (p < 0.01). Conclusions. Both retrograde and systemic ATL-146e therapies attenuate ischemic spinal cord injury, but combining the two routes was less effective. Given comparable results between the two routes and the simplicity of systemic delivery, peripheral venous ATL-146e at reperfusion should be preferred for spinal cord protection in thoracic aortic surgery.

AB - Background. Paraplegia remains a devastating complication of thoracic aortic surgery, which has been attenuated by retrograde adenosine and systemic adenosine A2A receptor activation. We hypothesized that despite retrograde spinal perfusion of an adenosine A2A agonist (ATL-146e), systemic therapy produces superior spinal cord protection with reduced inflammation. Methods. Forty pigs underwent 30-minute thoracic aortic cross-clamping. Pigs received: no therapy (control); retrograde saline (retrograde control); retrograde ATL-146e; systemic ATL-146e; systemic ATL-146e with retrograde saline; or systemic and retrograde ATL-146e. Retrograde therapies were given during ischemia. Systemic ATL-146e (0.06 μg·kg-1·min-1) was given intravenously for 3 hours at reperfusion. At 24 hours, motor function was assessed using the Tarlov scale. Tissue was analyzed for neuronal viability, microtubule-associated protein-2 expression, and neutrophil sequestration (myeloperoxidase activity). Results. Four pigs received retrograde barium showing both radiographic and histologic spinal cord perfusion. Tarlov scores at 24 hours were significantly improved versus both control groups in all ATL groups except the combined ATL-146e group (all p < 0.05). Neuronal viability by hematoxylin and eosin stain was significantly preserved in systemic ATL groups compared with both control groups (all p < 0.05). Microtubule-associated protein-2 expression was significantly preserved compared with both control groups in all systemic ATL groups. Systemic ATL significantly lowered myeloperoxidase activity versus both control groups (p < 0.01). Conclusions. Both retrograde and systemic ATL-146e therapies attenuate ischemic spinal cord injury, but combining the two routes was less effective. Given comparable results between the two routes and the simplicity of systemic delivery, peripheral venous ATL-146e at reperfusion should be preferred for spinal cord protection in thoracic aortic surgery.

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SN - 0003-4975

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JO - Annals of Thoracic Surgery

JF - Annals of Thoracic Surgery

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ER -

Comparison of systemic and retrograde delivery of adenosine A_2A agonist for attenuation of spinal cord injury after thoracic aortic cross-clamping

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