J Neurosurg 48:1002-1007, 1978
The histopathology of experimental spinal cord trauma The effect of systemic blood pressure STEPHEN E. RAWE, M.D., WILLIAM A. LEE, B.S., AND PHANOR L.
PEROT, JR., M . D . , P H . D .
Department of Neurosurgery, Medical University o f South Carolina, Charleston, South Carolina
v' The early sequential histopathological alterations following a concussive paraplegic injury to the posterior thoracic spinal cord in cats were studied. The lack of significant progression of hemorrhages over a 4-hour period after injury indicates that most hemorrhages probably occur within the first hour. The marked enhancement or retardation of hemorrhages in the post-injury period, when the blood pressure was increased or decreased, respectively, demonstrates the 10ss of autoregulation of spinal cord vasculature at the trauma site after a concussive paraplegic injury. Progressive edema formation was evident over a 4-hour period following injury, and it could be enhanced or retarded by elevation or reduction of the systemic blood pressure. KEY WORDS hemorrhage edema
9 experimental spinal cord injury 9 blood pressure 9 autoregulation 9 neuronal and axonal changes 9
A
RECENT study reports that the degree o f hemorrhagic involvement in both gray and white matter following an experimental, paraplegic concussive injury to the posterior spinal cord in cats could be correlated with the systemic blood pressure at 1 hour post-injury. 2~ A study was designed to investigate the histopathological changes that occurred from 1 to 4 hours when the systemic blood pressure was altered after injury. M a t e r i a l s and Methods
Adult cats weighing between 2.5 and 3.5 kg were used in this study. All animals were anesthetized with pentobarbital (35 m g / k g ) intraperitoneally. A tracheostomy was performed, and respirations were controlled by a 1002
small animal ventilator. A femoral artery and vein were cannulated for monitoring of systemic blood pressure and for the administration of intravenous fluids. The endtidal tracheal pCO2 was monitored and controlled between 2% and 4%. Body temperature was maintained at 36 ~ to 38 ~ C. The somatosensory cortical evoked potential (SEP) was recorded by stimulation of the lower extremities as described by D'Angelo, et al? Histopathological changes in 34 cats were studied over a 1- to 4-hour period. A laminectomy was performed from T2-6, and trauma was administered at the T-5 segmental level by dropping a 25-gm weight 20 cm onto a contoured impounder resting on the exposed posterior dura. This injury force has conJ. Neurosurg. / Volume 48 / June, 1978
The histopathology of experimental spinal cord trauma sistently produced permanent paraplegia in our experimental animals. The animals were divided into three groups according to their post-traumatic blood pressure. Fourteen animals remained normotensive (80 to 120 mm Hg) following injury. In the hypotensive group of animals, 14 cats had their blood pressure temporarily lowered to between 40 and 50 mm Hg by the administration of 2% to 4% halothane before trauma in order to evaluate the presence of the SEP. The blood pressure was then allowed to return to normal levels until 15 minutes after injury. At this time, systolic blood pressure was once again lowered to between 40 and 50 mm Hg, and allowed to remain at this level for the duration of the experiment. In the hypertensive group of animals, six cats had their systolic blood pressure increased to greater than 150 mm Hg by intravenous Aramine (metaraminol bitartrate) before injury in order to evaluate the presence of the SEP. The blood pressure was then allowed to return to normal levels until 15 minutes after injury, when it was again elevated to hypertensive levels. The animals were sacrificed at 1 hour, 2 hours, or 4 hours after injury. At the termination of the experiment, the animals were sacrificed by transection of the great thoracic vessels. The traumatized section was removed, placed in 10% formalin, and subsequently sectioned in 30-~t segments, and stained with hematoxylin and eosin (H & E). Histological sections of the traumatized cord segment and nontraumatized segments above and below the areas of trauma were observed without prior knowledge of the posttraumatic blood pressure. The quantitation of hemorrhages was performed by a Lovins field finder* under medium power (X 40). Results
An SEP from stimulation of the posterior tibial nerve was recorded in all animals before trauma and was present at hypotensive and hypertensive ranges during the test responses to halothane and Aramine, respectively. After trauma, the SEP was absent in all animals and had not returned by the time of sacrifice. A pressor response to spinal cord trauma was observed in all animals. *Lovins Micro-Slide Field Finder manufactured by W. & L.E. Gurley, Troy, New York. J. Neurosurg. / Volume 48 / June, 1978
The injury force in this experimental design invariably produced subarachnoid hemorrhage and contusion of the posterior surface of the cord. At 1 hour, hemorrhages were visualized in the gray and white matter. Hemorrhages in the latter area were predominantly localized in the perigray area, but were also randomly scattered throughout the peripheral white matter. Lateralization of hemorrhages in the gray and white matter was observed on the side of the cord when the impact was not imparted to the center of the posterior surface. Quantitatively, hemorrhagic involvement of the gray matter was 50%, and white matter was 6% for normotensive animals (Table 1). By 4 hours, hemorrhages had increased, but not significantly from 1 hour, to 61% for gray and 10% for white matter, and there appeared to be greater coalescence of hemorrhages. In the hypotensive group of animals, there was a marked reduction of hemorrhages which did not increase significantly by 4 hours (Fig. 1, Table 1). Coalescence of hemorrhages was less in the 4-hour hypotensive animals than 4hour normotensive ones. Hypertensive animals demonstrated a marked increase in hemorrhages at 1 hour, and extensive hemorrhagic involvement was noted throughout the white matter including the peripheral areas (Fig. 1, Table 1). No significant increase of hemorrhages was observed at 2 hours. Fourhour hypertensive animals were not considered valid because of the inability to maintain an elevated systemic blood pressure for that period of time. High-power observation of sections from normotensive animals revealed that many neurons were obscured and encrusted by red blood cells. Those neuronal cell bodies which were visualized were either angulated and shrunken or swollen. Except for somewhat greater coalescence of hemorrhages in the central gray matter, similar changes were observed at 4 hours in the normotensive animals. Severe neuronal changes were also evident in the hypotensive group of animals at all time periods. However, these changes appeared to be less marked than those of normotensive animals and more neurons were visualized. In the hypertensive group of animals, neuronal changes were severe, and the majority of neuronal cell bodies were obliterated by hemorrhages. Axonal swelling was evident throughout 1003
S. E. Rawe, W. A. Lee and P. L. Perot, Jr. TABLE 1
Number o f gray and white matter thoracic hemorrhages after injury Post-Injury
I hr
2 hrs
4 hrs
Blood Pressure Group
Gray Matter
White Matter
Gray Matter
White Matter
Gray Matter
White Matter
hypertensive cats mean hemorrhages (70) SEM no. cats
66* 11 3
16 6 3
70 10 3
16 11 3
normotensive cats mean hemorrhages (70) SEM no. cats
50* 4 4
6 I 4
48 7 5
4 2 5
61 18 5
10 4 5
hypotensive cats mean hemorrhages (70) SEM no. cats
12" 3 5
4 3 5
20 6 5
2 1 5
26 10 4
4 3 4
*There was a significant difference between the hypertensive a n d hypotensive cats, and between the normotensive and hypotensive cats; p < 0.001.
FIG. 1. Sequential pathological cord sections after injury. Left." O n e hour. hours. Right." F o u r hours. Top Row." Hypertensive. Middle Row: N o r m o t e n s i v e . Hypotensive. H & E, X 7. 1004
Center." Two Bottom Row:
J. Neurosurg. / Volume 48 / J u n e , 1978
The histopathology of experimental spinal cord trauma the white matter at 1 hour in normotensive traumatic systemic blood pressure? ~ The animals. An increase in periaxonal spaces was ability to markedly retard or enhance hemoralso present and appeared most marked in the rhagic involvement by lowering or raising anterior funiculi near the anterior median systemic blood pressure when the force of infissure, posterior perigray, and in the medial jury is kept constant is related to vascular three-fourths of the lateral funiculi. An in- damage in gray and white matter, and to the crease in extracellular space was evident in absence of autoregulation of spinal cord the central gray, anterior and posterior blood flow. This study histopathologically perigray, and in the posterior columns. demonstrated the loss of autoregulation in the Although periaxonal space enlargement was area of trauma over a 4-hour period following not as marked in the posterior columns, a concussive paraplegic injury. A relative lack swelling and disruption of normal axonal of hemorrhages in the peripheral white matter organization underlying the areas where the of normo- and hypotensive animals does not main force had been imparted was apparent. exclude vascular damage to this area. This is Posteriorly, the pia-arachnoid was disrupted, demonstrated by a marked increase in hemorand occasional polymorphonuclear cells and rhages in the peripheral white matter in red blood cells were observed in the periphery hypertensive animals. Griffiths and Miller8 of the white matter. Normal axonal struc- have demonstrated altered vascular pertures were best observed in the peripheral meability in the spinal cord at the site of white of the anterior and lateral funiculi. By 4 injury with the use of Evans blue albumin hours, axonal swelling and periaxonal spaces (EBA). Although extravasation of this fluorohad increased and were now more apparent in chrome dye was not apparent in the the periphery of the anterior and lateral peripheral white matter, staining of the funiculi. In hypotensive animals, these vascular wall was. Localization of this dye is changes were not as prominent as the normo- probably in the endothelial basement memtensive animals. The changes in the 4-hour brane, TM and its presence is the first indicahypotensive animals were less than the altera- tion of vascular abnormality. 21 Despite this tions observed in the normotensive animals at vascular abnormality, significant perfusion of 1 hour after injury. In contrast, hypertensive injured vasculature was present in the outer animals demonstrated a greater increase in two-thirds of the peripheral white matter as periaxonal clear spaces, axonal swelling, and visualized by thioflavine S, a dye that stains extracellular space than was observed in the the endothelium of blood vessels through normotensive animals at similar time periods. which it perfuses? The degree of trauma used in this experimental design most likely produces a significant vascular injury Discussion throughout the white matter; however, The finding of only a slight increase in gray because of its location and orientation, white and white matter hemorrhages following a matter vascularity, particularly in the concussive paraplegic injury to the spinal peripheral areas, may be more resistant to cord indicates that the majority of hemor- traumatic injury than gray matter vasrhages occurred during the first hour follow- culature. ing trauma. Although coalescence of hemorAutoregulation of spinal cord blood flow rhagic sites was apparent at later time (SCBF) has been documented by several periods, there did not appear to be a signifi- investigators in uninjured dogs and moncant progression of the hemorrhagic involve- keys. 7,13,15 Although studies of autoregulament from central gray to the peripheral tion by means of quantitative SCBF deterwhite matter. Ultrastructural studies5.e and minations have not been measured in the microangiographic studies suggest that the post-injury cord, trauma might be expected to hemorrhages are the result of shearing forces result in its impairment or absence. Impaired exerted on microvasculature by mechanical or abolished autoregulation from trauma may result in increased susceptibility of vastrauma. ~.4 This study confirmed earlier observations culature to mechanical disruption by sudden that the severity of hemorrhagic involvement, increases of perfusion pressure when Aramine particularly in the central gray at 1 hour after is administered. Markedly increased hemorinjury, could be correlated with the post- rhagic involvement throughout the gray and J. Neurosurg. / Volume 48 / June, 1978
1005
S. E. Rawe, W. A. Lee and P. L. Perot, Jr. white matter, even in peripheral white matter areas, occurred in this study when the animals were hypertensive after injury. This is probably secondary to rupture of already damaged endothelial tight junctions, g-" However, the lack of hemorrhagic involvement in nontraumatized cord segment indicates that hemorrhages are not solely related to systemic blood pressure elevation by Aramine. Halothane, a known cerebral vasodilator, 2,16,2~ impairs autoregulation, 1~,18 and results in a decrease in cerebral oxygen demand. a2,16,~7 Although the vasodilatory effect of haiothane might be expected to be beneficial to cord perfusion, the use of 2% to 4% concentrations in this study results in such significant hypotension that blood flow is probably not increased, TM and vessels are usually maximally dilated by the hypotension alone. The absence of autoregulation and the existence of a hypotensive blood pressure following injury most likely result in a decrease of perfusion and account for the diminution of hemorrhages from injured vasculature. Impairment of autoregulation by this agent could be further detrimental if blood pressure is raised too rapidly3~ Neuronal changes were severe at all time periods following injury regardless of blood pressure. The neuronal cell population observed in the hyper- and hypotensive animals appeared to be partly related to the amount of central hemorrhages that were present. Greater hemorrhages in the hypotensive animals increased the severity of neuronal changes while less severe changes were observed in the hypotensive animals with less hemorrhages. The progressive increase in periaxonal clear spaces, axonal swelling, and extracellular space over a 4-hour period is probably secondary to progressive edema formation. Edema formation could be retarded or enhanced by alterations of systemic blood pressure following traumatic injury. Hypotensive preparations displayed less increase in periaxonal spaces and axonal swelling for corresponding time intervals than did normotensive ones. Hypertensive preparations conversely demonstrated earlier increases in periaxonal spaces and axonal swelling. Klatzo, et al.,~ have demonstrated in a study of cold-injury edema that systolic blood pressure plays a significant role in the enhancement or ]006
retardation of edema formation. An outpouring of serum and red blood cells from disruption of microvasculature as a result of direct mechanical injury may significantly contribute to the increase in extracellular space. It appears that two mechanisms are responsible for the accentuation of edema formation as early as 1 hour following injury in the peripheral white matter of hypertensive animals. Edema formation centrally may be enhanced by the elevation of systemic blood pressure with a more rapid progression to the peripheral white matter. Also, altered vascular permeability and/or disruption of peripheral vasculature as evidenced by the presence of hemorrhages most likely lead to early edema formation in these peripheral areas. The less pronounced histopathological changes in periaxonal clear spaces and axonal swelling in the hypotensive preparations may be the result of retardation of edema formation from a low systolic blood pressure and less disruption of peripheral vasculature as evidenced by the lack of hemorrhages in the white matter. The results of this study suggest that elevation of the systemic blood pressure in the post-injury period after a concussive-type spinal cord injury may be harmful. Disruption of already damaged vasculature with increased hemorrhages and enhancement of edema formation may result. However, lowering the blood pressure in order to retard hemorrhages and edema formation might prove deleterious in that ischemic changes in the white matter vasculature may occur in the presence of an impaired autoregulation of spinal cord white matter vasculature. The maintenance of a normotensive range of blood pressure is probably optimal in the treatment of acute spinal cord injury. References
1. Allen WE III, D'Angelo CM, Kier EL: Correlation of microangiographic and electrophysiologic changes in experimental spinal cord trauma. Radiology 111:107-115, 1974 2. Christensen MS, H~edt-Rasmussen K, Lassen NA: Cerebral vasodilatation by halothane anaesthesia in man and its potentiation by hypotension and hypercapnia. Br J Anaesth 39:927-934, 1967 3. D'Angelo CM, VanGilder JC, Taub AT: Evoked cortical potentials in experimental spinal cord trauma. J Neurosurg 38:332-336, 1973 J. Neurosurg. / Volume 48 / June, 1978
The histopathology of experimental spinal cord trauma 4, Dohrmann G J, Allen WE III: Microcirculation of traumatized spinal cord. A correlation of microangiography and blood flow patterns in transitory and permanent paraplegia. J Trauma 15:1003-1013, 1975 5. Dohrmann G J, Wagner FC Jr, Bucy PC: Transitory traumatic paraplegia: electron microscopy of early alterations in myelinated nerve fibers. J Neurosurg 36:407-415, 1972 6. Goodman JH, Bingham WG Jr, Hunt WE: Ultrastructural blood-brain barrier alterations and edema formation in acute spinal cord trauma. J Neurosurg 44:418-424, 1976 7. Griffiths IR: Spinal cord blood flow in dogs: the effect of blood pressure. J Neurol Neurosurg Psychiatry 36:914-920, 1973 8. Griffiths IR, Miller R: Vascular permeability to protein and vasogenic oedema in experimental concussive injuries to the canine spinal cord. J Neurol Sci 22:291-304, 1974 9. Haggendal E, Johansson B: On the pathophysiology of the increased cerebrovascular permeability in acute arterial hypertension in cats. Acta Neurol Scand 48:265-270, 1972 10. H~ggengal E, Johansson B: Pathophysiological aspects of the blood brain barrier change in acute arterial hypertension. Eur Neurol 6:24-28, 1971 11. Johansson B, Li C-L, Olsson Y, et al: The effect of acute arterial hypertension on the blood-brain barrier to protein tracers. Acta Neuropathol 16:117-124, 1970 12. Keaney NP, Pickerodt VW, McDowall DG: Cerebral circulatory and metabolic effects of hypotension produced by deep halothane anaesthesia. J Neurol Neurosurg Psychiatry 36:898-905, 1973 13. Kindt GW: Autoregulation of spinal cord blood flow. Eur Neurol 6:19-23, 1971 14. Klatzo I, Wi~niewski CT, Steinwall O, et al: Dynamics of cold injury edema, in Klatzo I, Seitelberger F (eds): Brain Edema. New York: Springer-Verlag, 1967, pp 554-563
J. Neurosurg. / Volume 48 / June, I978
15. Kobrine AI, Doyle TF, Rizzoli HV: Spinal cord blood flow as affected by changes in systemic arterial blood pressure. J Neurosurg 44:12-15, 1976 16. McDowall DG: The effects of clinical concentrations of halothane on the blood flow and oxygen uptake of the cerebral cortex. Br J Anaesth 39:186-196, 1967 17. Michenfelder JD: In vivo toxic effects of halothane on canine cerebral metabolic pathways. Am J Physiol 229:1050-1055, 1975 18. Miletich D J, lvankovich AD, Albrecht RF, et al: Absence of autoregulation of cerebral blood flow during halothane and enflurane anesthesia. Anesth Analg 55:100-109, 1976 19. Olsson Y, Hossmann K-A: Fine structural localization of exudated protein tracers in the brain. Acta Neuropathol 16:103-116, 1970 20. Rawe SE, Roth RH, Collins WF: Norepinephrine levels in experimental spinal cord trauma. Part 2: Histopathological study of hemorrhagic necrosis. J Neurosurg 46: 350-357, 1977 21. Rinder L, Olsson Y: Studies on vascular permeability changes in experimental brain concussion. I. Distribution of circulating fluorescent indicators in brain and cervical cord after sudden mechanical loading of the brain. Acta Neuropathol 11:183-200, 1968 22. Wollman H, Alexander SC, Cohen P J, et al: Cerebral circulation of man during halothane anesthesia. Effects of hypocarbia and of dtubocurarine. Anesthesiology 25:180-184, 1964
This work was supported by NINCDS Spinal Cord Injury Grants NS 10174-02 and 10174-03. Address reprint requests to: Stephen E. Rawe, M.D., Medical University Hospital, Department of Neurosurgery, 171 Ashley Avenue, Charleston, South Carolina 29403.
"1007
The histopathology of experimental spinal cord trauma The effect of systemic blood pressure STEPHEN E. RAWE, M.D., WILLIAM A. LEE, B.S., AND PHANOR L.
PEROT, JR., M . D . , P H . D .
Department of Neurosurgery, Medical University o f South Carolina, Charleston, South Carolina
v' The early sequential histopathological alterations following a concussive paraplegic injury to the posterior thoracic spinal cord in cats were studied. The lack of significant progression of hemorrhages over a 4-hour period after injury indicates that most hemorrhages probably occur within the first hour. The marked enhancement or retardation of hemorrhages in the post-injury period, when the blood pressure was increased or decreased, respectively, demonstrates the 10ss of autoregulation of spinal cord vasculature at the trauma site after a concussive paraplegic injury. Progressive edema formation was evident over a 4-hour period following injury, and it could be enhanced or retarded by elevation or reduction of the systemic blood pressure. KEY WORDS hemorrhage edema
9 experimental spinal cord injury 9 blood pressure 9 autoregulation 9 neuronal and axonal changes 9
A
RECENT study reports that the degree o f hemorrhagic involvement in both gray and white matter following an experimental, paraplegic concussive injury to the posterior spinal cord in cats could be correlated with the systemic blood pressure at 1 hour post-injury. 2~ A study was designed to investigate the histopathological changes that occurred from 1 to 4 hours when the systemic blood pressure was altered after injury. M a t e r i a l s and Methods
Adult cats weighing between 2.5 and 3.5 kg were used in this study. All animals were anesthetized with pentobarbital (35 m g / k g ) intraperitoneally. A tracheostomy was performed, and respirations were controlled by a 1002
small animal ventilator. A femoral artery and vein were cannulated for monitoring of systemic blood pressure and for the administration of intravenous fluids. The endtidal tracheal pCO2 was monitored and controlled between 2% and 4%. Body temperature was maintained at 36 ~ to 38 ~ C. The somatosensory cortical evoked potential (SEP) was recorded by stimulation of the lower extremities as described by D'Angelo, et al? Histopathological changes in 34 cats were studied over a 1- to 4-hour period. A laminectomy was performed from T2-6, and trauma was administered at the T-5 segmental level by dropping a 25-gm weight 20 cm onto a contoured impounder resting on the exposed posterior dura. This injury force has conJ. Neurosurg. / Volume 48 / June, 1978
The histopathology of experimental spinal cord trauma sistently produced permanent paraplegia in our experimental animals. The animals were divided into three groups according to their post-traumatic blood pressure. Fourteen animals remained normotensive (80 to 120 mm Hg) following injury. In the hypotensive group of animals, 14 cats had their blood pressure temporarily lowered to between 40 and 50 mm Hg by the administration of 2% to 4% halothane before trauma in order to evaluate the presence of the SEP. The blood pressure was then allowed to return to normal levels until 15 minutes after injury. At this time, systolic blood pressure was once again lowered to between 40 and 50 mm Hg, and allowed to remain at this level for the duration of the experiment. In the hypertensive group of animals, six cats had their systolic blood pressure increased to greater than 150 mm Hg by intravenous Aramine (metaraminol bitartrate) before injury in order to evaluate the presence of the SEP. The blood pressure was then allowed to return to normal levels until 15 minutes after injury, when it was again elevated to hypertensive levels. The animals were sacrificed at 1 hour, 2 hours, or 4 hours after injury. At the termination of the experiment, the animals were sacrificed by transection of the great thoracic vessels. The traumatized section was removed, placed in 10% formalin, and subsequently sectioned in 30-~t segments, and stained with hematoxylin and eosin (H & E). Histological sections of the traumatized cord segment and nontraumatized segments above and below the areas of trauma were observed without prior knowledge of the posttraumatic blood pressure. The quantitation of hemorrhages was performed by a Lovins field finder* under medium power (X 40). Results
An SEP from stimulation of the posterior tibial nerve was recorded in all animals before trauma and was present at hypotensive and hypertensive ranges during the test responses to halothane and Aramine, respectively. After trauma, the SEP was absent in all animals and had not returned by the time of sacrifice. A pressor response to spinal cord trauma was observed in all animals. *Lovins Micro-Slide Field Finder manufactured by W. & L.E. Gurley, Troy, New York. J. Neurosurg. / Volume 48 / June, 1978
The injury force in this experimental design invariably produced subarachnoid hemorrhage and contusion of the posterior surface of the cord. At 1 hour, hemorrhages were visualized in the gray and white matter. Hemorrhages in the latter area were predominantly localized in the perigray area, but were also randomly scattered throughout the peripheral white matter. Lateralization of hemorrhages in the gray and white matter was observed on the side of the cord when the impact was not imparted to the center of the posterior surface. Quantitatively, hemorrhagic involvement of the gray matter was 50%, and white matter was 6% for normotensive animals (Table 1). By 4 hours, hemorrhages had increased, but not significantly from 1 hour, to 61% for gray and 10% for white matter, and there appeared to be greater coalescence of hemorrhages. In the hypotensive group of animals, there was a marked reduction of hemorrhages which did not increase significantly by 4 hours (Fig. 1, Table 1). Coalescence of hemorrhages was less in the 4-hour hypotensive animals than 4hour normotensive ones. Hypertensive animals demonstrated a marked increase in hemorrhages at 1 hour, and extensive hemorrhagic involvement was noted throughout the white matter including the peripheral areas (Fig. 1, Table 1). No significant increase of hemorrhages was observed at 2 hours. Fourhour hypertensive animals were not considered valid because of the inability to maintain an elevated systemic blood pressure for that period of time. High-power observation of sections from normotensive animals revealed that many neurons were obscured and encrusted by red blood cells. Those neuronal cell bodies which were visualized were either angulated and shrunken or swollen. Except for somewhat greater coalescence of hemorrhages in the central gray matter, similar changes were observed at 4 hours in the normotensive animals. Severe neuronal changes were also evident in the hypotensive group of animals at all time periods. However, these changes appeared to be less marked than those of normotensive animals and more neurons were visualized. In the hypertensive group of animals, neuronal changes were severe, and the majority of neuronal cell bodies were obliterated by hemorrhages. Axonal swelling was evident throughout 1003
S. E. Rawe, W. A. Lee and P. L. Perot, Jr. TABLE 1
Number o f gray and white matter thoracic hemorrhages after injury Post-Injury
I hr
2 hrs
4 hrs
Blood Pressure Group
Gray Matter
White Matter
Gray Matter
White Matter
Gray Matter
White Matter
hypertensive cats mean hemorrhages (70) SEM no. cats
66* 11 3
16 6 3
70 10 3
16 11 3
normotensive cats mean hemorrhages (70) SEM no. cats
50* 4 4
6 I 4
48 7 5
4 2 5
61 18 5
10 4 5
hypotensive cats mean hemorrhages (70) SEM no. cats
12" 3 5
4 3 5
20 6 5
2 1 5
26 10 4
4 3 4
*There was a significant difference between the hypertensive a n d hypotensive cats, and between the normotensive and hypotensive cats; p < 0.001.
FIG. 1. Sequential pathological cord sections after injury. Left." O n e hour. hours. Right." F o u r hours. Top Row." Hypertensive. Middle Row: N o r m o t e n s i v e . Hypotensive. H & E, X 7. 1004
Center." Two Bottom Row:
J. Neurosurg. / Volume 48 / J u n e , 1978
The histopathology of experimental spinal cord trauma the white matter at 1 hour in normotensive traumatic systemic blood pressure? ~ The animals. An increase in periaxonal spaces was ability to markedly retard or enhance hemoralso present and appeared most marked in the rhagic involvement by lowering or raising anterior funiculi near the anterior median systemic blood pressure when the force of infissure, posterior perigray, and in the medial jury is kept constant is related to vascular three-fourths of the lateral funiculi. An in- damage in gray and white matter, and to the crease in extracellular space was evident in absence of autoregulation of spinal cord the central gray, anterior and posterior blood flow. This study histopathologically perigray, and in the posterior columns. demonstrated the loss of autoregulation in the Although periaxonal space enlargement was area of trauma over a 4-hour period following not as marked in the posterior columns, a concussive paraplegic injury. A relative lack swelling and disruption of normal axonal of hemorrhages in the peripheral white matter organization underlying the areas where the of normo- and hypotensive animals does not main force had been imparted was apparent. exclude vascular damage to this area. This is Posteriorly, the pia-arachnoid was disrupted, demonstrated by a marked increase in hemorand occasional polymorphonuclear cells and rhages in the peripheral white matter in red blood cells were observed in the periphery hypertensive animals. Griffiths and Miller8 of the white matter. Normal axonal struc- have demonstrated altered vascular pertures were best observed in the peripheral meability in the spinal cord at the site of white of the anterior and lateral funiculi. By 4 injury with the use of Evans blue albumin hours, axonal swelling and periaxonal spaces (EBA). Although extravasation of this fluorohad increased and were now more apparent in chrome dye was not apparent in the the periphery of the anterior and lateral peripheral white matter, staining of the funiculi. In hypotensive animals, these vascular wall was. Localization of this dye is changes were not as prominent as the normo- probably in the endothelial basement memtensive animals. The changes in the 4-hour brane, TM and its presence is the first indicahypotensive animals were less than the altera- tion of vascular abnormality. 21 Despite this tions observed in the normotensive animals at vascular abnormality, significant perfusion of 1 hour after injury. In contrast, hypertensive injured vasculature was present in the outer animals demonstrated a greater increase in two-thirds of the peripheral white matter as periaxonal clear spaces, axonal swelling, and visualized by thioflavine S, a dye that stains extracellular space than was observed in the the endothelium of blood vessels through normotensive animals at similar time periods. which it perfuses? The degree of trauma used in this experimental design most likely produces a significant vascular injury Discussion throughout the white matter; however, The finding of only a slight increase in gray because of its location and orientation, white and white matter hemorrhages following a matter vascularity, particularly in the concussive paraplegic injury to the spinal peripheral areas, may be more resistant to cord indicates that the majority of hemor- traumatic injury than gray matter vasrhages occurred during the first hour follow- culature. ing trauma. Although coalescence of hemorAutoregulation of spinal cord blood flow rhagic sites was apparent at later time (SCBF) has been documented by several periods, there did not appear to be a signifi- investigators in uninjured dogs and moncant progression of the hemorrhagic involve- keys. 7,13,15 Although studies of autoregulament from central gray to the peripheral tion by means of quantitative SCBF deterwhite matter. Ultrastructural studies5.e and minations have not been measured in the microangiographic studies suggest that the post-injury cord, trauma might be expected to hemorrhages are the result of shearing forces result in its impairment or absence. Impaired exerted on microvasculature by mechanical or abolished autoregulation from trauma may result in increased susceptibility of vastrauma. ~.4 This study confirmed earlier observations culature to mechanical disruption by sudden that the severity of hemorrhagic involvement, increases of perfusion pressure when Aramine particularly in the central gray at 1 hour after is administered. Markedly increased hemorinjury, could be correlated with the post- rhagic involvement throughout the gray and J. Neurosurg. / Volume 48 / June, 1978
1005
S. E. Rawe, W. A. Lee and P. L. Perot, Jr. white matter, even in peripheral white matter areas, occurred in this study when the animals were hypertensive after injury. This is probably secondary to rupture of already damaged endothelial tight junctions, g-" However, the lack of hemorrhagic involvement in nontraumatized cord segment indicates that hemorrhages are not solely related to systemic blood pressure elevation by Aramine. Halothane, a known cerebral vasodilator, 2,16,2~ impairs autoregulation, 1~,18 and results in a decrease in cerebral oxygen demand. a2,16,~7 Although the vasodilatory effect of haiothane might be expected to be beneficial to cord perfusion, the use of 2% to 4% concentrations in this study results in such significant hypotension that blood flow is probably not increased, TM and vessels are usually maximally dilated by the hypotension alone. The absence of autoregulation and the existence of a hypotensive blood pressure following injury most likely result in a decrease of perfusion and account for the diminution of hemorrhages from injured vasculature. Impairment of autoregulation by this agent could be further detrimental if blood pressure is raised too rapidly3~ Neuronal changes were severe at all time periods following injury regardless of blood pressure. The neuronal cell population observed in the hyper- and hypotensive animals appeared to be partly related to the amount of central hemorrhages that were present. Greater hemorrhages in the hypotensive animals increased the severity of neuronal changes while less severe changes were observed in the hypotensive animals with less hemorrhages. The progressive increase in periaxonal clear spaces, axonal swelling, and extracellular space over a 4-hour period is probably secondary to progressive edema formation. Edema formation could be retarded or enhanced by alterations of systemic blood pressure following traumatic injury. Hypotensive preparations displayed less increase in periaxonal spaces and axonal swelling for corresponding time intervals than did normotensive ones. Hypertensive preparations conversely demonstrated earlier increases in periaxonal spaces and axonal swelling. Klatzo, et al.,~ have demonstrated in a study of cold-injury edema that systolic blood pressure plays a significant role in the enhancement or ]006
retardation of edema formation. An outpouring of serum and red blood cells from disruption of microvasculature as a result of direct mechanical injury may significantly contribute to the increase in extracellular space. It appears that two mechanisms are responsible for the accentuation of edema formation as early as 1 hour following injury in the peripheral white matter of hypertensive animals. Edema formation centrally may be enhanced by the elevation of systemic blood pressure with a more rapid progression to the peripheral white matter. Also, altered vascular permeability and/or disruption of peripheral vasculature as evidenced by the presence of hemorrhages most likely lead to early edema formation in these peripheral areas. The less pronounced histopathological changes in periaxonal clear spaces and axonal swelling in the hypotensive preparations may be the result of retardation of edema formation from a low systolic blood pressure and less disruption of peripheral vasculature as evidenced by the lack of hemorrhages in the white matter. The results of this study suggest that elevation of the systemic blood pressure in the post-injury period after a concussive-type spinal cord injury may be harmful. Disruption of already damaged vasculature with increased hemorrhages and enhancement of edema formation may result. However, lowering the blood pressure in order to retard hemorrhages and edema formation might prove deleterious in that ischemic changes in the white matter vasculature may occur in the presence of an impaired autoregulation of spinal cord white matter vasculature. The maintenance of a normotensive range of blood pressure is probably optimal in the treatment of acute spinal cord injury. References
1. Allen WE III, D'Angelo CM, Kier EL: Correlation of microangiographic and electrophysiologic changes in experimental spinal cord trauma. Radiology 111:107-115, 1974 2. Christensen MS, H~edt-Rasmussen K, Lassen NA: Cerebral vasodilatation by halothane anaesthesia in man and its potentiation by hypotension and hypercapnia. Br J Anaesth 39:927-934, 1967 3. D'Angelo CM, VanGilder JC, Taub AT: Evoked cortical potentials in experimental spinal cord trauma. J Neurosurg 38:332-336, 1973 J. Neurosurg. / Volume 48 / June, 1978
The histopathology of experimental spinal cord trauma 4, Dohrmann G J, Allen WE III: Microcirculation of traumatized spinal cord. A correlation of microangiography and blood flow patterns in transitory and permanent paraplegia. J Trauma 15:1003-1013, 1975 5. Dohrmann G J, Wagner FC Jr, Bucy PC: Transitory traumatic paraplegia: electron microscopy of early alterations in myelinated nerve fibers. J Neurosurg 36:407-415, 1972 6. Goodman JH, Bingham WG Jr, Hunt WE: Ultrastructural blood-brain barrier alterations and edema formation in acute spinal cord trauma. J Neurosurg 44:418-424, 1976 7. Griffiths IR: Spinal cord blood flow in dogs: the effect of blood pressure. J Neurol Neurosurg Psychiatry 36:914-920, 1973 8. Griffiths IR, Miller R: Vascular permeability to protein and vasogenic oedema in experimental concussive injuries to the canine spinal cord. J Neurol Sci 22:291-304, 1974 9. Haggendal E, Johansson B: On the pathophysiology of the increased cerebrovascular permeability in acute arterial hypertension in cats. Acta Neurol Scand 48:265-270, 1972 10. H~ggengal E, Johansson B: Pathophysiological aspects of the blood brain barrier change in acute arterial hypertension. Eur Neurol 6:24-28, 1971 11. Johansson B, Li C-L, Olsson Y, et al: The effect of acute arterial hypertension on the blood-brain barrier to protein tracers. Acta Neuropathol 16:117-124, 1970 12. Keaney NP, Pickerodt VW, McDowall DG: Cerebral circulatory and metabolic effects of hypotension produced by deep halothane anaesthesia. J Neurol Neurosurg Psychiatry 36:898-905, 1973 13. Kindt GW: Autoregulation of spinal cord blood flow. Eur Neurol 6:19-23, 1971 14. Klatzo I, Wi~niewski CT, Steinwall O, et al: Dynamics of cold injury edema, in Klatzo I, Seitelberger F (eds): Brain Edema. New York: Springer-Verlag, 1967, pp 554-563
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15. Kobrine AI, Doyle TF, Rizzoli HV: Spinal cord blood flow as affected by changes in systemic arterial blood pressure. J Neurosurg 44:12-15, 1976 16. McDowall DG: The effects of clinical concentrations of halothane on the blood flow and oxygen uptake of the cerebral cortex. Br J Anaesth 39:186-196, 1967 17. Michenfelder JD: In vivo toxic effects of halothane on canine cerebral metabolic pathways. Am J Physiol 229:1050-1055, 1975 18. Miletich D J, lvankovich AD, Albrecht RF, et al: Absence of autoregulation of cerebral blood flow during halothane and enflurane anesthesia. Anesth Analg 55:100-109, 1976 19. Olsson Y, Hossmann K-A: Fine structural localization of exudated protein tracers in the brain. Acta Neuropathol 16:103-116, 1970 20. Rawe SE, Roth RH, Collins WF: Norepinephrine levels in experimental spinal cord trauma. Part 2: Histopathological study of hemorrhagic necrosis. J Neurosurg 46: 350-357, 1977 21. Rinder L, Olsson Y: Studies on vascular permeability changes in experimental brain concussion. I. Distribution of circulating fluorescent indicators in brain and cervical cord after sudden mechanical loading of the brain. Acta Neuropathol 11:183-200, 1968 22. Wollman H, Alexander SC, Cohen P J, et al: Cerebral circulation of man during halothane anesthesia. Effects of hypocarbia and of dtubocurarine. Anesthesiology 25:180-184, 1964
This work was supported by NINCDS Spinal Cord Injury Grants NS 10174-02 and 10174-03. Address reprint requests to: Stephen E. Rawe, M.D., Medical University Hospital, Department of Neurosurgery, 171 Ashley Avenue, Charleston, South Carolina 29403.
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