Ignite Creation Date:
2024-05-05 @ 11:48 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00135278
Status:
COMPLETED
Last Update Posted:
2017-10-26
First Post:
2005-08-23
Brief Title:
Cerebrospinal Fluid CSF Drainage and Cytokine Profiling in the Treatment of Acute Spinal Cord Injury SCI
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
Cerebrospinal Fluid CSF Drainage and Cytokine Profiling in the Treatment of Acute Spinal Cord Injury SCI - A Pilot Study
Status:
COMPLETED
Status Verified Date:
2017-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The overall purpose of this pilot study is to evaluate CSF drainage as a potential neuroprotective strategy after acute spinal cord injury SCI
Detailed Description:
This pilot study will evaluate the safety and feasibility of a clinical trial protocol for cerebrospinal fluid CSF drainage as a potential treatment for patients with acute spinal cord injury Specifically the investigators will evaluate
patient eligibility and recruitment for such a study and how soon CSF drainage can be instituted in such patients
adverse events and safety of CSF drain insertion and drainage in the setting of acute spinal cord injury
neurologic recovery after injury and
cytokine expression within the CSF and blood after injury
Following informed consent patients with spinal cord injuries who agree to participate in the study will have a lumbar CSF drain placed and be randomized to either
CSF drainage to maintain a constant intrathecal pressure or
no CSF drainage
Both groups will have CSF and blood sampled at pre-defined intervals in order to evaluate CSF cytokine expression after acute spinal cord injury For comparison against the injured condition CSF and blood from a normal group of uninjured individuals will be obtained These individuals will be patients undergoing hip or knee surgery under a spinal anesthetic where a small sample of CSF can be taken when their intrathecal space is accessed for the anesthesia
Outcomes that will be measured in spinal cord injured patients include the eligibility and recruitment rate of patients the time required to institute lumbar drainage and adverse effects related to CSF drain insertion and CSF drainage Neurologic function will be measured according to American Spinal Injury Association ASIA standards Patient-reported quality of life and functional independence measurements will be evaluated CSF and serum will be evaluated for the expression of inflammatory cytokines
The results of this pilot study will provide feasibility and safety information that will be critical in the both the decision to pursue and in the planning of a larger prospective randomized clinical trial to formally assess the clinical efficacy of CSF drainage as a therapy for patients with acute spinal cord injury
BACKGROUND INFORMATIONSTUDY RATIONALE
Traumatic Spinal Cord Injuries - Epidemiology and Research Overview
Few traumas to the human body are as suddenly and permanently devastating as spinal cord injuries Unfortunately it is most often young highly productive otherwise healthy adults who sustain such injuries and thereafter suffer lifelong loss of movement sensation and bowel bladder and sexual function In North America over 10000 people sustain a spinal cord injury each year and currently there are estimated to be over 250000 individuals living with chronic spinal cord paralysis Sekhon and Fehlings 2001 Important advances in medical surgical and rehabilitative treatments have improved the clinical care of spinal cord injured patients over the past few decades Nevertheless there are still no convincingly effective treatments currently available to improve the neurological status of these patients and as such their paralysis is currently an incurable condition
This rather dismal neurologic prognosis has stimulated significant research efforts to understand the neurobiology of spinal cord injury and develop effective therapies for it This international effort has tremendously increased our understanding of the neuropathology of spinal cord injury and has shed much insight into the acute and chronic pathophysiologic processes that inhibit neural regeneration and functional recovery reviewed by Kwon et al 2002 The large majority of research into spinal cord repair strategies can be conceptually divided into two streams
research on the acute pathophysiologic processes that occur immediately or soon after injury with the aim of developing neuroprotective therapies that attenuate these processes to minimize secondary spinal cord damage and
research on the intrinsic and extrinsic impediments to axonal re-growth within the central nervous system with the aim of developing axonal regeneration therapies that would promote axonal growth across the injured spinal cord and thus mediate recovery after spinal cord injury Kwon et al 2004a
Pathophysiology of Traumatic Spinal Cord Injuries - The Role of Ischemia
The majority of individuals who sustain spinal cord injuries do not suffer a complete transection of their spinal cords even if they have functionally complete paralysis Rather while the initial primary mechanical impact interrupts axons at the site of injury and disrupts the local neuronal and glial cytoarchitecture a proportion of the spinal cord usually the outer rim escapes intact This spared tissue however is then subject to a complex cascade of acute pathophysiologic processes that cause further secondary damage These interrelated processes include ionic homeostasis abnormalities excitotoxicity programmed cell death tissue ischemia and inflammation Kwon et al 2004b Neuroprotective therapies aim to counteract these processes thereby averting further secondary damage and maximizing the extent of spared cord tissue Animal studies have demonstrated that significant neurologic function can be mediated by small amounts of spared cord tissue and in this regard even small neuroprotective effects might reap substantial functional benefits to patients
Vascular disruption and local tissue ischemia have long been recognized as important aspects of secondary damage following acute traumatic spinal cord injury Ischemia and resultant cellular energy failure is thought to contribute to the propagation of many other important pathophysiologic processes and in this regard has been argued by some to be the most critical component of secondary damage Amar and Levy 1999 Mechanical disruption of the microvasculature causes petechial hemorrhage and intravascular thrombosis which in combination with vasospasm of intact vessels and edema at the injury site can lead to profound local hypoperfusion and ischemia Tator and Fehlings 1991 This is primarily a microvascular phenomenon with the larger caliber vessels such as the anterior spinal artery normally being spared Koyanagi et al 1993 Human post-mortem studies have demonstrated that vascular perfusion is substantially worse in the grey matter than in the white matter which may be related to the disruption andor thrombosis of the sulcal arterial network that centrifugally supplies much of the grey matter Tator and Koyanagi 1997 The high metabolic requirements of neurons make the grey matter exquisitely sensitive to ischemia injury which can be compounded by the loss of autoregulatory mechanisms which normally maintain fairly constant microvascular hemodynamics within the spinal cord during systolic blood pressure fluctuations Senter and Venes 1979 The loss of autoregulation makes the cord vulnerable to further ischemic insult from systemic hypotension Kobrine et al 1975
The Role of Ischemia in Non-Traumatic Spinal Cord Injury
Up to this point the discussion has focused on spinal cord injuries caused by blunt trauma and the role that ischemia plays in the secondary injury cascade Ischemia alone however can also be the primary etiologic process behind paralysis in non-traumatic circumstances Such is the case in patients undergoing thoracoabdominal aortic aneurysm TAAA repair In these surgeries the aorta is clamped and segmental vessels ligated thus depriving the spinal cord of its blood supply to an extent that is influenced by the severity and location of the aneurysm and the duration of the vascular occlusion The incidence of paralysis caused by this ischemic insult has been estimated between 38 to 176 Crawford and Rubio 1973 but has been reported to be as high as 28 to 41 after the repair of particular types of aneurysms Crawford et al 1986 Safi et al 1996 As perioperative paraplegia is one of the most devastating complications of this surgery a number of adjunctive treatments have been investigated as prophylactic or therapeutic interventions These include generalized or local hypothermia medications such as steroids naloxone barbiturates papaverine reattachment of intercostal arteries and CSF drainage Wan et al 2001 In principle these interventions aim to reduce spinal cord ischemia by either improving vascular perfusion increasing cellular oxygen supply or by reducing metabolic activity decreasing cellular oxygen demand
CSF Drainage as a Method for Preventing or Treating Spinal Cord Ischemia
The drainage of CSF has emerged as an accepted intervention for reducing the risk of ischemic paralysis in patients undergoing thoracoabdominal aortic aneurysm repair An important determinant of oxygen supply to the spinal cord is the spinal cord perfusion pressure SCPP defined as the gradient between mean distal aortic arterial pressure MDAP and CSF pressure CSFP WADA et al 2001 Conceptually the drainage of CSF reduces CSF pressure and thus increases the perfusion pressure and oxygen delivery to the spinal cord When cross clamping of the aorta occurs the distal aortic pressure decreases and the gradient between arterial and CSF pressure narrows Additionally a significant increase in CSF pressure has been demonstrated to occur with aortic cross-clamping itself WADA et al 2001 which would serve to further reduce the spinal cord perfusion pressure The reasons for this increase in CSF pressure with aortic cross-clamping are unclear but may be related to changes in venous capacitance causing sequestration of venous blood within the dura and bony neural axis Piano and Gewertz 1990 Seminal animal experiments performed decades ago demonstrated that following descending aortic occlusion a decrease of arterial pressure to or below that of CSF pressure decreasing SCPP almost universally resulted in paraplegia while the drainage of CSF to reduce CSF pressure and thus increase SCPP was effective in preventing paraplegia MIYAMOTO et al 1960 Oka and Miyamoto 1987
Since then numerous clinical reports have described the use of CSF drainage in humans undergoing TAAA repair reviewed by Ling 2000 Ling and Arellano 2000 Normal CSF pressure in humans has been documented to be approximately 13 to 15 mmHg Drenger et al 1997 Increased CSF pressures of 21 to 25 mm Hg have been demonstrated with aortic cross clamping Drenger et al 1997 WADA et al 2001 It has been advocated therefore to drain CSF in a controlled manner to maintain CSF pressure at approximately 10 mm Hg during TAAA repair Carroccio et al 2003 A prospective randomized controlled trial by Svensson et al demonstrated a 12 2 of 17 incidence of neurologic deficit in patients treated with CSF drainage compared to a 44 7 of 16 incidence in the control group p00392 Svensson et al 1998 A more recent prospective randomized controlled trial of 145 patients by Coselli et al demonstrated with an intent-to-treat analysis a significant reduction in paraplegia with CSF drainage to keep the CSF pressure around 10 mmHg Coselli et al 2002 Neurologic deficits occurred in 2 of 82 patients 27 undergoing CSF drainage and 9 of 74 patients 122 in the control group p0026 representing an 80 reduction in relative risk Both of these prospective randomized studies were terminated early at a planned interim analysis due to the significant benefit demonstrated by CSF drainage Of note complications related to the CSF drainage such as headache meningitis or subdural hemorrhage were not observed in these studies
These prospective randomized studies illustrate the potential efficacy of CSF drainage in preventing paraplegia when the spinal cord is subjected to ischemic insult In addition to this CSF drainage has been reported to be effective as a treatment in cases where the ischemic insult has already resulted in paraplegia Such reports are obviously relevant to traumatic spinal cord injuries in which some ischemic damage would likely already be present by the time CSF drainage was instituted Ackerman and Traynelis reported on the institution of CSF drainage in 6 patients who suffered ischemic paralysis 5 of whom were between 12 and 40 hours post-TAAA repair Ackerman and Traynelis 2002 In four patients who had their CSF drainage started within 14 hours of the onset of their ischemic symptoms significant neurologic recovery was achieved In three of these patients the neurologic recovery occurred immediately after the CSF catheter was inserted In two patients who had their CSF drainage started 32 and 27 hours after the onset of symptoms no neurologic recovery was observed Safi et al reported on the initiation of CSF drainage in 8 patients presenting with neurologic deficits 1 to 14 days after TAAA repair Safi et al 1997 They observed substantial neurologic recovery of at least 2 Frankel grades in all 8 patients The interpretation of these results requires acknowledgement of the fact that other treatments such as steroids and vascular support were also instituted but they do suggest that the principles of modulating spinal cord perfusion pressure with CSF drainage are still applicable in patients who have already suffered ischemic injury to the spinal cord
The Inflammatory Reaction to Spinal Cord Injury and CSF Cytokines
As stated earlier secondary damage to the spinal cord after the initial mechanical impact is mediated by a number of pathophysiologic processes including ionic homeostasis abnormalities excitotoxicity programmed cell death tissue ischemia and inflammation The preceding discussion has focused on tissue ischemia and how this might be affected by CSF drainage Inflammation appears to also play an important role in the pathophysiology of acute spinal cord injury and has thus been the focus of increasing attention in recent years The inflammatory response to spinal cord injury is mediated by cytokines that influence vascular permeability and regulate migration of inflammatory cells such as neutrophils and macrophages into the spinal cord Kwon et al 2004b The list of cytokines thought to be relevant to the inflammatory response after spinal cord injury is long and includes IL-1 IL-1 TNF IL-6 IL-10 VEGF and a variety of leukotrienes Mueller et al 2003Widenfalk et al 2003 Mitsuhashi et al 1994 Xu et al 1990 Bartholdi and Schwab 1997 Carmel et al 2001 Hayashi et al 2000 Pan et al 2002 Wang et al 1997 Recently a study of the injured spinal cords of 11 patients who died shortly after their trauma demonstrated the presence of IL-1 IL-6 and TNF positive cells within the spinal cord within 24 hours of injury Yang et al 2004
While some aspects of the inflammatory and immunologic response mediated by these cytokines may be beneficial after spinal cord injury others may be detrimental Bethea 2000 For example after a contusion spinal cord injury transgenic mice lacking the TNF receptor were found to have increased apoptosis a larger area of secondary injury and worse locomotor scores than wild-type mice Kim et al 2001 Conversely the systemic administration of IL-10 significantly reduced neuronal damage after an excitotoxic spinal cord injury Brewer et al 1999 A more sophisticated understanding of these complex responses is obviously needed Nevertheless these animal studies demonstrate the proof of concept that the manipulation of these cytokine responses has the potential to influence outcome after spinal cord injury and therefore may represent the targets for neuroprotective intervention The levels of expression for each cytokine appear to change over time and the temporal specificity of the expression likely also influences the inflammatory response
Are CSF Cytokine Measurements Representative of the Events in the Cord
Without question the most direct method of examining the cytokine response after spinal cord injury would be to obtain samples of the cord itself While this has largely been the method by which such phenomena have been examined in animal models it is obviously not possible in living human patients The recent study by Yang et al evaluated the spinal cord tissue from patients who had died but did not sample the CSF to determine how closely the cord changes were reflected in the CSF space In a rat spinal cord contusion injury model Wang et al demonstrated an increase in IL-1 in both the spinal cord tissue itself and in the CSFWang et al 1997 While the IL-10 concentration was much lower in the CSF than in the cord the increase in IL-10 in the CSF after spinal cord injury paralleled the increase observed in the cord These animal data suggest that cytokine analysis of the CSF can provide some meaningful data about what is happening within the cord
There is to our knowledge only one human study that has examined cytokine levels within the CSF of patients after acute blunt spinal cord injury This study examined levels of the eicosanoids LTC4 TXB2 and 6-keto-PGF1 between 0 and 17 days post-injury and then again at 6 months post-injuryNishisho et al 1996 These authors found an increase in all three eicosanoids and found that LTC4 levels correlated to some extent with injury severity In a study of patients undergoing thoracoabdominal aortic aneurysm repair possibly inducing ischemic insults to the spinal cord Kunihara et al demonstrated increased levels of IL-8 that were independent of serum levels and in particular noted sustained IL-8 elevation in a patient who unfortunately became paraplegic after the operationKunihara et al 2001 In a study of CSF from adult patients with severe brain injury Csuka et al demonstrated increases in IL-10 that were independent of serum IL-10 levelsCsuka et al 1999 While direct comparison with the spinal cord tissue is not possible in these human studies they do suggest that CNS injury is associated with cytokine changes that can be detected in the CSF
The involvement of cytokines in the inflammatory process and their presence in the CSF raises the potential for an additional benefit to CSF drainage which has not yet been explored in humans Kunihara and colleagues demonstrated a significant increase in the pro-inflammatory cytokine interleukin-8 IL-8 within the spinal cords of New Zealand white rabbits subjected to aortic cross-clamping Kunihara et al 2000 They went on to show that levels of IL-8 in addition to other inflammatory cytokines such as IL-10 and IL-6 were significantly elevated in the CSF of human patients undergoing TAAA repair Interestingly a patient in this series who suffering ischemic paraplegia after the TAAA had the most dramatically increased and sustained levels of IL-8 within the CSF Kunihara et al 2001 It has been proposed by these authors and others that the drainage of such pro-inflammatory CSF cytokines away from the spinal cord may itself be neuroprotective Kunihara et al 2001 Tang et al 1996 Svensson et al 1998 This hypothesis however has not been further evaluated in traumatic or non-traumatic spinal cord injuries As yet it is unclear how much CSF would need to be drained in order to achieve an effective reduction in local cytokine concentration
Summary
In summary the drainage of CSF has been shown in human clinical studies to be neuroprotective in the setting of ischemic injury to the spinal cord both with respect to prevention and treatment Given that ischemia is also a well recognized contributor to the secondary injury cascade following traumatic spinal cord injury there is a cogent rationale for the evaluation of CSF drainage in this setting acknowledging the desperate need for the development of effective treatments for such patients To our knowledge there have been no previously reported evaluations of CSF drainage in human patients who have suffered an acute traumatic spinal cord injury
Also given the enormous current worldwide interest in the inflammatory response to spinal cord injury it is reasonable to conclude that promising experimental neuroprotective interventions will be forthcoming within the near future If such strategies are to be moved from the animal models within the laboratory setting and into human patients it would be extremely useful to characterize the inflammatory response in humans and compare it to available animal data Such knowledge would not only be helpful in predicting which experimental therapies would be beneficial but also would be helpful in the definition of parameters for monitoring the effectiveness of therapeutic interventions In this regard changes in cytokineschemokines may become an additional outcome measure for the evaluation of therapeutic efficacy Moreover insights gained here may direct laboratory animal studies towards clinically relevant parameters
patient eligibility and recruitment for such a study and how soon CSF drainage can be instituted in such patients
adverse events and safety of CSF drain insertion and drainage in the setting of acute spinal cord injury
neurologic recovery after injury and
cytokine expression within the CSF and blood after injury
Following informed consent patients with spinal cord injuries who agree to participate in the study will have a lumbar CSF drain placed and be randomized to either
CSF drainage to maintain a constant intrathecal pressure or
no CSF drainage
Both groups will have CSF and blood sampled at pre-defined intervals in order to evaluate CSF cytokine expression after acute spinal cord injury For comparison against the injured condition CSF and blood from a normal group of uninjured individuals will be obtained These individuals will be patients undergoing hip or knee surgery under a spinal anesthetic where a small sample of CSF can be taken when their intrathecal space is accessed for the anesthesia
Outcomes that will be measured in spinal cord injured patients include the eligibility and recruitment rate of patients the time required to institute lumbar drainage and adverse effects related to CSF drain insertion and CSF drainage Neurologic function will be measured according to American Spinal Injury Association ASIA standards Patient-reported quality of life and functional independence measurements will be evaluated CSF and serum will be evaluated for the expression of inflammatory cytokines
The results of this pilot study will provide feasibility and safety information that will be critical in the both the decision to pursue and in the planning of a larger prospective randomized clinical trial to formally assess the clinical efficacy of CSF drainage as a therapy for patients with acute spinal cord injury
BACKGROUND INFORMATIONSTUDY RATIONALE
Traumatic Spinal Cord Injuries - Epidemiology and Research Overview
Few traumas to the human body are as suddenly and permanently devastating as spinal cord injuries Unfortunately it is most often young highly productive otherwise healthy adults who sustain such injuries and thereafter suffer lifelong loss of movement sensation and bowel bladder and sexual function In North America over 10000 people sustain a spinal cord injury each year and currently there are estimated to be over 250000 individuals living with chronic spinal cord paralysis Sekhon and Fehlings 2001 Important advances in medical surgical and rehabilitative treatments have improved the clinical care of spinal cord injured patients over the past few decades Nevertheless there are still no convincingly effective treatments currently available to improve the neurological status of these patients and as such their paralysis is currently an incurable condition
This rather dismal neurologic prognosis has stimulated significant research efforts to understand the neurobiology of spinal cord injury and develop effective therapies for it This international effort has tremendously increased our understanding of the neuropathology of spinal cord injury and has shed much insight into the acute and chronic pathophysiologic processes that inhibit neural regeneration and functional recovery reviewed by Kwon et al 2002 The large majority of research into spinal cord repair strategies can be conceptually divided into two streams
research on the acute pathophysiologic processes that occur immediately or soon after injury with the aim of developing neuroprotective therapies that attenuate these processes to minimize secondary spinal cord damage and
research on the intrinsic and extrinsic impediments to axonal re-growth within the central nervous system with the aim of developing axonal regeneration therapies that would promote axonal growth across the injured spinal cord and thus mediate recovery after spinal cord injury Kwon et al 2004a
Pathophysiology of Traumatic Spinal Cord Injuries - The Role of Ischemia
The majority of individuals who sustain spinal cord injuries do not suffer a complete transection of their spinal cords even if they have functionally complete paralysis Rather while the initial primary mechanical impact interrupts axons at the site of injury and disrupts the local neuronal and glial cytoarchitecture a proportion of the spinal cord usually the outer rim escapes intact This spared tissue however is then subject to a complex cascade of acute pathophysiologic processes that cause further secondary damage These interrelated processes include ionic homeostasis abnormalities excitotoxicity programmed cell death tissue ischemia and inflammation Kwon et al 2004b Neuroprotective therapies aim to counteract these processes thereby averting further secondary damage and maximizing the extent of spared cord tissue Animal studies have demonstrated that significant neurologic function can be mediated by small amounts of spared cord tissue and in this regard even small neuroprotective effects might reap substantial functional benefits to patients
Vascular disruption and local tissue ischemia have long been recognized as important aspects of secondary damage following acute traumatic spinal cord injury Ischemia and resultant cellular energy failure is thought to contribute to the propagation of many other important pathophysiologic processes and in this regard has been argued by some to be the most critical component of secondary damage Amar and Levy 1999 Mechanical disruption of the microvasculature causes petechial hemorrhage and intravascular thrombosis which in combination with vasospasm of intact vessels and edema at the injury site can lead to profound local hypoperfusion and ischemia Tator and Fehlings 1991 This is primarily a microvascular phenomenon with the larger caliber vessels such as the anterior spinal artery normally being spared Koyanagi et al 1993 Human post-mortem studies have demonstrated that vascular perfusion is substantially worse in the grey matter than in the white matter which may be related to the disruption andor thrombosis of the sulcal arterial network that centrifugally supplies much of the grey matter Tator and Koyanagi 1997 The high metabolic requirements of neurons make the grey matter exquisitely sensitive to ischemia injury which can be compounded by the loss of autoregulatory mechanisms which normally maintain fairly constant microvascular hemodynamics within the spinal cord during systolic blood pressure fluctuations Senter and Venes 1979 The loss of autoregulation makes the cord vulnerable to further ischemic insult from systemic hypotension Kobrine et al 1975
The Role of Ischemia in Non-Traumatic Spinal Cord Injury
Up to this point the discussion has focused on spinal cord injuries caused by blunt trauma and the role that ischemia plays in the secondary injury cascade Ischemia alone however can also be the primary etiologic process behind paralysis in non-traumatic circumstances Such is the case in patients undergoing thoracoabdominal aortic aneurysm TAAA repair In these surgeries the aorta is clamped and segmental vessels ligated thus depriving the spinal cord of its blood supply to an extent that is influenced by the severity and location of the aneurysm and the duration of the vascular occlusion The incidence of paralysis caused by this ischemic insult has been estimated between 38 to 176 Crawford and Rubio 1973 but has been reported to be as high as 28 to 41 after the repair of particular types of aneurysms Crawford et al 1986 Safi et al 1996 As perioperative paraplegia is one of the most devastating complications of this surgery a number of adjunctive treatments have been investigated as prophylactic or therapeutic interventions These include generalized or local hypothermia medications such as steroids naloxone barbiturates papaverine reattachment of intercostal arteries and CSF drainage Wan et al 2001 In principle these interventions aim to reduce spinal cord ischemia by either improving vascular perfusion increasing cellular oxygen supply or by reducing metabolic activity decreasing cellular oxygen demand
CSF Drainage as a Method for Preventing or Treating Spinal Cord Ischemia
The drainage of CSF has emerged as an accepted intervention for reducing the risk of ischemic paralysis in patients undergoing thoracoabdominal aortic aneurysm repair An important determinant of oxygen supply to the spinal cord is the spinal cord perfusion pressure SCPP defined as the gradient between mean distal aortic arterial pressure MDAP and CSF pressure CSFP WADA et al 2001 Conceptually the drainage of CSF reduces CSF pressure and thus increases the perfusion pressure and oxygen delivery to the spinal cord When cross clamping of the aorta occurs the distal aortic pressure decreases and the gradient between arterial and CSF pressure narrows Additionally a significant increase in CSF pressure has been demonstrated to occur with aortic cross-clamping itself WADA et al 2001 which would serve to further reduce the spinal cord perfusion pressure The reasons for this increase in CSF pressure with aortic cross-clamping are unclear but may be related to changes in venous capacitance causing sequestration of venous blood within the dura and bony neural axis Piano and Gewertz 1990 Seminal animal experiments performed decades ago demonstrated that following descending aortic occlusion a decrease of arterial pressure to or below that of CSF pressure decreasing SCPP almost universally resulted in paraplegia while the drainage of CSF to reduce CSF pressure and thus increase SCPP was effective in preventing paraplegia MIYAMOTO et al 1960 Oka and Miyamoto 1987
Since then numerous clinical reports have described the use of CSF drainage in humans undergoing TAAA repair reviewed by Ling 2000 Ling and Arellano 2000 Normal CSF pressure in humans has been documented to be approximately 13 to 15 mmHg Drenger et al 1997 Increased CSF pressures of 21 to 25 mm Hg have been demonstrated with aortic cross clamping Drenger et al 1997 WADA et al 2001 It has been advocated therefore to drain CSF in a controlled manner to maintain CSF pressure at approximately 10 mm Hg during TAAA repair Carroccio et al 2003 A prospective randomized controlled trial by Svensson et al demonstrated a 12 2 of 17 incidence of neurologic deficit in patients treated with CSF drainage compared to a 44 7 of 16 incidence in the control group p00392 Svensson et al 1998 A more recent prospective randomized controlled trial of 145 patients by Coselli et al demonstrated with an intent-to-treat analysis a significant reduction in paraplegia with CSF drainage to keep the CSF pressure around 10 mmHg Coselli et al 2002 Neurologic deficits occurred in 2 of 82 patients 27 undergoing CSF drainage and 9 of 74 patients 122 in the control group p0026 representing an 80 reduction in relative risk Both of these prospective randomized studies were terminated early at a planned interim analysis due to the significant benefit demonstrated by CSF drainage Of note complications related to the CSF drainage such as headache meningitis or subdural hemorrhage were not observed in these studies
These prospective randomized studies illustrate the potential efficacy of CSF drainage in preventing paraplegia when the spinal cord is subjected to ischemic insult In addition to this CSF drainage has been reported to be effective as a treatment in cases where the ischemic insult has already resulted in paraplegia Such reports are obviously relevant to traumatic spinal cord injuries in which some ischemic damage would likely already be present by the time CSF drainage was instituted Ackerman and Traynelis reported on the institution of CSF drainage in 6 patients who suffered ischemic paralysis 5 of whom were between 12 and 40 hours post-TAAA repair Ackerman and Traynelis 2002 In four patients who had their CSF drainage started within 14 hours of the onset of their ischemic symptoms significant neurologic recovery was achieved In three of these patients the neurologic recovery occurred immediately after the CSF catheter was inserted In two patients who had their CSF drainage started 32 and 27 hours after the onset of symptoms no neurologic recovery was observed Safi et al reported on the initiation of CSF drainage in 8 patients presenting with neurologic deficits 1 to 14 days after TAAA repair Safi et al 1997 They observed substantial neurologic recovery of at least 2 Frankel grades in all 8 patients The interpretation of these results requires acknowledgement of the fact that other treatments such as steroids and vascular support were also instituted but they do suggest that the principles of modulating spinal cord perfusion pressure with CSF drainage are still applicable in patients who have already suffered ischemic injury to the spinal cord
The Inflammatory Reaction to Spinal Cord Injury and CSF Cytokines
As stated earlier secondary damage to the spinal cord after the initial mechanical impact is mediated by a number of pathophysiologic processes including ionic homeostasis abnormalities excitotoxicity programmed cell death tissue ischemia and inflammation The preceding discussion has focused on tissue ischemia and how this might be affected by CSF drainage Inflammation appears to also play an important role in the pathophysiology of acute spinal cord injury and has thus been the focus of increasing attention in recent years The inflammatory response to spinal cord injury is mediated by cytokines that influence vascular permeability and regulate migration of inflammatory cells such as neutrophils and macrophages into the spinal cord Kwon et al 2004b The list of cytokines thought to be relevant to the inflammatory response after spinal cord injury is long and includes IL-1 IL-1 TNF IL-6 IL-10 VEGF and a variety of leukotrienes Mueller et al 2003Widenfalk et al 2003 Mitsuhashi et al 1994 Xu et al 1990 Bartholdi and Schwab 1997 Carmel et al 2001 Hayashi et al 2000 Pan et al 2002 Wang et al 1997 Recently a study of the injured spinal cords of 11 patients who died shortly after their trauma demonstrated the presence of IL-1 IL-6 and TNF positive cells within the spinal cord within 24 hours of injury Yang et al 2004
While some aspects of the inflammatory and immunologic response mediated by these cytokines may be beneficial after spinal cord injury others may be detrimental Bethea 2000 For example after a contusion spinal cord injury transgenic mice lacking the TNF receptor were found to have increased apoptosis a larger area of secondary injury and worse locomotor scores than wild-type mice Kim et al 2001 Conversely the systemic administration of IL-10 significantly reduced neuronal damage after an excitotoxic spinal cord injury Brewer et al 1999 A more sophisticated understanding of these complex responses is obviously needed Nevertheless these animal studies demonstrate the proof of concept that the manipulation of these cytokine responses has the potential to influence outcome after spinal cord injury and therefore may represent the targets for neuroprotective intervention The levels of expression for each cytokine appear to change over time and the temporal specificity of the expression likely also influences the inflammatory response
Are CSF Cytokine Measurements Representative of the Events in the Cord
Without question the most direct method of examining the cytokine response after spinal cord injury would be to obtain samples of the cord itself While this has largely been the method by which such phenomena have been examined in animal models it is obviously not possible in living human patients The recent study by Yang et al evaluated the spinal cord tissue from patients who had died but did not sample the CSF to determine how closely the cord changes were reflected in the CSF space In a rat spinal cord contusion injury model Wang et al demonstrated an increase in IL-1 in both the spinal cord tissue itself and in the CSFWang et al 1997 While the IL-10 concentration was much lower in the CSF than in the cord the increase in IL-10 in the CSF after spinal cord injury paralleled the increase observed in the cord These animal data suggest that cytokine analysis of the CSF can provide some meaningful data about what is happening within the cord
There is to our knowledge only one human study that has examined cytokine levels within the CSF of patients after acute blunt spinal cord injury This study examined levels of the eicosanoids LTC4 TXB2 and 6-keto-PGF1 between 0 and 17 days post-injury and then again at 6 months post-injuryNishisho et al 1996 These authors found an increase in all three eicosanoids and found that LTC4 levels correlated to some extent with injury severity In a study of patients undergoing thoracoabdominal aortic aneurysm repair possibly inducing ischemic insults to the spinal cord Kunihara et al demonstrated increased levels of IL-8 that were independent of serum levels and in particular noted sustained IL-8 elevation in a patient who unfortunately became paraplegic after the operationKunihara et al 2001 In a study of CSF from adult patients with severe brain injury Csuka et al demonstrated increases in IL-10 that were independent of serum IL-10 levelsCsuka et al 1999 While direct comparison with the spinal cord tissue is not possible in these human studies they do suggest that CNS injury is associated with cytokine changes that can be detected in the CSF
The involvement of cytokines in the inflammatory process and their presence in the CSF raises the potential for an additional benefit to CSF drainage which has not yet been explored in humans Kunihara and colleagues demonstrated a significant increase in the pro-inflammatory cytokine interleukin-8 IL-8 within the spinal cords of New Zealand white rabbits subjected to aortic cross-clamping Kunihara et al 2000 They went on to show that levels of IL-8 in addition to other inflammatory cytokines such as IL-10 and IL-6 were significantly elevated in the CSF of human patients undergoing TAAA repair Interestingly a patient in this series who suffering ischemic paraplegia after the TAAA had the most dramatically increased and sustained levels of IL-8 within the CSF Kunihara et al 2001 It has been proposed by these authors and others that the drainage of such pro-inflammatory CSF cytokines away from the spinal cord may itself be neuroprotective Kunihara et al 2001 Tang et al 1996 Svensson et al 1998 This hypothesis however has not been further evaluated in traumatic or non-traumatic spinal cord injuries As yet it is unclear how much CSF would need to be drained in order to achieve an effective reduction in local cytokine concentration
Summary
In summary the drainage of CSF has been shown in human clinical studies to be neuroprotective in the setting of ischemic injury to the spinal cord both with respect to prevention and treatment Given that ischemia is also a well recognized contributor to the secondary injury cascade following traumatic spinal cord injury there is a cogent rationale for the evaluation of CSF drainage in this setting acknowledging the desperate need for the development of effective treatments for such patients To our knowledge there have been no previously reported evaluations of CSF drainage in human patients who have suffered an acute traumatic spinal cord injury
Also given the enormous current worldwide interest in the inflammatory response to spinal cord injury it is reasonable to conclude that promising experimental neuroprotective interventions will be forthcoming within the near future If such strategies are to be moved from the animal models within the laboratory setting and into human patients it would be extremely useful to characterize the inflammatory response in humans and compare it to available animal data Such knowledge would not only be helpful in predicting which experimental therapies would be beneficial but also would be helpful in the definition of parameters for monitoring the effectiveness of therapeutic interventions In this regard changes in cytokineschemokines may become an additional outcome measure for the evaluation of therapeutic efficacy Moreover insights gained here may direct laboratory animal studies towards clinically relevant parameters
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| V05-0160 | None | None | None |