Cerebrospinal Fluid (CSF) Drainage and Cytokine Profiling in the Treatment of Acute Spinal Cord Injury (SCI)
Condition: Spinal Cord Injuries
MeSH terms: Spinal Cord Injuries; Wounds and Injuries
Study type: Interventional

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 INFORMATION/STUDY 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 10,000 people sustain a spinal
      cord injury each year, and currently there are estimated to be over 250,000 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 and/or 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 3.8 to 17.6% (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 (p=0.0392) (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 (2.7%) undergoing CSF drainage and 9 of 74 patients
      (12.2%) in the control group (p=0.026), 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., 2003;Widenfalk 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 CSF.(Wang
      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-injury.(Nishisho 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 operation.(Kunihara 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 levels.(Csuka 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 cytokines/chemokines 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.
    

Intervention name(s): CSF Drainage; No CSF Drainage
Intervention type(s): Procedure; Procedure
Intervention description(s): See Detailed Description; See Detailed Description
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Neuroprotection; inflammation; cytokines; CSF