Gregory W. J. Hawryluk and Michael D. Cusimano
✓ Recombinant activated factor VII (rFVIIa) is a relatively new pharmaceutical agent developed for use in patients with hemophilia in whom inhibitors to clotting factors VIII or IX have developed. Use of this drug has become common in recent years because of its efficacy and safety in patients with coagulation disorders as well as in patients who are at high risk for thromboembolism, even when other means of establishing hemostasis have failed. The use of rFVIIa in neurosurgery has lagged behind its use in other fields, although there is a growing body of literature on such uses. In this article the authors review the history and science of rFVIIa as well as dosing and safety information. Various uses pertinent to the neurosurgeon are reviewed, including the treatment of patients with coagulation disorders, those suffering trauma, and those with perioperative hemorrhage, intracerebral hemorrhage, or subarachnoid hemorrhage. Based on their review of the uses of rFVIIa, the authors conclude that rFVIIa is a safe and effective agent with the potential to revolutionize the treatment of neurosurgical patients with hemorrhage. Cost is a major impediment to the widespread use of rFVIIa, and there is some evidence that its use in the neurosurgical population may be subject to higher risk than in other populations studied thus far. Although further study is needed to better delineate the safety and efficacy of the drug in many nonlicensed uses, it is clear that rFVIIa is an agent with tremendous promise.
Gregory W. J. Hawryluk, Perry A. Ball, Zachary L. Hickman and Joshua E. Medow
Lonnie Schneider, Ethan Reichert, Jenna Faulkner, Brielle Reichert, Joshua Sonnen and Gregory W. J. Hawryluk
Recent research demonstrates that victims of spinal cord injury (SCI) are at increased risk for dementia and that encephalitis can occur as a consequence of isolated SCI. We theorize that autoimmunity to the central nervous system (CNS) could explain these phenomena and undertook this study to determine whether peripheral inoculation with spinal cord homogenate on 1 or 2 occasions is associated with CNS-directed autoimmunity and neurodegeneration in a rat model.
Rats were subcutaneously inoculated with saline or 75 mg of allogeneic spinal cord tissue on 1 or 2 occasions. Animals underwent Morris Water Maze testing, and serial serum samples were collected. Animals were sacrificed 8 weeks following the first inoculation. Autoantibody titers to myelin antigens MAG and GM1 were measured in serum. Immunohistochemistry was used to identify autoantibodies targeting NeuN-labeled neurons and CC1-labeled oligodendrocytes. Quantitative real-time polymerase chain reaction (qPCR) and western blotting were performed for pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 and the cell death marker caspase 3 as well as the neurodegenerative proteins tau and β-amyloid in both brain and spinal cord. Fluoro-Jade B was used to stain degenerating neurons, facilitating counting.
Animals inoculated with spinal cord homogenate exhibited increased titers of autoantibodies to MAG and GM1 and autoantibodies binding to neurons and oligodendrocytes. Double-inoculated animals demonstrated a significant increase in the expression of pro-inflammatory cytokines in the brain (TNF-α, p = 0.016; IL-6, p = 0.009) as well as the spinal cord (TNF-α, p = 0.024; IL-6, p = 0.002). The number of degenerating neurons was significantly increased in the brain and spinal cord of inoculated animals (p < 0.0001 and p = 0.028, respectively). Elevated expression of tau and β-amyloid was seen in brain of double-inoculated animals (p = 0.003 and p = 0.009, respectively). Inflammatory marker expression in the brain was positively correlated with anti-myelin autoimmune antibody titers and with tau expression in the brain. Inoculated animals showed impaired memory function in Morris Water Maze testing (p = 0.043).
The results of these experiments demonstrate that peripheral exposure to spinal cord antigens is associated with CNS-directed autoimmunity and inflammation in the brain and spinal cord as well as degeneration of CNS cells, memory impairment, and production of neurodegenerative proteins particularly when this exposure is repeated. These data support CNS autoimmunity as a candidate mechanism for the dementia that can follow SCI and perhaps other posttraumatic dementias such as chronic traumatic encephalopathy.
Jian Guan, Michael Karsy, Andrea A. Brock, Ilyas M. Eli, Holly K. Ledyard, Gregory W. J. Hawryluk and Min S. Park
Hypovitaminosis D is highly prevalent among the general population. Studies have shown an association between hypovitaminosis D and multiple negative outcomes in critical care patients, but there has been no prospective evaluation of vitamin D in the neurological critical care population. The authors examined the impact of vitamin D deficiency on in-hospital mortality and a variety of secondary outcomes.
The authors prospectively collected 25-hydroxy vitamin D levels of all patients admitted to the neurocritical care unit (NCCU) of a quaternary-care center over a 3-month period. Demographic data, illness acuity, in-hospital mortality, infection, and length of hospitalization were collected. Univariate and multivariable logistic regression were used to examine the effects of vitamin D deficiency.
Four hundred fifteen patients met the inclusion criteria. In-hospital mortality was slightly worse (9.3% vs 4.5%; p = 0.059) among patients with deficient vitamin D (≤ 20 ng/dl). There was also a higher rate of urinary tract infection in patients with vitamin D deficiency (12.4% vs 4.2%; p = 0.002). For patients admitted to the NCCU on an emergency basis (n = 285), higher Simplified Acute Physiology Score II (OR 13.8, 95% CI 1.7–110.8; p = 0.014), and vitamin D deficiency (OR 3.0, 95% CI 1.0–8.6; p = 0.042) were significantly associated with increased in-hospital mortality after adjusting for other factors.
In the subset of patients admitted to the NCCU on an emergency basis, vitamin D deficiency is significantly associated with higher in-hospital mortality. Larger studies are needed to confirm these findings and to investigate the role of vitamin D supplementation in these patients.
Gregory W. J. Hawryluk, James Rowland, Brian K. Kwon and Michael G. Fehlings
Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed. Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials) also showed some promise, but we are unaware of plans for future trials with these agents. These studies have, however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who are understandably desperate for any intervention that might improve their function. Taken together, recent advances suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective therapies for SCI may become available over the next decade.
James W. Rowland, Gregory W. J. Hawryluk, Brian Kwon and Michael G. Fehlings
This review summarizes the current understanding of spinal cord injury pathophysiology and discusses important emerging regenerative approaches that have been translated into clinical trials or have a strong potential to do so. The pathophysiology of spinal cord injury involves a primary mechanical injury that directly disrupts axons, blood vessels, and cell membranes. This primary mechanical injury is followed by a secondary injury phase involving vascular dysfunction, edema, ischemia, excitotoxicity, electrolyte shifts, free radical production, inflammation, and delayed apoptotic cell death. Following injury, the mammalian central nervous system fails to adequately regenerate due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic gliotic scar. Regenerative approaches to block inhibitory signals including Nogo and the Rho-Rho–associated kinase pathways have shown promise and are in early stages of clinical evaluation. Cell-based strategies including using neural stem cells to remyelinate spared axons are an attractive emerging approach.
Jian Guan, Michael Karsy, Andrea A. Brock, Ilyas M. Eli, Gabrielle M. Manton, Holly K. Ledyard, Gregory W. J. Hawryluk and Min S. Park
Vitamin D deficiency has been associated with a variety of negative outcomes in critically ill patients, but little focused study on the effects of hypovitaminosis D has been performed in the neurocritical care population. In this study, the authors examined the effect of vitamin D deficiency on 3-month outcomes after discharge from a neurocritical care unit (NCCU).
The authors prospectively analyzed 25-hydroxy vitamin D levels in patients admitted to the NCCU of a quaternary care center over a 6-month period. Glasgow Outcome Scale (GOS) scores were used to evaluate their 3-month outcome, and univariate and multivariate logistic regression was used to evaluate the effects of vitamin D deficiency.
Four hundred ninety-seven patients met the inclusion criteria. In the binomial logistic regression model, patients without vitamin D deficiency (> 20 ng/dl) were significantly more likely to have a 3-month GOS score of 4 or 5 than those who were vitamin D deficient (OR 1.768 [95% CI 1.095–2.852]). Patients with a higher Simplified Acute Physiology Score (SAPS II) (OR 0.925 [95% CI 0.910–0.940]) and those admitted for stroke (OR 0.409 [95% CI 0.209–0.803]) or those with an “other” diagnosis (OR 0.409 [95% CI 0.217–0.772]) were significantly more likely to have a 3-month GOS score of 3 or less.
Vitamin D deficiency is associated with worse 3-month postdischarge GOS scores in patients admitted to an NCCU. Additional study is needed to determine the role of vitamin D supplementation in the NCCU population.
Scarring after spinal cord injury
Michael G. Fehlings and Gregory W. J. Hawryluk
Gregory W. J. Hawryluk, Nicolas Phan, Adam R. Ferguson, Diane Morabito, Nikita Derugin, Campbell L. Stewart, M. Margaret Knudson, Geoffrey Manley and Guy Rosenthal
The optimal site for placement of tissue oxygen probes following traumatic brain injury (TBI) remains unresolved. The authors used a previously described swine model of focal TBI and studied brain tissue oxygen tension (PbtO2) at the sites of contusion, proximal and distal to contusion, and in the contralateral hemisphere to determine the effect of probe location on PbtO2 and to assess the effects of physiological interventions on PbtO2 at these different sites.
A controlled cortical impact device was used to generate a focal lesion in the right frontal lobe in 12 anesthetized swine. PbtO2 was measured using Licox brain tissue oxygen probes placed at the site of contusion, in pericontusional tissue (proximal probe), in the right parietal region (distal probe), and in the contralateral hemisphere. PbtO2 was measured during normoxia, hyperoxia, hypoventilation, and hyperventilation.
Physiological interventions led to expected changes, including a large increase in partial pressure of oxygen in arterial blood with hyperoxia, increased intracranial pressure (ICP) with hypoventilation, and decreased ICP with hyperventilation. Importantly, PbtO2 decreased substantially with proximity to the focal injury (contusion and proximal probes), and this difference was maintained at different levels of fraction of inspired oxygen and partial pressure of carbon dioxide in arterial blood. In the distal and contralateral probes, hypoventilation and hyperventilation were associated with expected increased and decreased PbtO2 values, respectively. However, in the contusion and proximal probes, these effects were diminished, consistent with loss of cerebrovascular CO2 reactivity at and near the injury site. Similarly, hyperoxia led to the expected rise in PbtO2 only in the distal and contralateral probes, with little or no effect in the proximal and contusion probes, respectively.
PbtO2 measurements are strongly influenced by the distance from the site of focal injury. Physiological alterations, including hyperoxia, hyperventilation, and hypoventilation substantially affect PbtO2 values distal to the site of injury but have little effect in and around the site of contusion. Clinical interpretations of brain tissue oxygen measurements should take into account the spatial relation of probe position to the site of injury. The decision of where to place a brain tissue oxygen probe in TBI patients should also take these factors into consideration.