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Crozier-Shaw et al. Neuroimmunol Neuroinflammation 2020;7:335-44 I http://dx.doi.org/10.20517/2347-8659.2019.005 Page 339

astrocytes and form a glial scar. Within and around the glial scar, cells deposit extracellular matrix proteins
[16]
that affect axon growth . This can result in axonal growth inhibitors and then prevent axonal regeneration.
[17]
Glial scar formation is one of the main causes of the limited regenerative capability of the CNS .
Macrophage activation also plays an important cellular role in regulating neuronal damage in the injured
spinal cord. Macrophages have the ability to promote the repair of injured tissue by regulating transitions
through the different phases of the healing response. In the injured spinal cord, pro-inflammatory
[18]
macrophages potentiate a prolonged inflammatory phase and remodelling is not properly initiated .

Vascular changes
Mechanical damage to the spinal cord results in immediate vasospasm of superficial vessels and
intraparenchymal haemorrhage. This damage initially occurs in the highly vascularised, yet most vulnerable
[10]
grey matter . This leads to immediate mechanical damage to the grey matter microvasculature, which
[19]
further impairs the microcirculation to the cord and impedes perfusion . The impaired blood flow of
the damaged spinal cord may then beecome further damaged by systemic responses to the injury such as
[13]
hypotension, bradycardia and a decreased CO2, leading to further ischemic damage .
Free radical damage
Cells under stress, in pro-inflammatory states such as the acutely injured spinal cord, generate large
quantities of free radicals. These reactive species lead to ionic dysregulation when generated in excess.
They can overload and block normal cellular signalling pathways. Impaired electron pumps such as
Na /K /ATPase causes increased intracellular calcium. This leads to apoptosis, as well as mitochondrial
+
+
dysfunction, contributing to ongoing spinal cord damage [20,21] . Redox potentials within the cells then
plummet and result in oxidative damage. Such oxidative damage can continue for up to five days following
the initial injury, contributing to the pathogenesis of secondary injury. Proteins and nucleic acids are
damaged by the free radicals from red-ox reactions, leading to further ongoing damage to the spinal
[10]
cord .

MANAGEMENT STRATEGIES IN SPINAL CORD INJURY
Management strategies for acute SCIs are typically focused on negating any secondary insult, mediated by
the vascular, inflammatory and free radical changes after the primary injury. A thorough grounding in the
mechanisms described above is therefore essential for guiding appropriate management.

Cardiovascular support
Cardiovascular support for acute SCIs is essential in maintaining spinal cord perfusion after a traumatic
injury. As described, physical damage to the cord results in immediate vasospasm of the microvasculature
of the cord. Maintaining an adequate mean arterial pressure optimises cord perfusion. In particular,
patients with complete high cervical SCIs are likely to develop spinal shock with loss of sympathetic drive.
[22]
This results in hypotension due to the loss of peripheral vascular tone and concomitant bradycardia .
These patients are more likely to require vasopressor support to maintain their mean arterial pressure at
the required levels, compared to incomplete injuries and those with thoracic or lumbar levels of injury (P =
[23]
0.001) .

An observational study of 91 patients demonstrated that spinal cord perfusion pressure is an independent
[24]
predictor of neurologic recovery in acute SCI [odds ratio (OR) = 1.039, P = 0.002] . These study findings
support the need for vasopressor support in acute SCI.

High levels of evidence are not available but cohort studies have demonstrated improvement in neurologic
outcomes in patients with high average mean arterial pressure values. A mean arterial pressure of 85-90