Dr Brian Fiani and co-authors discuss how hyperbaric oxygen therapy (HBOT) has shown promise as a potential regenerative healing approach to spinal cord injuries.
Spinal cord injury (SCI) pathophysiology consists of a primary and secondary phase. The primary phase is the initial insult where the damage first occurs, with some form of force imposed directly on the spinal cord. The outcome of the primary injury leads to the delayed secondary phase, which can involve, but not be limited to inflammation, ischemia, edema, vascular dysfunction and/or apoptotic cell death within the spinal cord. Catching the secondary phase early is critical to rehabilitation and is the major therapeutic avenue that current rehabilitation options target.
HBOT has shown promise as a potential regenerative healing approach to SCI. Historically, HBOT has involved placing a patient in an environment with increased pressure, then having the patient inspire 100% oxygen. HBOT offers potential neuroregenerative benefits, which could drastically increase patient outcomes compared to treatments whose goals are to minimize furthering damage.
After inhalation, the perfused oxygen is transported in the blood through two predominant forms: the vast majority by reversibly binding to hemoglobin in the red blood cells, and a minor fraction by physically dissolving in the plasma. As the heme moieties in the red blood cells are nearly saturated with oxygen even at normal atmospheric pressure, this method of oxygen transport can no longer be capitalised on to substantially increase the oxygen carrying capacity of blood. However, as the solubility of oxygen increases with increase in pressure, delivering oxygen at higher pressures can dramatically enhance oxygen transport via plasma. While the mechanisms by which HBOT may improve outcomes in spinal cord injury are not completely understood, the following processes are considered to be the predominant mechanisms by which HBOT may exert its action and minimize the damage.
HBOT helps in increasing the concentration of oxygen in the bloodstream and tissues, thereby achieving much higher partial pressures than those achievable while breathing pure oxygen under normobaric conditions. This, in turn, helps to improve oxygenation to the injured areas. The increased oxygenation has been shown to stimulate the growth and survival of neural cells, as well as improve blood flow to the affected area.
HBOT has been shown to reduce inflammation in the affected area, which can reduce the severity of spinal cord injury. Secondary SCI involves a polarized response of primary mediators of inflammation (macrophages/microglia), leading to increased activation of pro-inflammatory classical (M1) macrophages. It is thought that HBOT decreases M1 phenotype and correspondingly reduces the production of cytokines and other inflammatory mediators, which can damage neural cells. The reduced intensity of inflammation would also prevent from glial scar formation, and would accompany improved axonal growth, lesser dendritic degeneration, significantly greater myelin sparing, leading to greater functional recovery.
HBOT has been shown to stimulate the growth of new blood vessels, which can improve blood flow to the affected area. The mobilization of stem/progenitor cells from the bone marrow by exposure to HBOT may also occur through a nitric oxide-dependent process, via release of the stem cell active cytokine, cKit ligand (stem cell factor, SCF). However, smaller increase in oxygen concentration (hyperoxia) at relatively normal pressures may also invoke similar transcriptional responses for stem cell mobilization seen at hyperbaria, with decreased expression of systemic inflammatory cytokines such as TNF-α, suggesting that the effect could possibly be due to oxygen levels alone. Regardless, this improved blood flow caused by recruitment of progenitors and neovascularisation can help in providing essential nutrients and oxygen to the injured area, thereby promoting the ischemic wound healing.
Damage of spinal neurons, glia, and microvascular cells by free radical-induced, iron-catalysed lipid peroxidation and protein oxidative/nitrative damage, has long been considered the hallmark for secondary pathophysiology of acute SCI. Therefore, the alleviation of oxidative stress has been considered to be a potentially effective strategy for therapeutic intervention of SCI. HBOT has been shown to reduce oxidative stress, which can damage neural cells. It is thought to do this by reducing the production of free radicals by increasing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase, and decreasing the levels of malondialdehyde and other end products of polyunsaturated fatty acids peroxidation in the cells.
All the aforementioned effects of HBOT in the management of SCI have been studied to be implicated by a gamut of upregulation of antioxidant genes and downregulation of pro-inflammatory genes. These include the decreased expression of genes such as GDNF, HMGB1, iNOS, NF-κβ, AQP4, AQP9, ASC, TLR-4, NALP-3, CHOP, RAGE, MCP-1, IL-1β, IL-6, MMP-2, MMP-9, MPO, p65, reduced cytochrome c release and reduced caspases 1, 3 and 9; and increased expression of genes for heme oxygenase-1, VEGF, Nrf-2, HSP32. These measures contribute to increased cell viability by anti-apoptotic activity, attenuation of oxidative stress and decrease in cell damage, demonstrated by fewer injured neurons, as well as increased autophagy indicated by increased Beclin-1 and LC3-II. Experimental studies have shown that these multifarious mechanisms ultimately account for the neuroprotective benefits and improved spinal cord oxygen tension caused by HBOT, although the exact pathways underlying the therapeutic effects remain conflicted.
Generally, regenerative approaches for spinal cord injury seek patients who are of a younger age, injuries that are within the acute phase, incomplete injuries, injuries that are non-penetrating in nature, and patients with a higher ASIA score. Patients who fit that profile are most predicted to benefit most from HBOT in terms of recovering sensory and motor function. However, patients outside of this profile may also benefit from HBOT. Pre-clinical and initial clinical studies have reported encouraging signs that HBOT can promote neuroprotective mechanisms, relieve the inflammatory response of the spinal cord, and induce sensory and motor recovery for the patient. HBOT could be used as a combination therapy that can be supplemented with physical and occupational therapy to create better outcomes for patients facing the burden of SCI.
Corresponding Author: Brian Fiani, DO
Institution: Mendelson Kornblum Orthopedics and Spine Specialists (Michigan)
Co-Authors: Haytham Alqasmi, Bashar Jawich, Ryan Jarrah, Sufyan Ibrahim, Archis Bhandarkar
