Combining a Cardiocentric Hemodynamic Management Approach with Ethyl Nitrate Inhalation to Reduce Secondary Hypoxic Injury Following SCI

In the field of spinal cord injury, there has been a lot of recent excitement around different approaches (e.g., epidural stimulation) aimed at improving functional, real-world outcomes for people who sustain a spinal cord injury. The reality, however, is that these approaches, whilst exciting, are still very much in the early stages of testing and development. When a patient sustains a spinal cord injury, they want to know what can be done now to improve their function as much as possible. At present, one of the only available treatment options is to manage their cardiovascular system such that blood flow to the injured spinal cord is optimized, but without further increasing bleeding at the injury site itself. Preventing bleeding at the center of the injury in the spinal cord is important, because it helps to prevent the initial injury from spreading and impacting more spinal cord tissue, which in turn makes the outcomes of the spinal cord injury far worse.

Over the last 3 years our team has sought to bring a new approach to the acute cardiovascular management of patients who sustain a spinal cord injury. In a series of studies, we first demonstrated that the function of the heart is immediately reduced following a spinal cord injury, and this reduction in function coincides with reduced oxygen delivery and blood flow to the spinal cord. This is an important observation, because reduced oxygen delivery and blood flow to the spinal cord leads to further damage of the critical spinal cord tissue around the injury site and worsens outcomes for the patient. We next showed that if we treat the reduction in heart function post-injury, we can increase oxygenation and blood flow within the spinal cord. Finally, we have been able to show that this new approach prevents the typical reduction in cardiovascular function that happens in the chronic stage post-injury.

In the present project, we are proposing to further improve blood flow profiles in the spinal cord. Whilst our data so far is able to show improved function of the cardiovascular system in the chronic stage following injury, we did not fully normalize blood flow in the spinal cord, nor did we prevent bleeding at the center of the injury within the spinal cord itself. To address these remaining concerns, we plan to extend our previous study to test whether targeting the heart and the spinal cord blood vessels using a combinational approach produces more favorable functional outcomes than targeting just the heart alone. To improve blood flow in the spinal cord surrounding the injury, we will take advantage of a new compound that can be added to the air going into a ventilator. This new compound is unique in that it will cause the blood vessels in the spinal cord to dilate (further open) when the spinal cord oxygen levels begin to drop (as is the case after spinal cord injury). As these blood vessels open up, they provide a route for the blood to flow away from the injury site and therefore, are expected to prevent bleeding at the injury site.

Since true measurements of heart function and spinal cord blood flow are very 'invasive' (meaning we need to put the tools to measure them inside the heart and spinal cord), we are not able to perform these experiments in humans. Instead, we will use both pig and rat models of spinal cord injury interchangeably throughout the project. Because of the ethical implications of using large animal models for research, we will use pigs only to test the therapeutic potential of this approach – all other studies to determine the mechanisms by which this therapy works will be performed in rodents models. While the rodent model is good for conducting more rapid fundamental research studies, we ultimately want to test whether this approach works in the pig because both the heart and spinal cord are very similar to humans, meaning if we find a positive effect in the pig, then it increases our chances of finding a positive effect in humans.

We expect that this research will help with the acute care and management of SCI patients during the first 7 to 10 days post-injury. Given that this approach targets a reduction in cardiovascular function, we expect that this new approach will be most relevant to people who have sustained a traumatic upper-thoracic or cervical spinal cord injury (approximately 60%-70% of the population). The long-term potential benefits of this treatment approach, which is applied in the acute setting, include a greater preservation of spinal cord tissue, which will enable more nerves to travel from the brain down the spinal cord. If more spinal cord tissue can be spared at the injury site, then this new treatment approach would be expected to improve long-term cardiovascular and motor function, thereby improving functional independence and reducing the odds for cardiovascular disease.