Neuro-Inflammation in Extremity Trauma: Risk Verification in Elbow Trauma: The NERVE Study

Chronic pain after limb fractures remains a challenging clinical problem although scientific and technological advances have made major contributions to improve patient outcomes. Nonetheless, even with an anatomical restoration of the bone architecture, many patients still have major functional limitations and persistent pain. This results in a work productivity loss. In the United States, upper limb injuries generate the highest direct and indirect costs (740M$), followed by lower limb fractures (562M$). Although outcomes following a fracture vary significantly, a "simple" fracture occurring at any time can become a turning point in the patient's life, where they can no longer achieve their pre-fracture functional status. The Canadian Pain Task Force estimates that 8 million Canadians suffer from chronic pain, costing $40 billion annually. This includes a large and understudied group of patients with post traumatic chronic pain, which occurs in up to 50% of patients following fractures. For these patients, opioids are meant to alleviate pain, but substance use disorder is a common problem. Indeed, approximately half of all patients with fractures have significant pain leading to persistent opioid intake 3 months post injury and 40% will suffer from a neuropathic type of pain, which is poorly controlled by medications. Opioid use is also associated with an increased sensitivity to pain (hyperalgesia) and patient dissatisfaction with injury outcome. Complications from prolonged opioid use are numerous, varying from constipation to overdose death. Canada is second worldwide, behind the United States, when it comes to opioid use and mortality. The majority of opioid dependant users were first exposed to opioids through medical prescriptions. This makes it imperative to improve the understanding of pain mechanisms to find alternative treatments to opioids in the management of these injuries.

In clinical practice, it is striking to see how two patients with a similar injury can exhibit completely opposite outcomes: one who has completely healed from the injury and the other with a stiff and painful joint. The reasons for these variations are unclear. A study have shown that only 3.3% of the differences in patient pain levels could be attributed to fracture severity. Given the enormous societal burden of limb injuries it is time for research to investigate the factors that contribute to the 97% of unexplained variability related to post fracture pain. The investigator working hypothesis is that the variability in post-fracture pain is caused by differences in expression of specific proinflammatory cytokines with nociceptive effects. This would explain why most studies strictly focusing on the orthopedic component of limb injury have yielded little improvement in preventing the adverse outcomes experienced by patients, namely chronic pain and loss of function.

Basic science studies have shown that in chronic pain cases, the resolution process following initial inflammation is deficient, leading to an excessive inflammatory response spreading throughout the nervous system long after the injury. This response, globally referred to as neuroinflammation (NI), has been associated with central sensitization, central nervous system (CNS) hyperactivity, allodynia and hyperalgesia. Surprisingly, NI is hardly studied in acute fracture cases, which is shocking given that it could explain chronic pain and disability. Also, some surgical factors may increase peripheral nerve injury (PNI).

Among all upper limb fractures, elbow trauma is the injury most frequently associated with a severe impact on patient function and quality of life. One of the main causes for poor outcomes is the complexity of the elbow joint, which involves three bones and two planes of motion, essential to the position of the hand in space. The flexion extension axis is crucial for eating and hygiene, while forearm pro-supination is mandatory for most professions, from office work to manual labour. Following surgical treatment of an elbow fracture, patients often present with complications, even with adequate bone healing. Indeed, one third of patients complain of ulnar nerve symptoms after distal humerus fracture fixation, and 50% of patients treated surgically for elbow fracture-dislocations will have disabling stiffness and chronic pain. The elbow is ideal to study neuroinflammation and pain as it involves 3 major nerves close to the joint: the radial, ulnar and median nerves. Elbow injury also has a high incidence of associated mild traumatic brain injury (MTBI) and peripheral nerve injury (PNI), 20% and 15% respectively.

1.2 Neuroinflammation Neuroinflammation (NI) can take different forms: central and peripheral. Prevouis investigator's results showed that 23.5% of isolated limb injuries also exhibit a mild traumatic brain injury (mTBI). More specifically, the investigators reported that 20% of ambulatory patients with an elbow fracture have a traumatic brain injury (TBI). Previous studies done by the investigator's team showed that outcomes of patients with a TBI, even mTBI, and a fracture is much poorer, compared to a group of similar patients without TBI, causing a work cessation three time longer (averaging 299 days versus 105 days). Central NI alters acute pain and increases the risk of chronic pain following a limb injury. At the time of brain trauma, brain-resident cells, such as microglia, will produce cytokines and other inflammatory mediators that spread through the peripheral circulatory system causing hypersensitivity and peripheral pain. Damage to the blood-brain barrier (BBB) following traumatic injury, allows circulating peripheral immune cells, produced in response to the fracture and present in high numbers at the site of injury and in immune organs, and the released cytokines to reach the brain and create a hyperactive inflammatory state. Astrocytes and endothelial cells also play a key role in this phenomenon. Importantly, research on US military veterans with orthopaedic injuries has revealed that the presence of mTBI significantly increases the risk of chronic pain and NI, as measured by higher levels of TNF and IL-6. A recent article in Nature also reported that the combined impact of mTBI and fracture to the brain could be permanent, because of the brain's immune memory. Therefore, both the traumatized brain and the fractured limb will evolve more poorly than if each lesion had occurred independently.

There is a spectrum of PNI that can occur at the time of the fracture or during their surgical treatment. It is estimated that these lesions affect between 3% and 10% of trauma extremity patients. In the elbow, certain types of injuries have a much higher rate of PNI; up to 30%. The most benign are called neuropraxia and consist of segmental demyelination. The symptoms include numbness and weakness for a period ranging from a few days to a few weeks. Axonotmesis is a rupture of the axons while the nerve sheath remains intact. Spontaneous healing is possible but will take months. Severe lesions consist in a complete nerve rupture, called neurotmesis. This is rare and requires surgical treatment. The precise incidence of neuropraxia is unknown, because pain following a trauma often hides neurological injury symptoms that heal on their own. These transient lesions contribute to the chronic pain mechanisms, which often lead to persistent opioid consumption.

Neuroinflammation can be the result of an altered, uncontrolled immune response to the peripheral injury. Proinflammatory cytokines such as TNF, IL-1, and IL-6 are rapidly produced after injury, and sometimes expressed for prolonged periods of time if there is no resolution of inflammation solve. Importantly, these proinflammatory cytokines play a major role in the transition from acute to chronic pain, acting as potent mediators of excitatory activity in the CNS through modulation of the glutaminergic system. This increase in excitatory activity also decreases the gamma-aminobutyric acid (GABA) activity, which further affects CNS homeostasis. Neuroinflammation markers consequently increase in the circulatory system. Preliminary experiments in patients with fractures found a strong correlation between plasma levels of proinflammatory cytokines, as well as some less frequently studied biomarkers such as C1qA, and chronic pain. Notably, the C1qA protein was involved in the development of neuropathic pain in animal models and showed variations related to the sex of rodents. In an ongoing study, the investigators demonstrated that NI biomarkers played a role in pain and outcome after human fracture, including TREM2, IL16, CCL22, VEGF-a (appendix), amongst others.

1.3 Surgical factors A literature review shows that tourniquet use and nerve dissection may play a role in elbow surgery outcome. While a tourniquet is often used to avoid bleeding and give better visibility, the tourniquet causes an inflammatory ischemia/reperfusion reaction. Several studies have shown an impact of the tourniquet on pain in lower limb surgery. Using a tourniquet to treat ankle fractures is associated with a greater consumption of opioids for the first 24 hours and more pain at 5 days and 6 weeks post-surgery. Tourniquet duration was also correlated with increased opioid consumption in a Danish study on 603 patients; patients took 0,43 mg more morphine for each additional 10 minutes with the tourniquet. Furthermore, British Medical Council Neurology guidelines for tourniquet use report an increased risk of complex regional pain syndrome in surgeries with a tourniquet. Peripheral nerve ischemia during tourniquet use, for up to 120 minutes, could promote NI. However, there is a lack of data specific to elbow surgery and tourniquet use, as reported by a meta-analysis. Surgical nerve dissection may also cause peripheral nerve inflammation. A recent systematic review of elbow fractures reported that ulnar nerve transposition is related to more chronic symptoms than nerve identification only. The quality of the articles involved in the review was modest and electromyography (EMG) was not used to measure impairment.

In summary, limb fractures are associated with a high risk of sequelae, even with proper healing of osseous and ligamentous components. Pain and disability leading to chronic opioid intake is a major concern. Elbow joint fractures are an excellent subgroup to study this phenomenon because of the high incidence of concomitant central and peripheral neurological injuries. Moreover, having a homogenous patient group will make it easier to compare functional outcomes with joint specific questionnaires and functional evaluation. The Nerve pilot study is well supported by the basic science literature and designed to study the mechanisms leading to neuro-inflammation in injured human patients, with the long-term goal of understanding factors increasing NI (e.g., concomitant head injury, peripheral nerve injury, surgical factors, demographic characteristics) and its consequences (e.g., acute and chronic pain, disability). It is expected that studying the surgical factors that increase NI will allow surgeons to choose different therapeutic options.