Cervical Sympathetic Block as a Modulator of Secondary Injury Mechanisms in Traumatic Brain Injury

Traumatic brain injury (TBI) follows a biphasic clinical course in which an initial mechanical insult is followed by a prolonged secondary injury cascade that drives ongoing neurological deterioration. Secondary injury processes include neuroinflammation, blood-brain barrier (BBB) disruption, mitochondrial dysfunction, oxidative stress, maladaptive gene regulation, and neuronal apoptosis. Current TBI management strategies primarily address intracranial pressure, cerebral perfusion, and oxygenation but do not directly target these downstream biological mechanisms. Cervical sympathetic blockade (CSB) involves administration of local anesthetic to the cervical sympathetic ganglia, typically at the C6 level or at combined C6/C4 levels, resulting in transient interruption of sympathetic outflow. The cervical sympathetic system has functional connections to immune organs, including the thymus, spleen, and bone marrow, suggesting a role in immune modulation. Emerging preclinical and clinical evidence indicates that CSB may attenuate secondary injury mechanisms after TBI. This review synthesizes available evidence to evaluate the therapeutic potential of CSB in TBI and to delineate its mechanistic effects on secondary injury pathways.

We conducted a comprehensive narrative review of preclinical and clinical studies examining the effects of CSB in TBI and related neurological conditions. Literature searches were performed using PubMed and Google Scholar, supplemented by citation tracking of relevant studies. Included evidence encompassed randomized controlled trials, prospective cohort studies, retrospective case series, and mechanistic animal models. Outcomes of interest included clinical symptom burden, inflammatory cytokines, BBB integrity markers, mitochondrial and oxidative stress measures, gene expression profiles, and apoptotic signaling. Evidence from related conditions such as subarachnoid hemorrhage, migraine, and postoperative cognitive dysfunction was incorporated to inform mechanistic interpretation.

Available clinical studies, though limited in size, demonstrate rapid and sustained reductions in TBI-related symptom burden following CSB. Randomized controlled trials show that CSB significantly reduces pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), as well as neuronal injury markers such as S100β and neuron-specific enolase, likely mediated by downregulation of nuclear factor kappa-B (NF-κB) signaling. Observational studies corroborate reductions in inflammatory biomarkers and markers of BBB disruption. Preclinical models demonstrate that CSB mitigates mitochondrial oxidative stress through enhancement of antioxidant defenses and suppression of Reactive Oxygen Species Modulator 1 (Romo1) expression. Additional studies show that CSB shifts the Bax/Bcl-2 ratio toward an anti-apoptotic profile, promoting neuronal survival. Clinical data from subarachnoid hemorrhage and surgical populations further support improved cognitive and functional outcomes accompanied by reduced inflammatory signaling.

CSB targets multiple convergent mechanisms of secondary brain injury that are not addressed by current standard TBI management, including neuroinflammation, oxidative stress, mitochondrial dysfunction, dysregulated gene expression, and apoptosis. Clinical improvements following CSB are accompanied by measurable biological changes, supporting a mechanistically grounded therapeutic effect. Limitations of the current evidence include small sample sizes, heterogeneous populations, and reliance on surrogate biomarkers. Larger, well-controlled trials are needed to define efficacy, optimize patient selection, and assess long-term neurological outcomes. CSB represents a promising, mechanism-driven intervention with potential relevance for both civilian and military TBI populations.