Role of dexmedetomidine in brain injury: a systematic review

Extensive literature search was performed for articles in PubMed and Google Scholar databases, from January 2000 till November 30, 2024. Keywords as “Dexmedetomidine”, “Brain injury”, “Intracranial hemorrhage”, “Traumatic” and “Status epilepticus” were used in varied ways, using “and” as search operator. Supplemental search was performed in cited references.

This review considered studies that demonstrated the effects of dexmedetomidine on patients or rats with different types of brain injury such as traumatic brain injury, intracerebral hemorrhage, status epilepticus, and ischemic brain injury, it also included papers demonstrating dexmedetomidine effects on craniocerebral surgeries and on patients with traumatic brain injuries.

This review considered any animal studies, case report, cross-sectional studies, observational studies, retrospective analysis, systematic review and meta-analysis demonstrating the effects of dexmedetomidine of different types of brain injury.

This review excluded papers that had not fitted the scope of the review, and those not published in English, or no English translation is available for them.

Humble et al. showed that dexmedetomidine administration is associated with a significant reduction in systolic and diastolic blood pressure, mean arterial pressure (MAP), and heart rate, during drug infusion. They have shown that once infusion has been stopped, systolic, diastolic, and mean arterial pressure and heart rate have returned to their pre-infusion level. They have also explained that this reduction was statistically significant but not clinically significant. Also, Richmond-agitation sedation scale (RASS) and Glasgow coma scale (GCS) have improved from pre-infusion to infusion time periods (Humble et al. 2016).

Yang et al. compared the effects of dexmedetomidine with standard therapy in patients with acute brain injury, and they found that heart rate (HR) and MAP reduced significantly in dexmedetomidine group compared to the standard therapy group. Also, Glasgow coma scale (GCS), bispectral index (BIS), APACHE II score, and oxygenation index (PaO₂/FiO₂) were significantly improved in dexmedetomidine group compared to the other control group. Dexmedetomidine group also showed significantly shorter duration of mechanical ventilation and no unexpected extubation, which has happened in the standard therapy groups. All these findings suggest that dexmedetomidine is safe, effective, and improve neurological functions in acute brain injury (Yang et al. 2020).

Khalili et al. showed that the administration of dexmedetomidine in patients with moderate-to-severe traumatic brain injury is associated with significant reduction of intensive care unit and hospital length of stay and significant improvement of patients’ functional outcomes as indicated by 6-month Glasgow outcome scale extended (GOSE) compared with placebo group (Khalili et al. 2023).

Xu et al. have found that dexmedetomidine significantly reduced in-hospital death among patients with traumatic brain injury. Dexmedetomidine significantly improved the survival of patients with traumatic brain injury irrespective of the starting time, the dose, or the duration of use (Xu et al. 2022).

Jeon et al. have found in a study that they have performed on rats that dexmedetomidine intrathecal administration is associated with the reduction of TBI-induced mechanical allodynia for up to 2 weeks after injury through the immediate inhibition of brain-derived neurotrophic factor level in the cerebrospinal fluid (c-BDNF), this inhibition also reduces the occurrence of TBI-induced chronic neuropathic pain (Jeon et al. 2023).

Hatfield et al. have found in their review that dexmedetomidine is a safe and an effective sedative in traumatic brain injury patients. They have explained multiple aspects of dexmedetomidine effects including its effect on cerebral physiology and how it is not clinically different from other sedative on Intracranial Pressure (ICP) deviations. They have demonstrated that dexmedetomidine has significantly reduced agitation and delirium, and that RASS was significantly improved and maintained within target levels when dexmedetomidine was used in traumatic brain injury patients. They have also explained the adverse effects of dexmedetomidine on systemic hemodynamics and showed that dexmedetomidine may cause reduction in systolic blood pressure, mean arterial pressure, and heart rate during its infusion (Hatfield et al. 2024).

Hwang et al. have performed a study on rats in which they have induced intracranial hemorrhage (ICH) to study the effects of dexmedetomidine. They have found that dexmedetomidine has significantly reduced ICH-induced impairment of short-term memory and spatial learning memory by expressing anti-apoptotic properties through increasing brain-derived neurotrophic factor (BDNF) expression in the hippocampus of the rats. They suggested that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in patients with ICH (Hwang et al. 2013).

Eser et al. have performed a study in rats in which they have made a transient global ischemic/reperfusion injury and used dexmedetomidine to assess its neuroprotective effect. The results have shown that dexmedetomidine has significantly reduced the levels of tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), and nitric oxide (NO), while increased the activity of superoxide dismutase (SOD), and catalase (CA), and significantly reduced the number of apoptotic neurons. These findings show the neuroprotective effects of dexmedetomidine in ischemia (Eser et al. 2008).

Jiang et al. have found that dexmedetomidine is associated with reduction in the release of neuroendocrine hormones and inflammatory mediators, it also maintains intracranial homeostasis, and reduces ischemic brain injury, which suggest its neuroprotective properties (Jiang et al. 2017).

Whittington et al. have studied the effects of dexmedetomidine on cocaine-induced seizures in rats and have found that dexmedetomidine effectively increases seizures threshold in cocaine-induced seizures by reducing the response of extracellular dopaminergic neurotransmitters response to cocaine (Whittington et al. 2002).

Kan et al. have found that dexmedetomidine has significantly reduced the number and the cumulative time of repeated seizures in rats with self-sustaining status epilepticus probably through the reduction of the levels of Glutamate and glutathione/malondialdehyde (GSH/MDA) in hippocampus tissue (Kan et al. 2013).

Interesting findings were reported by Xu et al. study which state that dexmedetomidine significantly reduced the seizures activity, increased the long-term potentiation of convulsive status epilepticus, and improved the spatial cognitive function in rats with convulsive status epilepticus (Xu et al. 2018).

However, one case report published by Kubota et al. suggested that dexmedetomidine is inducing both epileptic seizures and non-epileptic movement in neonates during artificial ventilation (Kubota et al. 2013).

Another study performed by Yu et al. have demonstrated that dexmedetomidine administration preoperatively is associated with a significant reduction in the posttraumatic stress disorder (PTSD), compared with placebo group (Yu et al. 2023).

The finding of Shaboob et al. study demonstrated that the preoperative administration of dexmedetomidine is associated with a reduction in the inflammatory and oxidative response to surgery, with ameliorated cognitive function impairment that may be aggravated by the surgery (Shaboob and Mostafa 2023).

Dong et al. have compared different doses of dexmedetomidine and their effect on patients undergoing craniocerebral trauma surgery; and found that although both doses (0.5 μg/kg and 1 μg/kg) provided a protective effect on brain function compared to placebo group, the lower dose which was 0.5 μg/kg showed better hemodynamics and protective function (Dong et al. 2023).

Traumatic brain injury (TBI) is a major problem worldwide, because of its complicated symptoms and unfavorable outcomes on patients’ health. The management of this condition focuses on effectively controlling mean arterial pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), seizures control, and other measures (Luo et al. 2010; Marehbian et al. 2017).

The pathophysiological changes that happen in traumatic brain injury include inflammation, microglial activation, and neuronal death; these changes eventually affect the cognitive function of the patients (Luo et al. 2010). Dexmedetomidine have shown to reduce all these pathological changes and facilitate neuronal recovery (Hu et al. 2022).

Dexmedetomidine administration in traumatic brain injury has been found to reduce MAP, HR, systolic and diastolic blood pressure. it also improved Richmond-agitation sedation scale (RASS), Glasgow coma scale (GCS), bispectral index (BIS), APACHE II score, and oxygenation index (PaO₂/FiO₂) (Humble et al. 2016; Yang et al. 2020).

Dexmedetomidine was also found to reduce the duration of mechanical ventilation, the length of stay in intensive care unit, and hospital’s length of stay with a significant improvement in patients’ functional outcomes as indicated by Glasgow outcome scale extended (GOSE). It has also improved patients’ survival and reduced the occurrence of TBI-induced chronic neuropathic pain (Jeon et al. 2023; Khalili et al. 2023; Xu et al. 2022).

Dexmedetomidine was also found to reduce agitation and delirium, and maintain RASS score within target levels. Its sympatholytic properties reduce catecholamines release, making it an ideal treatment for autonomic dysregulation and paroxysmal sympathetic hyperactivity which might happen in patients with severe traumatic brain injury, this results in improved outcomes of patients with traumatic brain injury.

Intracerebral hemorrhage (ICH) may result in an irreversible damage to the central nervous system affecting its function. Short-term and learning memory problems are the most encountered consequences of intracerebral hemorrhage (MacLellan et al. 2009; Xiong et al. 2016).

Animal studies have found that dexmedetomidine has significantly reduced ICH-induced impairment of short-term memory and spatial learning memory by expressing an anti-apoptotic properties. They suggested that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in patients with ICH (Hwang et al. 2013).

Further studies to reach a definitive conclusion regarding dexmedetomidine effects on human with ICH are warranted.

Cerebral ischemia can result from cardiac arrest, ischemic shock, or complicating heart surgery. Ischemia causes several negative effects including decreased motor control, seizures, cognitive impairment, and may even extend to coma or death. During brain ischemia, the production of reactive oxygen species is increased in neurons (Busl and Greer 2010; Endesfelder et al. 2017; Eser et al. 2008).

Dexmedetomidine was found to reduce the release of neuroendocrine hormones, and inflammatory mediators, such as Tumor Necrosis Factor-alpha (TNF-α), Malondialdehyde (MDA), and Nitric Oxide (NO). It also increases the activity of Superoxide Dismutase (SOD) and Catalase (CAT). Dexmedetomidine maintained intracranial homeostasis and reduced ischemic brain injury. These findings demonstrate the neuroprotective effects of dexmedetomidine in ischemia (Eser et al. 2008).

Status epilepticus is a medical emergency that could precipitate a permanent neurological damage and negatively affect cognitive function (Walker 2018).

Dexmedetomidine was found to effectively increase seizures threshold, it also reduced the number and the cumulative time of repeated seizures in status epilepticus and reduced seizures activity and improved spatial cognitive function (Kan et al. 2013; Whittington et al. 2002; Xu et al. 2018).

However, one case report revealed that dexmedetomidine is inducing both epileptic seizures and non-epileptic movement in neonates during artificial ventilation (Kubota et al. 2013).

Since there is conflicting evidence about the effect of dexmedetomidine in status epilepticus, further studies should be performed to clarify its effects.

Craniocerebral operation may cause post-traumatic distress syndrome (PTSD), postoperative cognitive impairment, ischemic brain injury, or neurological dysfunction due to neuroendocrine reaction or neuroinflammation (Dong et al. 2023).

Dexmedetomidine is associated with reduced hemodynamic responses to intubation and surgical stimulation as MAP and HR, it is also found to reduce the level of NSE and IL-6, which indicated that it reduces the immunologic reaction during the operation (Hou et al. n.d.).

Dexmedetomidine administration preoperatively is associated with significant reduction in PTSD and cognitive function impairment that may be aggravated by the surgery (Shaboob and Mostafa 2023; Yu et al. 2023).

Numerous studies have demonstrated that dexmedetomidine has neuroprotective properties, including the ability to lower oxidative stress and the inflammatory response, inhibit apoptosis, shield the blood–brain barrier (BBB), preserve the equilibrium of the coagulation–anticoagulant system, and avoid vasospasm (Liu et al. 2022; Wang et al. 2016). The neuroprotective benefits of dexmedetomidine in preventing inflammatory reactions, lowering the release of neuroendocrine hormones, and preserving intracranial homeostasis were validated by a meta-analysis involving 879 patients (Wang et al. 2016). According to a previous published review, dexmedetomidine’s neuroprotective effects mostly included reducing autophagy and apoptosis, inhibiting inflammatory responses, preserving the blood–brain barrier, and promoting stable cell architectures. As a result, dexmedetomidine can give patients with brain injuries a significant edge in their neurological rehabilitation.

Dexmedetomidine has demonstrated potent neuroprotective benefits, including preserving hemodynamic stability, lowering neuronal mortality, protecting the blood–brain barrier, and lowering postoperative agitation and cognitive impairment (Tao et al. 2024).

Curiously, a recent meta-analysis by Gatica et al. (2023) discovered that dexmedetomidine may significantly alter the production of IL-1β and IL-6 in the central nervous system and could also reduce oxidative stress and apoptosis in vitro (Gatica et al. 2023).

In summary, dexmedetomidine guarantees improved sedation and analgesia during traumatic brain injury surgery, lowers postoperative complications, suppresses immune cell migration and activation, controls autophagy, and prevents neuroinflammation and neuronal death. Through a variety of methods, dexmedetomidine, is considered a strong neuroprotective drug, that may enhance cognitive performance, reduce brain damage in pathological and surgical circumstances, and offer neuroprotection in complicated disorders like sepsis. These results provide credence to the use of dexmedetomidine in critical care and neurosurgical anesthesia, especially when neuroprotective measures are required.