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Perspectives on Dexmedetomidine Use for Neurosurgical Patients

Lin, Nan MD, PhD*; Vutskits, Laszlo MD, PhD; Bebawy, John F. MD; Gelb, Adrian W. MB, ChB§

Journal of Neurosurgical Anesthesiology: October 2019 - Volume 31 - Issue 4 - p 366–377
doi: 10.1097/ANA.0000000000000554
Review Articles

The α2-adrenergic receptor agonist dexmedetomidine has sedative, anxiolytic, analgesic, and sympatholytic effects. The potential advantages of neuroprotection, minimal impact on neuronal function, stable hemodynamics, opioid and anesthesia sparing effects, and minimal respiratory depression during awake procedures render it an effective anesthetic adjuvant in various neurosurgical settings. However, both the benefits and drawbacks of the use dexmedetomidine in neuroanesthesia should be considered. This narrative review will summarize the applications of dexmedetomidine in various neurosurgical settings, highlighting evidence regarding both its common and controversial uses.

*Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Fengtai District, Beijing, China

Department of Anesthesiology, Pharmacology and Intensive Care, University Hospitals of Geneva, Geneva, Switzerland

Departments of Anesthesiology & Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL

§Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA

Supported by Beijing Municipal Administration of Hospitals’ Youth Program (QML20160503) and by the National Natural Science Foundation of China (Grant No.1701038).

The authors have no funding or conflicts of interest to disclose.

Address correspondence to: Adrian W. Gelb, MB, ChB, Department of Anesthesia & Perioperative Care, University of California San Francisco, 500 Parnassus Ave., MUE 408, San Francisco, CA 94143 (e-mail:

Received March 27, 2018

Accepted September 6, 2018

Dexmedetomidine is a highly selective α2-adrenergic receptor agonist acting on central presynaptic α2-receptors primarily in the pontine locus ceruleus and peripheral postsynaptic α2-receptors on vascular smooth muscle.1,2 The clinical neurological effects of dexmedetomidine mimic “natural sleep,” perhaps through impairing neural interconnectivity, and the drug has been widely used in the perioperative setting to provide sedation, anxiolysis, analgesia, and sympatholysis.3,4

Many of the pharmacodynamic and pharmacokinetic characteristics of dexmedetomidine make it an appealing adjunct during neurosurgical anesthesia.5–7 Unlike other sedatives, dexmedetomidine has the advantages of less respiratory depression, minimized impact on neural function, including less interruption of neurophysiological monitoring, the potential for neuroprotection, and maintenance of airway reflexes and patency during awake procedures. Its effects on cerebral hemodynamics and physiology are summarized in Table 1, of which the benefits include no increase in intracranial pressure (ICP) and an unchanged cerebral metabolic rate equivalent/cerebral blood flow (CBF) ratio.8 The interaction between peripheral and cerebral vascular effects of low-dose to medium-dose of dexmedetomidine are shown graphically in Figure 1.





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Cerebral Vascular Disease

Carotid endarterectomy (CEA) is performed for significant carotid artery disease. Patients frequently have concomitant peripheral vascular disease and other related comorbidities, and are prone to hemodynamic fluctuations caused by surgical stimulation or perioperative medications. Intraoperative hypotension and the reduction in CBF caused by dexmedetomidine can potentially risk inadequate oxygen delivery that may necessitate the use of intracarotid shunts during awake CEA, although a prospective case series showed that dexmedetomidine as the primary sedative did not increase the incidence of shunts as compared with historical controls.9 Hypotensive episodes in the post anesthesia care unit after CEA, however, are more frequent with dexmedetomidine, and patients may require more hemodynamic interventions.10,11 Some patients are prone to develop cerebral hyperperfusion following CEA due to impaired cerebral autoregulation and systematic elevated blood pressure, and this can present with postoperative neurological deficits.12 However, there is no direct clinical evidence that dexmedetomidine exacerbates impaired dynamic cerebral vascular autoregulation in carotid artery stenosis. Similarly, there is no human evidence that dexmedetomidine worsens or causes cerebral ischemia, although high-dose dexmedetomidine was found to be associated with ischemic brain injury exacerbation in animals.13

In healthy subjects receiving dexmedetomidine, cerebral metabolic rate of oxygen consumption (CMRO2) is decreased with CMRO2-CBF coupling unchanged,14 indicating that brain tissue oxygen delivery is little affected. This relationship was preserved when using dexmedetomidine in patients with unruptured intracranial aneurysms or arterial venous malformations.15 Patients with intracranial aneurysms are at risk of aneurysmal rupture during hypertensive episodes. In a small retrospective study, sedation after unruptured cerebral aneurysm clipping with dexmedetomidine infusion (0.4 to 0.9 μg/kg/h) showed comparable blood pressure to propofol (0.5 to 5.0 mg/kg/h), but with a lower heart rate.16 Sixty-six percent of dexmedetomidine sedated patients, however, required additional propofol boluses to prevent agitation while intubated.16 In a recent case series of 12 patients, coil embolization of intracranial aneurysms was performed successfully under monitored anesthesia care (MAC) with dexmedetomidine without adverse hemodynamic or respiratory events.17 Nevertheless, these case series are retrospective and underpowered, and prospective randomized trials are needed to elucidate the effectiveness and safety of adding dexmedetomidine during intracranial aneurysm surgery, which requires systemic and cerebral hemodynamic stability.

Subarachnoid hemorrhage (SAH) and cerebral parenchymal hemorrhage are devastating complications often caused by cerebral vascular diseases which may result in cerebral arterial vasospasm resulting in decreased CBF. Animal studies of SAH have found that dexmedetomidine attenuated brain edema, reduced vasospasm,18 and ameliorated neurological deficits.19,20 The possible mechanisms of this phenomenon are related to activation of extracellular signal-regulated kinase,19 enhanced cell survival and cell growth, as well as inhibition of cell apoptosis.21 Clinical neuronal protection related to dexmedetomidine use in patients with SAH has not been confirmed, however. Neurogenic myocardial stunning may occur after SAH and lead to hemodynamic disturbances, but whether dexmedetomidine protects or worsens cardiac function under this condition is unknown.

Regional cerebral ischemia sometimes occurs due to impaired intracranial hemodynamics or blood supply during cerebrovascular surgeries, whereas global cerebral ischemia is likely a result of systemic hypotension. To mitigate the latter, anesthetic choice is frequently considered with respect to “neuronal protection.” Animal studies have implied that after focal cerebral infarction, dexmedetomidine infusion improved microregional oxygen supply/consumption balance, thereby decreasing cortical infarction size with more cell survival compared with saline.22 This neuronal protective effect of dexmedetomidine was stronger when combined with propofol23 or lidocaine.24 Dexmedetomidine preconditioning25 or postconditioning26,27 was associated with less neuron loss and better improved neurofunction in rats following hypoxia-induced global ischemia. However, this neuroprotective effect in cerebral ischemia was not mediated by central α-adrenoceptors28 and not related to the inhibition of presynaptic norepinephrine or glutamate release,29 but rather by inhibiting the stress hormone and inflammatory response,26,30 as well as through activation of a signaling pathway of cell growth, proliferation, and survival.31 In humans, impaired neuronal and neurocognitive function are caused not only by intracranial vascular disease, but also by space-occupying lesions and other forms of brain parenchymal damage which can lead to cerebral hemorrhagic or ischemic stroke. In response to stroke, certain inflammatory mediators and stress hormones are activated, which can be inhibited by dexmedetomidine based on preclinical studies. Nevertheless, very few clinical studies evaluate whether dexmedetomidine reduces stroke-related inflammation and stress hormone response, or whether there is a clinical neuroprotective function by dexmedetomidine.

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Intracranial Tumor Surgery

The use of dexmedetomidine as part of a multimodal anesthesia strategy during intracranial tumor resection has been recently investigated. Stable hemodynamics in supratentorial brain tumor resection prevents sudden increases in ICP and brain swelling. Randomized controlled trials in supratentorial brain tumor resection demonstrated that dexmedotomidine as an anesthetic adjuvant resulted in less cardiovascular variability during operations and an early emergence.32,33 For endoscopic tumor resection such as transnasal transsphenoidal pituitary adenomectomy, optimizing surgical conditions also requires stable hemodynamics as well as minimization of intraoperative bleeding for a better-visualized surgical field. In a prospective randomized controlled trial, infusing dexmedetomidine at 0.7 μg/kg/h as an adjunct to propofol-fentanyl anesthesia in this setting improved hemodynamic stability and reduced fentanyl and antihypertensive agent consumption.34 A systematic review of 254 patients from 5 randomized controlled trials involving functional endoscopic sinus surgery found that dexmedetomidine provided better surgical visibility than saline control or sevoflurane alone as its hypotensive action and hemodynamic stability reduced intraoperative bleeding, although the quality of the operative field was similar among dexmedetomidine, esmolol, and remifentanil groups.35

Neurological deficit is one of the core outcomes in intracranial tumor surgery. However, the multitude of potential confounding variables, including anesthetics, surgical techniques, and tumor histologic type and location, makes it difficult to single out any particular factor’s effects on outcomes. In a recent randomized controlled trial, 4 commonly used anesthetic agents for neurosurgery with different mechanisms of action (midazolam, propofol, fentanyl, and dexmedetomidine) were titrated to an equivalent mild sedation in patients with supratentorial mass lesions before any surgical intervention.36 Dexmedetomidine compared with the other agents resulted in a much lower incidence of unmasked or exacerbated neurological deficits. This may be attributable to brain reorganization in which compensations are less sensitive to central α2-agonist dexmedetomidine sedation.37 Patients with high-grade gliomas were more susceptible to exacerbated neurological deficits than those with low-grade gliomas regardless of the sedative used. How global and regional cerebral hemodynamics are affected by the interaction of tumor and dexmedetomidine, as well as how this phenomenon affects outcomes, is unknown. A recent animal study found α2-adrenoceptor expression in C6 glioma cells (a malignant glioma cell line),38 so that dexmedetomidine may have an interaction with the tumor through regulating multiple molecular signal pathways and directly activating α2-adrenoceptors in gliomas. This seems to indicate that the “response” of tumors to anesthetics is strongly associated with the tumors’ histologic properties. Even if tumor location is accounted for, and that such interaction must be taken into consideration when evaluating anesthetic-related oncology outcomes.

Most brain tumor studies are anatomically rather than histologically based. The brain’s connectivity and integration, and subsequent compensation, involves complex networks involving both cortical and subcortical structures, and is often more complicated in the setting of neuronal injury. This affected connectivity and compensation does vary among different lesions, depending on location, size, and tumor development. Benign and malignant tumors affect cerebral physiology in different ways and may have different “behaviors” in the setting of different sedatives/hypnotics. Therefore, to evaluate dexemedetomidine’s effects on neurological outcome in brain tumor patients, extensive disease-centered studies with carefully defined clinical phenotypes are needed.

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Epilepsy Surgeries Requiring Intraoperative Mapping

Localization of seizure foci and monitoring of brain function in epilepsy surgeries are crucial, and these are usually achieved by use of the electroencephalogram (EEG) and/or electrocorticography (ECoG).39 As these monitoring modalities are readily affected by most anesthetic agents, anesthesia management can be challenging with the need to balance adequate anesthetic maintenance while satisfying necessary electroencephalographic parameters. Hence, understanding of the benefits and drawbacks of dexmedetomidine application in these scenarios and its interaction with EEG/ECoG monitoring in the epilepsy population is important. For example, a reduced seizure threshold caused by dexmedetomidine might result in a false-positive leading to an “over-aggressive” resection, while abolished epileptiform discharges may cause a false-negative and result in surgical resection being aborted.

Genetically epilepsy-prone rats have been shown to possess norepinephrine abnormalities in the central nervous system, displaying noradrenergic terminal deficiencies and a decreased amount of norepinephrine release.40–42 As dexmedetomidine has the property of reducing central noradrenergic transmission, early studies proposed proconvulsant effects of dexmedetomidine and seizure threshold reduction.43,44 Conversely, in other animal models, dexmedetomidine increased seizure threshold.45,46 This inconsistency may stem from seizure architectures involving different neurotransmitter pathways that may be modulated by dexmedetomidine to generate proconvulsant or anticonvulsant effects. The interaction between dexmedetomidine and different central nerve system excitatory agents implies disparate impacts on EEG interpretation.

The changes in frontal and parieto-occipital EEG frequencies are similar during dexmedetomidine sedation and natural non-rapid eye movement sleep.47,48 Although ECoG and EEG are well preserved as a whole and no major adverse clinical effects have been described following dexmedetomidine, there have been cases exhibiting increased seizure foci activity thereby challenging the suggestion that dexmedetomidine has anticonvulsant effects in humans.49–51 While it remains unclear why the effects of dexmedetomidine on epileptiform activity are variable, drug combinations, individual phenotypes, and preexisting neurological deficits may all be contributing factors.50

Small case series describe clinical experience with dexmedetomidine in adult patients undergoing resection of epileptogenic foci, and report satisfactory operating conditions without a reduction in epileptiform activity,50 the ability to obtain ECoG information, or the ability to perform cortical mapping.49 In general, a “low dose” is recommended, whereby administration can be started with a bolus of 0.3 to 0.5 μg/kg over 10 minutes followed by an infusion of 0.2 to 0.5 μg/kg/h,49,50 remembering that individual infusion rates vary. It is important to note, however, that patients with seizure disorders taking P450 enzyme–inducing anticonvulsant medications (eg, phenytoin and carbamazepine) have an increased plasma clearance of dexmedetomidine,52 indicating that higher doses might be necessary to maintain the desired sedation level.

While dexmedetomidine has been successfully used as an adjuvant during epilepsy surgeries, future randomized controlled trials will be necessary to determine its proconvulsant or anticonvulsant effects, especially in terms of dosing, drug combination, and interaction with specific seizure characteristics in both the adult and pediatric populations.

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Stereotactic Neurosurgery/Deep Brain Stimulation

Stereotactic neurosurgeries such as deep brain stimulator (DBS) placement are treatments for patients with neurological movement disorders, for example, Parkinson disease (PD), Tourette Syndrome, or Obsessive-Compulsive Disorder.53 The subthalamic nucleus, globus pallidus interna, and ventralis intermedius nucleus of the thalamus are the 3 common target areas.53,54 The anesthetic considerations include an awake and cooperative patient, stable hemodynamics, maintenance of ventilation, airway reflexes and patency due to limited airway access because of a head frame, as well as minimizing anesthetic interference with microelectrode recordings (MER) and macrostimulation.

Propofol is commonly used as the sole sedative during DBS placement under MAC,55 and these cases may include scalp blocks and/or local anesthesia with a background infusion of short acting sedatives and narcotics (eg, remifentanil) during the procedure.53 Propofol can decrease subthalamic nucleus activity and interfere with MER, although this interference can be terminated rapidly by stopping its administration.56 This suppression is mediated by GABA inhibitory pathways in the subthalamic nucleus and globus pallidus that contain abundant GABAergic innervations.53 To avoid this, dexmedetomidine has been suggested as an alternative sedative agent. It has been reported that dexmedetomidine (1.5 μg/kg bolus over 20 min followed by 0.2 to 0.5 μg/kg/h infusion) effectively controlled propofol-induced dyskinesia during bilateral subthalamic nucleus DBS placement without adverse effect on MER.57 The mechanism of occasional tremor reduction or suppression in PD patients sedated with dexmedetomidine is still unclear.58

The effects of dexmedetomidine on MERs in different subcortical neurons are still under investigation. A study of a wide range of dexmedetomidine boluses over 10 minutes (0.5 to 1 μg/kg) followed by an infusion (0.1 to 1 μg/kg/h) compared with saline in PD patients demonstrated an increased firing rate and decreased number of bursts and percentage of spikes in bursts of the dorsal but not ventral subthalamic nucleus. There was no effect on local field potentials (LFPs), beta power, and spike oscillations in the beta frequency.59 However, this study failed to demonstrate a dose-related effect on MER properties and clinical outcomes. A subsequent smaller study found that dexmedetomidine infusion with intermittent propofol administration decreased the firing rate of globus pallidus internal neurons without affecting clinical target localization.60 However, it should be noted that interaction with propofol may affect the accuracy of MER acquisition. An investigation of 10 cases studied low-dose dexmedetomidine infusion at 0.2 μg/kg/h or stepwise propofol infusion on the effect of power distribution of LFPs in subthalamic nuclei during DBS surgeries for PD. This study demonstrated minimal change in power spectra with and without such a dose of dexmedetomidine sedation, while in the same patients a few days after the first DBS stage, when using propofol sedation (0.5 to 2.5 μg/mL), beta LFP activity was lost as propofol dose increased.61 Although a low concentration of dexmedetomidine has little effects on LFP activity, such a low dose may be insufficient to provide adequate sedation.

Dexmedetomidine has been shown to possess other advantages in DBS surgeries, including easily arousable sedation, good patient cooperation, and no respiratory depression.60,62,63 In long duration bilateral DBS procedures, a high incidence of patient anxiety, fear, confusion, or restlessness can occur, causing the procedure to be halted. Dexmedetomidine sedation has been shown to inhibit agitation and stress in prolonged surgery.62 Hypertension during DBS placement, predisposing to intracranial hemorrhage, may occur when sympatholytic medications are withdrawn, leading to the incremental use of antihypertensive drugs intraoperatively, especially for those who are elderly, have preexisting hypertension, diabetes mellitus, or have had PD for >10 years.64 Therefore, blood pressure control and the maintenance of hemodynamic stability are important. A 3-year retrospective study compared DBS surgeries performed with 0.3 to 0.8 μg/kg/h dexmedetomidine infusion titrating to Observer Assessment of Alertness and Sedation scale 4 versus patients without sedation, and found that dexmedetomidine not only protected electrophysiological mapping but also provided better hemodynamic stability.65

Lower infusion rates of dexmedetomidine are recommended for DBS surgery. High-dose (>0.8 μg/kg/h) infusion should be avoided for several reasons. Over-sedation (bispectral index<80) may abolish MER by suppressing neuronal firing, decreasing background electrical activity and spike amplitudes,60 and thus delaying the commencement of MER66 or causing failure to guide electrode placement.59 It may also increase the risk of respiratory suppression, especially in patients with obstructive sleep apnea,65 and result in clinically significant bradycardia.

Anxiety and failure to cooperate are more frequent in pediatric awake stereotactic neurosurgeries, thus hampering the procedure and increasing the risk of intracerebral bleeding. A combination of dexmedetomidine and propofol infusion in pediatric DBS placement provided a safe, efficacious, and well-tolerated sedation with minimal respiratory depression.67 The combination of three non-GABAergic agents (dexmedetomidine, ketamine, and opioids) in pediatric DBS surgery might be an optional anesthesia strategy to preserve MERs.68

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Traumatic Brain Injury (TBI)

Sedation in TBI may have therapeutic significance besides facilitating airway control. The purpose of sedation in TBI includes optimizing CMRO2 and CBF, reducing elevated ICP, and preventing secondary brain injury.69

In a retrospective case series, in which 85 severe TBI patients in the intensive care unit (ICU) received a median dose of dexmedetomidine of 0.49 μg/kg/h for 32 hours (median infusion period) to maintain “cooperative sedation,” midazolam and propofol requirements nearly disappeared indicating the effectiveness of dexmedetomidine as the sole agent for mild sedation for TBI patients.70 Another prospective study observed 198 severe TBI patients who received dexmedetomidine and/or propofol sedation. Dexmedetomidine was associated with longer “calm to light sedation” targets compared with propofol alone in the first 7 days after infusion.71 Although dexmedetomidine was associated with a higher degree of hypotension compared with propofol, there were no differences in adverse events between the groups.71 However, a prospective randomized controlled trial to elucidate the optimal time and dose, as well as other potential effects of dexmedetomidine, on clinical outcomes is lacking.

Patients with a history of alcohol abuse that suffer TBI are common, and they are more likely to have uncontrolled agitation related to alcohol withdrawal. A case report of an alcohol-dependent TBI patient showed that dexmedetomidine as a continuous infusion (0.5 to 1.5 μg/kg/h for 8 d) facilitated sedation and controlled agitation when benzodiazepine treatment failed, without neurological or respiratory depression.72 The finding from this case may call for additional studies to validate the safety and efficacy of dexmedetomidine as an alternative adjuvant or first-line strategy in treating agitation and alcohol withdrawal following TBI. Currently, there is no prospective randomized controlled trial that clarifies the role of dexmedetomidine in the care of TBI patients.

Systemic hypotension or hypertension can be disastrous for TBI patients with impaired cerebral autoregulation because it can decrease cerebral perfusion pressure, increase ICP, and lead to poor clinical outcomes. Moderate to severe TBI patients may also suffer paroxysmal sympathetic hyperactivity (PSH) due to elevated ICP, which presents with elevated heart rate, blood pressure, respiratory rate, temperature, sweating, and posturing.73 A case report showed that 0.2 to 0.7 μg/kg/h dexmedetomidine continuous infusion effectively controlled this syndrome when routine medication therapy failed.74 Schomer et al75 retrospectively collected a small series of 23 TBI patients in the neurosurgical intensive care unit who experienced refractory intracranial hypertension. Dexmedetomidine was infused at 0.2 to 0.7 μg/kg/h as an adjunct sedative to background fentanyl, midazolam, and/or propofol sedative-analgesic regimens to control episodes of severe intracranial hypertension. This study primarily compared the frequency of using rescue therapies for ICP control (eg, hyperosmolar fluid boluses and CSF drainage via extraventricular drains) in 2 time periods, 24 hours before, and 24 hours after, dexmedetomidine initiation, and found no difference between groups. However, this study did not clearly define the titration protocol and infusion duration of dexmedetomidine. Another retrospective study included 90 severe TBI patients who received dexmedetomidine or propofol/midazolam sedation in the neuro ICU for consecutive days, and found that the dexmedetomidine regimen group had a lower probability to be diagnosed with PSH.76 However, there are no prospective and high-quality studies elucidating the safety and efficacy of the preventive treatment of PSH with dexmedetomidine.

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Spinal Cord Injury

Interest in the potential protective effects of dexmedetomidine in relation to spinal cord injuries has grown in the past decade. Recent animal studies have found that intravenous dexmedetomidine attenuated spinal ventral neuronal degeneration and preserved neurological function and neuronal viability after transient spinal cord ischemia77 or ischemia-reperfusion.78 These beneficial effects were associated with improved cell survival and antiapoptotic factors,78 as well as with the attenuation of microglial activation, proinflammatory cytokine production,79 decreased interleukin-6, tumor necrosis factor-alpha, and reduced neutrophil infiltration, all of which indicate an anti-inflammatory effect.80

Clinically, there is no direct evidence of improved functional outcome by virtue of dexmedetomidine’s theoretical spinal cord protective or anti-inflammatory effects. In a single case of a focal inflammatory spinal cord disorder, namely transverse myelitis, hemodynamic instability was reported as the major concern response.81 In that case, dexmedetomidine sedation resulted in severe hypertension and bradycardia, which may have been due to an exaggerated peripheral vasoconstrictor response due to the lack of spinal reflexes. In terms of injury biomarkers, a prospective study found reduced levels of the stress hormone cortisol and the inflammatory response marker interleukin-10 after intraoperative dexmedetomidine infusion in cervical spine surgery.82 However, those stress response biomarkers and cytokine concentrations could not be correlated with any postoperative functional recovery parameter. Traumatic and ischemic spinal cord injuries differ, not only in their etiologies, but also in the constellation of biomarkers which are released. Furthermore, stress response and inflammatory markers released in response to surgical intervention form their own subset as well. Lastly, the biochemically protective effects of dexmedetomidine that have been observed in animal studies do not translate into clinical observation.

Although dexmedetomidine does not attenuate the injury in patients with cervical cord lesions, its practical use lies perhaps in helping to prevent secondary injury by facilitating awake fiberoptic intubation. Dexmedetomidine sedation-facilitated intubation and awake positioning was reported to be successful in a case of spinal cord injury.83 A subsequent randomized controlled trial related to the performance of awake fiberoptic intubation in simulated cervical injury patients found that adding dexmedetomidine sedation (1 μg/kg bolus over 10 min followed by 0.5 to 0.7 μg/kg/h) did not compromise hemodynamic instability and resulted in better patient tolerance and satisfaction compared with the use of midazolam alone.84

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Intraoperative Neurophysiology Monitoring

Intraoperative neurological injuries are usually detected as changes in the latencies or amplitudes of evoked potentials (EPs). As such, intraoperative EP monitoring in spine surgeries should preferably be minimally affected by the anesthetic regimen.85 Dexmedetomidine has been increasingly used to reduce the requirement of other anesthetics that may impair EP signal acquisition, and its effects on EPs have been observed and investigated thoroughly in spine surgery. The effects of dexmedetomidine on EPs are, however, controversial in both animal and human studies. For somatosensory EPs (SSEPs), a clinically relevant infusion rate of dexmedetomidine in animals only slightly increased their amplitude and prolonged their latency, and SSEPs were little affected even at a larger dexmedetomidine dose.86 Human cases have reported that administration of dexmedetomidine (0.2 to 0.7 μg/kg/h) in spine surgeries slightly inhibited later cortical SSEP peaks but did not affect latency.87 SSEPs are generally well maintained under dexmedetomidine during spine surgeries, with retention of the ability to monitor consistent and reproducible potentials.88–92 For motor evoked potentials (MEPs), most clinical studies found that clinically relevant doses of dexmedetomidine also do not affect the signal,88,89,91,92 but patients receiving a higher loading dose (1 μg/kg)93 or with a higher plasma concentration (0.8 ng/mL)90 do experience MEP amplitude reduction or even signal loss.94 Higher anesthetic concentrations (eg, inhalational agents), can interfere with neurophysiological monitoring, and intraoperative dexmedetomidine infusion compared with oral clonidine premedication more effectively reduced isoflurane requirements during spine surgery,95 in turn minimizing the suppress of neurophysiological monitoring.

Of note, all currently available evidence regarding the effects of dexmedetomidine on EPs stems from spine surgeries. The impact of dexmedetomidine on EPs in the setting of different neuronal pathologic diseases may vary, especially for those with impaired cerebrospinal tracts. However, the pharmacological mechanism by which dexmedetomidine may compromise spinal neuronal pathways remains to be elucidated, as does the effect exerted on EPs by its interaction with anesthetics in different anesthetic regimens. As for intracranial surgeries, knowledge of how dexmedetomidine affects EP acquisition and the latencies and amplitudes of MEPs and SSEPs for intracranial tumor or cerebrovascular pathologies is lacking.

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Awake Craniotomy

Awake craniotomy is performed in patients with intracranial lesions in or near eloquent brain areas requiring cortical mapping and intraoperative neurofunctional testing to maximize resection while reducing risk of disability. Two different anesthesia management regimens are advocated: the “asleep-awake-asleep” technique in which endotracheal intubation or laryngeal mask airway placement is performed for the asleep portions of the procedure, and the “awake-awake-awake” technique in which mild sedation without invasive airway manipulation96,97 is used during the pre-mapping and post-mapping phases.10,11 Local anesthetic infiltration to the incision site and/or a scalp block is generally used with both approaches. Special anesthesia considerations during the “awake” portion of any such procedure include the need for cooperative sedation and sufficient analgesia without respiratory depression, as well as the need for minimal interference with neurofunctional testing or cortical mapping.

Solely propofol-based sedation with an unprotected airway in “asleep-awake-asleep” craniotomy, compared with general anesthesia, carries the concerns of a higher incidence of respiratory depression in obese patients, arterial hemoglobin desaturation, a higher level of PaCO2, hypertension, hypotension, and tachycardia.98 Therefore, dexmedetomidine has been introduced and reported as a useful adjuvant during “awake” state sedation,99–102 or even as an effective rescue sedative when a propofol-remifentanil regimen results in over-sedation, respiratory depression, or discomfort.103 Other case reports have demonstrated that planned endotracheal intubation or laryngeal mask airway placement was able to be avoided outright with the use of dexmedetomidine.102,104,105 In high-risk patients with airway compromise and severe comorbidities, continuous infusion of dexmedetomidine (0.5 to 1.0 μg/kg loading dose followed by 0.2 to 0.7 μg/kg/h infusion) as the primary sedative combined with scalp nerve block and small doses of opioid was reported to facilitate prolonged and complex “awake” procedures without any airway manipulation required.100,101 Dexmedetomidine was well-tolerated in obstructive sleep apnea patients who needed continuous positive airway pressure during awake craniotomy.106 A recent prospective, randomized study compared dexmedetomidine to propofol-remifentanil based conscious sedation in awake craniotomy for supratentorial tumor resection, in which the incidence of respiratory depression or airway obstruction was 20% with propofol-remifentanil sedation versus zero in the dexmedetomidine group.96 Nevertheless, both strategies achieved the same efficacy of sedation and ability to provide adequate conditions for intraoperative mapping.96

Although the requirement for adequate sedation in the absence of functional impairment is easily achieved with dexmedetomidine, in a case series (N=10) with dexmedetomidine infusion at a low dose, 3 subjects had postoperative transient reading difficulty or weakness and one had a permanent language deficit.107 To avoid neurofunctional testing failure, dexmedetomidine is usually discontinued49,101,104 or reduced105 to 0.1 to 0.2 μg/kg/h 10 to 20 minutes before mapping/testing and then resumed afterward.49 There is no evidence that the intraoperative conditions for testing provided by any sedative, including dexmedetomidine or propofol, can be linked to better or worse postoperative neurological outcomes, and there is no consensus on the optimal anesthetic protocol for awake craniotomy.97,108,109 Larger prospective comparison trials rather than case reports are needed in the future.

In a particular case, dexmedetomidine was successfully used for awake craniotomy in a pregnant patient with oligoastrocytoma without notable maternal or fetal adverse effects, its success being attributed to its central sedative and analgesic effects.110 However, the safety of using dexmedetomidine in the obstetric population is still unclear.110

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Sedation in Pediatric Patients With Neurosurgical Diseases

Sedation is usually required for imaging studies (eg, magnetic resonance imaging [MRI], computed tomography [CT]) in pediatric patients. Separation, confinement, and an unfamiliar environment create agitation and anxiety for children, and in situations in which general anesthesia may not be preferred, effective sedation with minimal respiratory depression is highly beneficial. A previous review extensively summarized early clinical studies of using dexmedetomidine as the primary or rescue sedative during MRI or CT examination in pediatric populations.48 In this review, dexmedetomidine was superior to midazolam but inferior to propofol in providing effective sedation,111 and this may be because propofol led to fewer procedure interruptions and better parental satisfaction according to a comparison study of 1- to 7-year-old children undergoing MRI with propofol or dexmedetomidine sedation.112 Furthermore, the recovery time was slower in the dexmedetomidine cohort compared with those who received propofol. However, the dosage of dexmedetomidine ranged widely, from 0.3 to 2 μg/kg bolus over 10 to 15 minutes followed by 0.5 to 1.5 μg/kg/h infusion rate, and there was no optimal dosage identified.

For outpatient EEG monitoring in children, intravenously administered dexmedetomidine provides effective sedation without agitation, hemodynamic fluctuation, or respiratory depression, and was superior to midazolam in terms of minimum “drug effect” on the quality of acquired EEG.47,102,113 Dexmedetomidine increased the power at the high frequency bandwidth (theta, alpha, and beta), but did not alter delta bandwidth and total EEG power.48 The rate of spike activity was increased under dexmedetomidine, but no new spike foci were detected.48 In neonates, such EEG changes may be related either to epileptic seizures or to nonepileptic abnormal movements, even if MRI is normal and no seizure disorder history is present.51 Magnetoencephalography uses a weak magnetic signal to detect epileptic discharges and is little affected by dexmedetomidine.114

Sedation for intracranial radiotherapy for a 21-month-old child was reported to be safely achieved with dexmedetomidine sedation, providing a smooth sedation “induction” and fairly rapid recovery with airway protection.115 Perioperative infusion of dexmedetomidine at 0.2 μg/kg/h as an adjunct sedative reduced sevoflurane-related emergence delirium in children aged 1 to 10 years.116 Children with TBI may require prolonged sedation, but hypertension may occur when switching to dexmedetomidine infusion up to 4 μg/kg/h,117 as is sometimes used in adults. Clinical research defining the optimal dosing strategy and duration of dexmedetomidine infusion for sedation in pediatric TBI is lacking. Notably, dexmedetomidine was reported to be associated with significant bradycardia during therapeutic hypothermia when combined with remifentanil for sedation in children with TBI.118 Further trials are needed to elucidate the cardiovascular side effects relating to the doses and infusion rate of dexmedetomidine in children with neurological injury.

Some preclinical studies have shown that dexmedetomidine attenuated anesthetic-induced neurotoxicity, hence exerting a neuroprotective effect. In neonatal rats, dexmedetomidine inhibited neuroapoptosis induced by isoflurane,119,120 sevoflurane,121 propofol122 or ketamine,123 and the neurocognitive impairment caused by those anesthetic agents was prevented by dexmedetomidine. In contrast, another animal study found that exposure to dexmedetomidine produced significant cellular degeneration and apoptosis in primary sensory brain regions, indicating a neurotoxic effect, which may have been due to the use of higher doses and frequencies of administration.124 Despite the few animal studies implying the above effects, there is a lack of clinical evidence regarding the potential neuronal protective or toxic effects of dexmedetomidine in developing human brains following neurological injury, or how dexmedetomidine affects CBF, CMRO2, and ICP in children.125 Further translational studies and clinical evidence are needed.

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Benefits of Analgesia in Neurosurgery

Postoperative pain following craniotomy or spinal surgery may be significant and can lead to postoperative agitation and hypertension, which should be properly managed to minimize potential intracerebral hemorrhage and/or vasogenic edema. Opioids are effective in controlling pain but may cause respiratory depression. Dexmedetomidine can maintain airway reflexes and patency in spontaneously breathing patients while providing analgesic effects. The mechanism of dexmedetomidine’s analgesia occurs through pontospinal inhibitory pathways by activating the locus ceruleus and noradrenergic nuclei, then via its descending projections to the superficial dorsal horn of spinal cord, where there is a facilitated inhibitory synaptic response producing antinociceptive effects.126 Likewise, dexmedetomidine ameliorates neuropathic pain after spinal nerve injury by a mechanism also related to stimulation of spinal α2-adrenergic receptors, resulting in KCl-evoked acetylcholine release from synaptosomes in the α2-adrenergic-cholinergic circuit.127

A previous meta-analysis included eight small sample size randomized controlled trials and found that dexmedetomidine reduced intraoperative opioid consumption during intracranial procedures,128 although the administration time and dose were variable among the included studies. Subsequent randomized controlled trials demonstrated that infusion of dexmedetomidine between 0.2 and 0.7 μg/kg/h during and after the operation reduced postoperative pain after craniotomy and spine surgeries.34,129–132 It should be noted that although dexmedetomidine was associated with less hyperalgesia compared with remifentanil,130 its analgesic effect was not as potent as that of remifentanil,133 and those receiving dexmedetomidine had longer emergence times.130,134 To avoid such delayed emergence, a particular study made use of a 0.4 or 0.8 μg/kg bolus of dexmedetomidine for 10 minutes 1 h before the end of supratentorial craniotomy, with its secondary outcome showing less postsurgical pain compared with control during emergence and after transport to the ICU.135 The analgesic efficacy of dexmedetomidine has also been shown in studies in spine surgery, mainly lumbar laminectomy, discectomy, or posterior lumbar interbody fusion. It has been reported that good tolerance and intraoperative cooperation was also achieved in minimally invasive spine surgery under MAC by using dexmedetomidine, without the risk of respiratory depression.136 Compared with oral clonidine premedication, dexmedetomidine possesses a noninferior opioid and anesthetic-sparing effect, and equal postoperative recovery time, hemodynamic stability, and blood loss during spine surgery.137 A randomized controlled trial study found that intraoperative dexmedetomidine infusion at 0.5 μg/kg/h compared with saline improved the quality of recovery and reduced fatigue in the early postoperative period after major spine surgery,82 when continuously infusing 0.2 μg/kg/h for another 24 hours postoperatively. A similar regimen can likewise reduce pain scores, with less rescue analgesic requirement and the same recovery time, in cervical spine surgery.131 The effectiveness of dexmedetomidine as an analgesic was demonstrated both when given as an intravenous infusion134,138 and as an epidural injection.139 For spinal tumor surgery, no retrospective or prospective study of dexmedetomidine’s analgesic efficacy was identified.

Neither for craniotomy nor for spinal surgery has a standard dexmedetomidine administration strategy been established with regards to dose, time of initiation, duration, and combination with other drugs. Moreover, the intensity of pain varies with different craniotomy approaches, for example, supratentorial craniotomies are associated with less pain than infratentorial procedures.140

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The Neurocritical Care Unit

The application of dexmedetomidine for TBI patients in the neurocritical care unit has been discussed in a previous section above. In this section, we review recent clinical evidence related to adding dexmedetomidine as an adjuvant agent or as the sole sedative in neurosurgical patients requiring postoperative mechanical ventilation in the ICU. A recent well-designed randomized controlled trial compared the infusion of dexmedetomidine for <7 days with saline in a propofol-based sedation regimen in the general ICU (including only a few neurosurgical patients) in patients with agitated delirium and requiring mechanical ventilation.141 This study found that dexmedetomidine facilitated early extubation and was associated with more ventilator-free hours. It is exceptionally important in the neurosurgical population to control agitation and provide analgesia, so as to improve tolerance to mechanical ventilation and accelerate time to extubation in order to maintain intracranial homeostasis and enable early neurological assessment. Another randomized control trial enrolled 150 craniotomy patients who were not extubated when admitted to the neuro ICU, where dexmedetomidine infusion at 0.6 μg/kg/h was initiated 2 hours after craniotomy and up until 30 minutes after extubation, or for a maximum 24 hours.142 Patients who received dexmedetomidine demonstrated a decreased incidence of agitation compared with the saline group. Most studies do demonstrate a significant reduction of opioid requirement when using dexmedetomidine,143,144 and this analgesic effect may be an important reason for less agitation and better ventilator tolerance. In a prospective randomized control study of 90 neurosurgical patients requiring short-term postoperative ventilation for about 12 hours, dexmedetomidine, midazolam, or propofol all provided effective sedation and stable hemodynamic stability.143 Compared with propofol and midazolam sedation, however, dexmedetomidine was associated with a longer time to extubation. Severe hemodynamic compromise that may worsen outcome is another vital concern for neurocritical care patients receiving continuous sedation. A retrospective propensity-matched cohort data analysis of 342 patients from 2 medical centers showed that dexmedetomidine and propofol were associated with an equal prevalence of hypotension (defined as MAP <60 mm Hg, 23% vs. 26%) and bradycardia (defined as heart rate <50 beats/min, 8.6% vs. 5.5%).145 However, other studies frequently demonstrate that dexmedetomidine is more commonly associated with bradycardia142,143 which requires close attention, especially with higher doses and longer durations of infusion, as are used when weaning off other sedatives in the neurocritical care unit.146 Interestingly, a prospective study found that dexmedetomidine improved cognitive function in neuro ICU for patients without forebrain injury compared with propofol, which reduced cognitive function.147 This was attributed to the better antiagitation and analgesic effects of dexmedetomidine. Although, this study had a small sample size, the neurocognitive functional outcome difference observed was interesting and important. Clearly, in order to properly evaluate any clinically relevant neuroprotective effects of dexmedetomidine in this setting, a more highly powered clinical study is needed.

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In recent years there has been increasing interest in the application of dexmedetomidine to various neurological clinical scenarios. The prevailing thought is that dexmedetomidine may be associated with less cerebral hemodynamic perturbation, minimal neurophysiological monitoring interference, a greater ability to achieve cooperative sedation without respiratory compromise in awake procedures, and acceptable pain control (alone or in combination with more potent analgesics). Low-range to mid-range infusion doses of dexmedetomidine seem to exert the above benefits in perioperative neurosurgical care based on some current clinical evidence, although very notably there is yet no standard dexmedetomidine administration strategy for these indications. Dexmedetomidine may result in severe bradycardia and hypotension and hence, should be used very cautiously in patients with compromised brain perfusion or systemic hemodynamic instability. It should be noted that although the analgesic effects of dexmedetomidine have been demonstrated in many clinical settings, it is not a potent analgesic in its own right, but rather should be considered as an adjunct to a “true” analgesic, such as an opioid.

Despite the purported benefits of dexmedetomidine mentioned above, it is critical to note that many uncertainties regarding its clinical use in neuroanesthesia remain. It is unclear whether it is proconvulsant or anticonvulsant, or how it affects EPs in different cerebral pathologies, and there is a lack of clinical evidence regarding neuronal protection or toxicity following neuronal injury in both children and adults. Further disease-based translational studies are required to understand both short-term and long-term neurological and neurocognitive outcomes after dexmedetomidine administration.

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1. Lehtimaki J, Leino T, Koivisto A, et al. In vitro and in vivo profiling of fadolmidine, a novel potent alpha(2)-adrenoceptor agonist with local mode of action. Eur J Pharmacol. 2008;599:65–71.
2. Seyrek M, Halici Z, Yildiz O, et al. Interaction between dexmedetomidine and alpha-adrenergic receptors: emphasis on vascular actions. J Cardiothorac Vasc Anesth. 2011;25:856–862.
3. Hashmi JA, Loggia ML, Khan S, et al. Dexmedetomidine disrupts the local and global efficiencies of large-scale brain networks. Anesthesiology. 2017;126:419–430.
4. Mashour GA. Network inefficiency: a rosetta stone for the mechanism of anesthetic-induced unconsciousness. Anesthesiology. 2017;126:366–368.
5. Farag E, Argalious M, Sessler DI, et al. Use of α2-agonists in neuroanesthesia: an overview. Ochsner J. 2011;11:57–69.
6. Bekker A, Sturaitis MK. Dexmedetomidine for neurological surgery. Neurosurgery. 2005;57:1–10.
7. Aryan HE, Box KW, Ibrahim D, et al. Safety and efficacy of dexmedetomidine in neurosurgical patients. Brain Inj. 2006;20:791–798.
8. Wang X, Ji J, Fen L, et al. Effects of dexmedetomidine on cerebral blood flow in critically ill patients with or without traumatic brain injury: a prospective controlled trial. Brain Inj. 2013;27:1617–1622.
9. Bekker A, Gold M, Ahmed R, et al. Dexmedetomidine does not increase the incidence of intracarotid shunting in patients undergoing awake carotid endarterectomy. Anesth Analg. 2006;103:955–958.
10. Bekker AY, Basile J, Gold M, et al. Dexmedetomidine for awake carotid endarterectomy: efficacy, hemodynamic profile, and side effects. J Neurosurg Anesthesiol. 2004;16:126–135.
11. McCutcheon CA, Orme RM, Scott DA, et al. A comparison of dexmedetomidine versus conventional therapy for sedation and hemodynamic control during carotid endarterectomy performed under regional anesthesia. Anesth Analg. 2006;102:668–675.
12. Moulakakis KG, Mylonas SN, Sfyroeras GS, et al. Hyperperfusion syndrome after carotid revascularization. J Vasc Surg. 2009;49:1060–1068.
13. Nakano T, Okamoto H. Dexmedetomidine-induced cerebral hypoperfusion exacerbates ischemic brain injury in rats. J Anesth. 2009;23:378–384.
14. Drummond JC, Dao AV, Roth DM, et al. Effect of dexmedetomidine on cerebral blood flow velocity, cerebral metabolic rate, and carbon dioxide response in normal humans. Anesthesiology. 2008;108:225–232.
15. Drummond JC, Sturaitis MK. Brain tissue oxygenation during dexmedetomidine administration in surgical patients with neurovascular injuries. J Neurosurg Anesthesiol. 2010;22:336–341.
16. Yokota H, Yokoyama K, Noguchi H, et al. Post-operative dexmedetomidine-based sedation after uneventful intracranial surgery for unruptured cerebral aneurysm: comparison with propofol-based sedation. Neurocrit Care. 2011;14:182–187.
17. Lee HH, Jung YJ, Choi BY, et al. Usefulness of dexmedetomidine during intracerebral aneurysm coiling. J Korean Neurosurg Soc. 2014;55:185–189.
18. Ayoglu H, Gul S, Hanci V, et al. The effects of dexmedetomidine dosage on cerebral vasospasm in a rat subarachnoid haemorrhage model. J Clin Neurosci. 2010;17:770–773.
19. Wang Y, Han R, Zuo Z. Dexmedetomidine post-treatment induces neuroprotection via activation of extracellular signal-regulated kinase in rats with subarachnoid haemorrhage. Br J Anaesth. 2016;116:384–392.
20. Cosar M, Eser O, Fidan H, et al. The neuroprotective effect of dexmedetomidine in the hippocampus of rabbits after subarachnoid hemorrhage. Surg Neurol. 2009;71:54–59.
21. Hwang L, Choi IY, Kim SE, et al. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus. Int J Mol Med. 2013;31:1047–1056.
22. Chi OZ, Grayson J, Barsoum S, et al. Effects of dexmedetomidine on microregional O2 balance during reperfusion after focal cerebral ischemia. J Stroke Cerebrovasc Dis. 2015;24:163–170.
23. Wang Z, Kou D, Li Z, et al. Effects of propofol-dexmedetomidine combination on ischemia reperfusion-induced cerebral injury. NeuroRehabilitation. 2014;35:825–834.
24. Goyagi T, Nishikawa T, Tobe Y, et al. The combined neuroprotective effects of lidocaine and dexmedetomidine after transient forebrain ischemia in rats. Acta Anaesthesiol Scand. 2009;53:1176–1183.
25. Ding XD, Zheng NN, Cao YY, et al. Dexmedetomidine preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest. Int J Neurosci. 2016;126:249–256.
26. Ren X, Ma H, Zuo Z. Dexmedetomidine postconditioning reduces brain injury after brain hypoxia-ischemia in neonatal rats. J Neuroimmune Pharmacol. 2016;11:238–247.
27. Eser O, Fidan H, Sahin O, et al. The influence of dexmedetomidine on ischemic rat hippocampus. Brain Res. 2008;1218:250–256.
28. Brede M, Braeuninger S, Langhauser F, et al. Alpha(2)-adrenoceptors do not mediate neuroprotection in acute ischemic stroke in mice. J Cereb Blood Flow Metab. 2011;31:e1–e7.
29. Engelhard K, Werner C, Kaspar S, et al. Effect of the alpha2-agonist dexmedetomidine on cerebral neurotransmitter concentrations during cerebral ischemia in rats. Anesthesiology. 2002;96:450–457.
30. Zeng X, Wang H, Xing X, et al. Dexmedetomidine protects against transient global cerebral ischemia/reperfusion induced oxidative stress and inflammation in diabetic rats. PLoS One. 2016;11:e0151620.
31. Zhu YM, Wang CC, Chen L, et al. Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats. Brain Res. 2013;1494:1–8.
32. Tanskanen PE, Kytta JV, Randell TT, et al. Dexmedetomidine as an anaesthetic adjuvant in patients undergoing intracranial tumour surgery: a double-blind, randomized and placebo-controlled study. Br J Anaesth. 2006;97:658–665.
33. Soliman RN, Hassan AR, Rashwan AM, et al. Prospective, randomized study to assess the role of dexmedetomidine in patients with supratentorial tumors undergoing craniotomy under general anaesthesia. Middle East J Anaesthesiol. 2011;21:325–334.
34. Gopalakrishna KN, Dash PK, Chatterjee N, et al. Dexmedetomidine as an anesthetic adjuvant in patients undergoing transsphenoidal resection of pituitary tumor. J Neurosurg Anesthesiol. 2015;27:209–215.
35. Snidvongs K, Tingthanathikul W, Aeumjaturapat S, et al. Dexmedetomidine improves the quality of the operative field for functional endoscopic sinus surgery: systematic review. J Laryngol Otol. 2015;129(suppl 3):S8–S13.
36. Lin N, Han R, Zhou J, et al. Mild sedation exacerbates or unmasks focal neurologic dysfunction in neurosurgical patients with supratentorial brain mass lesions in a drug-specific manner. Anesthesiology. 2016;124:598–607.
37. Duffau H. The huge plastic potential of adult brain and the role of connectomics: new insights provided by serial mappings in glioma surgery. Cortex. 2014;58:325–387.
38. Tanabe K, Matsushima-Nishiwaki R, Kozawa O, et al. Dexmedetomidine suppresses interleukin-1beta-induced interleukin-6 synthesis in rat glial cells. Int J Mol Med. 2014;34:1032–1038.
39. King-Stephens D, Mirro E, Weber PB, et al. Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography. Epilepsia. 2015;56:959–967.
40. Yan QS, Jobe PC, Dailey JW. Thalamic deficiency in norepinephrine release detected via intracerebral microdialysis: a synaptic determinant of seizure predisposition in the genetically epilepsy-prone rat. Epilepsy Res. 1993;14:229–236.
41. Dailey JW, Mishra PK, Ko KH, et al. Noradrenergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats. Epilepsia. 1991;32:168–173.
42. Jobe PC, Ko KH, Dailey JW. Abnormalities in norepinephrine turnover rate in the central nervous system of the genetically epilepsy-prone rat. Brain Res. 1984;290:357–360.
43. Tanaka K, Oda Y, Funao T, et al. Dexmedetomidine decreases the convulsive potency of bupivacaine and levobupivacaine in rats: involvement of alpha2-adrenoceptor for controlling convulsions. Anesth Analg. 2005;100:687–696.
44. Mirski MA, Rossell LA, McPherson RW, et al. Dexmedetomidine decreases seizure threshold in a rat model of experimental generalized epilepsy. Anesthesiology. 1994;81:1422–1428.
45. Whittington RA, Virag L, Vulliemoz Y, et al. Dexmedetomidine increases the cocaine seizure threshold in rats. Anesthesiology. 2002;97:693–700.
46. Kan MC, Wang WP, Yao GD, et al. Anticonvulsant effect of dexmedetomidine in a rat model of self-sustaining status epilepticus with prolonged amygdala stimulation. Neurosci Lett. 2013;543:17–21.
47. Aksu R, Kumandas S, Akin A, et al. The comparison of the effects of dexmedetomidine and midazolam sedation on electroencephalography in pediatric patients with febrile convulsion. Paediatr Anaesth. 2011;21:373–378.
48. Mason KP, O’Mahony E, Zurakowski D, et al. Effects of dexmedetomidine sedation on the EEG in children. Paediatr Anaesth. 2009;19:1175–1183.
49. Souter MJ, Rozet I, Ojemann JG, et al. Dexmedetomidine sedation during awake craniotomy for seizure resection: effects on electrocorticography. J Neurosurg Anesthesiol. 2007;19:38–44.
50. Talke P, Stapelfeldt C, Garcia P. Dexmedetomidine does not reduce epileptiform discharges in adults with epilepsy. J Neurosurg Anesthesiol. 2007;19:195–199.
51. Kubota T, Fukasawa T, Kitamura E, et al. Epileptic seizures induced by dexmedetomidine in a neonate. Brain Dev. 2013;35:360–362.
52. Flexman AM, Wong H, Riggs KW, et al. Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study. Anesthesiology. 2014;120:1118–1125.
53. Grant R, Gruenbaum SE, Gerrard J. Anaesthesia for deep brain stimulation: a review. Curr Opin Anaesthesiol. 2015;28:505–510.
54. Volkmann J. Deep brain stimulation for the treatment of Parkinson’s disease. J Clin Neurophysiol. 2004;21:6–17.
55. Khatib R, Ebrahim Z, Rezai A, et al. Perioperative events during deep brain stimulation: the experience at cleveland clinic. J Neurosurg Anesthesiol. 2008;20:36–40.
56. Raz A, Eimerl D, Zaidel A, et al. Propofol decreases neuronal population spiking activity in the subthalamic nucleus of Parkinsonian patients. Anesth Analg. 2010;111:1285–1289.
57. Deogaonkar A, Deogaonkar M, Lee JY, et al. Propofol-induced dyskinesias controlled with dexmedetomidine during deep brain stimulation surgery. Anesthesiology. 2006;104:1337–1339.
58. Honorato-Cia C, Martinez-Simon A, Alegre M, et al. Factors associated with tremor changes during sedation with dexmedetomidine in Parkinson’s disease surgery. Stereotact Funct Neurosurg. 2015;93:393–399.
59. Krishna V, Elias G, Sammartino F, et al. The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson’s disease. Eur J Neurosci. 2015;42:2070–2077.
60. Kwon WK, Kim JH, Lee JH, et al. Microelectrode recording (MER) findings during sleep-awake anesthesia using dexmedetomidine in deep brain stimulation surgery for Parkinson’s disease. Clin Neurol Neurosurg. 2016;143:27–33.
61. Martinez-Simon A, Alegre M, Honorato-Cia C, et al. Effect of dexmedetomidine and propofol on basal ganglia activity in Parkinson disease: a controlled clinical trial. Anesthesiology. 2017;126:1033–1042.
62. Sassi M, Zekaj E, Grotta A, et al. Safety in the use of dexmedetomidine (precedex) for deep brain stimulation surgery: our experience in 23 randomized patients. Neuromodulation. 2013;16:401–406.
63. Morace R, De Angelis M, Aglialoro E, et al. Sedation with alpha-2 agonist dexmedetomidine during unilateral subthalamic nucleus deep brain stimulation: a preliminary report. World Neurosurg. 2016;89:320–328.
64. Rajan S, Deogaonkar M, Kaw R, et al. Factors predicting incremental administration of antihypertensive boluses during deep brain stimulator placement for Parkinson’s disease. J Clin Neurosci. 2014;21:1790–1795.
65. Rozet I, Muangman S, Vavilala MS, et al. Clinical experience with dexmedetomidine for implantation of deep brain stimulators in Parkinson’s disease. Anesth Analg. 2006;103:1224–1228.
66. Trombetta C, Deogaonkar A, Deogaonkar M, et al. Delayed awakening in dystonia patients undergoing deep brain stimulation surgery. J Clin Neurosci. 2010;17:865–868.
67. Sebeo J, Deiner SG, Alterman RL, et al. Anesthesia for pediatric deep brain stimulation. Anesthesiol Res Pract. 2010;2010:401419.
68. Hippard HK, Watcha M, Stocco AJ, et al. Preservation of microelectrode recordings with non-GABAergic drugs during deep brain stimulator placement in children. J Neurosurg Pediatr. 2014;14:279–286.
69. Oddo M, Crippa IA, Mehta S, et al. Optimizing sedation in patients with acute brain injury. Crit Care. 2016;20:128.
70. Humble SS, Wilson LD, Leath TC, et al. ICU sedation with dexmedetomidine after severe traumatic brain injury. Brain Inj. 2016;30:1266–1270.
71. Pajoumand M, Kufera JA, Bonds BW, et al. Dexmedetomidine as an adjunct for sedation in patients with traumatic brain injury. J Trauma Acute Care Surg. 2016;81:345–351.
72. Tang JF, Chen PL, Tang EJ, et al. Dexmedetomidine controls agitation and facilitates reliable, serial neurological examinations in a non-intubated patient with traumatic brain injury. Neurocrit Care. 2011;15:175–181.
73. Baguley IJ, Perkes IE, Fernandez-Ortega JF, et al. Paroxysmal sympathetic hyperactivity after acquired brain injury: consensus on conceptual definition, nomenclature, and diagnostic criteria. J Neurotrauma. 2014;31:1515–1520.
74. Goddeau RP Jr, Silverman SB, Sims JR. Dexmedetomidine for the treatment of paroxysmal autonomic instability with dystonia. Neurocrit Care. 2007;7:217–220.
75. Schomer KJ, Sebat CM, Adams JY, et al. Dexmedetomidine for refractory intracranial hypertension. J Intensive Care Med. 2017;96:885066616689555.
76. Tang Q, Wu X, Weng W, et al. The preventive effect of dexmedetomidine on paroxysmal sympathetic hyperactivity in severe traumatic brain injury patients who have undergone surgery: a retrospective study. PeerJ. 2017;5:e2986.
77. Goyagi T, Tobe Y. Dexmedetomidine improves the histological and neurological outcomes 48 h after transient spinal ischemia in rats. Brain Res. 2014;1566:24–30.
78. Bell MT, Puskas F, Bennett DT, et al. Dexmedetomidine, an alpha-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion. J Thorac Cardiovasc Surg. 2014;147:500–506.
79. Bell MT, Agoston VA, Freeman KA, et al. Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia. J Vasc Surg. 2014;59:1090–1097.
80. Can M, Gul S, Bektas S, et al. Effects of dexmedetomidine or methylprednisolone on inflammatory responses in spinal cord injury. Acta Anaesthesiol Scand. 2009;53:1068–1072.
81. Shah S, Sangari T, Qasim M, et al. Severe hypertension and bradycardia after dexmedetomidine for radiology sedation in a patient with acute transverse myelitis. Paediatr Anaesth. 2008;18:681–682.
82. Bekker A, Haile M, Kline R, et al. The effect of intraoperative infusion of dexmedetomidine on the quality of recovery after major spinal surgery. J Neurosurg Anesthesiol. 2013;25:16–24.
83. Sriganesh K, Ramesh VJ, Veena S, et al. Dexmedetomidine for awake fibreoptic intubation and awake self-positioning in a patient with a critically located cervical lesion for surgical removal of infra-tentorial tumour. Anaesthesia. 2010;65:949–951.
84. Chopra P, Dixit MB, Dang A, et al. Dexmedetomidine provides optimum conditions during awake fiberoptic intubation in simulated cervical spine injury patients. J Anaesthesiol Clin Pharmacol. 2016;32:54–58.
85. Soghomonyan S, Moran KR, Sandhu GS, et al. Anesthesia and evoked responses in neurosurgery. Front Pharmacol. 2014;5:74.
86. Li BH, Lohmann JS, Schuler HG, et al. Preservation of the cortical somatosensory-evoked potential during dexmedetomidine infusion in rats. Anesth Analg. 2003;96:1155–1160.
87. Bloom M, Beric A, Bekker A. Dexmedetomidine infusion and somatosensory evoked potentials. J Neurosurg Anesthesiol. 2001;13:320–322.
88. Bala E, Sessler DI, Nair DR, et al. Motor and somatosensory evoked potentials are well maintained in patients given dexmedetomidine during spine surgery. Anesthesiology. 2008;109:417–425.
89. Tobias JD, Goble TJ, Bates G, et al. Effects of dexmedetomidine on intraoperative motor and somatosensory evoked potential monitoring during spinal surgery in adolescents. Paediatr Anaesth. 2008;18:1082–1088.
90. Mahmoud M, Sadhasivam S, Salisbury S, et al. Susceptibility of transcranial electric motor-evoked potentials to varying targeted blood levels of dexmedetomidine during spine surgery. Anesthesiology. 2010;112:1364–1373.
91. Rozet I, Metzner J, Brown M, et al. Dexmedetomidine does not affect evoked potentials during spine surgery. Anesth Analg. 2015;121:492–501.
92. Li Y, Meng L, Peng Y, et al. Effects of Dexmedetomidine on motor- and somatosensory-evoked potentials in patients with thoracic spinal cord tumor: a randomized controlled trial. BMC Anesthesiol. 2016;16:51.
93. Mahmoud M, Sadhasivam S, Sestokas AK, et al. Loss of transcranial electric motor evoked potentials during pediatric spine surgery with dexmedetomidine. Anesthesiology. 2007;106:393–396.
94. Chen Z, Lin S, Shao W. Effects on somatosensory and motor evoked potentials of senile patients using different doses of dexmedetomidine during spine surgery. Ir J Med Sci. 2015;184:813–818.
95. Mariappan R, Ashokkumar H, Kuppuswamy B. Comparing the effects of oral clonidine premedication with intraoperative dexmedetomidine infusion on anesthetic requirement and recovery from anesthesia in patients undergoing major spine surgery. J Neurosurg Anesthesiol. 2014;26:192–197.
96. Goettel N, Bharadwaj S, Venkatraghavan L, et al. Dexmedetomidine vs propofol-remifentanil conscious sedation for awake craniotomy: a prospective randomized controlled trial. Br J Anaesth. 2016;116:811–821.
97. Ghazanwy M, Chakrabarti R, Tewari A, et al. Awake craniotomy: a qualitative review and future challenges. Saudi J Anaesth. 2014;8:529–539.
98. Skucas AP, Artru AA. Anesthetic complications of awake craniotomies for epilepsy surgery. Anesth Analg. 2006;102:882–887.
99. Bekker AY, Kaufman B, Samir H, et al. The use of dexmedetomidine infusion for awake craniotomy. Anesth Analg. 2001;92:1251–1253.
100. Chung YH, Park S, Kim WH, et al. Anesthetic management of awake craniotomy with laryngeal mask airway and dexmedetomidine in risky patients. Korean J Anesthesiol. 2012;63:573–575.
101. Garavaglia MM, Das S, Cusimano MD, et al. Anesthetic approach to high-risk patients and prolonged awake craniotomy using dexmedetomidine and scalp block. J Neurosurg Anesthesiol. 2014;26:226–233.
102. Sheshadri V, Chandramouli BA. Pediatric awake craniotomy for seizure focus resection with dexmedetomidine sedation-a case report. J Clin Anesth. 2016;32:199–202.
103. Moore TA II, Markert JM, Knowlton RC. Dexmedetomidine as rescue drug during awake craniotomy for cortical motor mapping and tumor resection. Anesth Analg. 2006;102:1556–1558.
104. Almeida AN, Tavares C, Tibano A, et al. Dexmedetomidine for awake craniotomy without laryngeal mask. Arq Neuropsiquiatr. 2005;63:748–750.
105. Everett LL, van Rooyen IF, Warner MH, et al. Use of dexmedetomidine in awake craniotomy in adolescents: report of two cases. Paediatr Anaesth. 2006;16:338–342.
106. Huncke T, Chan J, Doyle W, et al. The use of continuous positive airway pressure during an awake craniotomy in a patient with obstructive sleep apnea. J Clin Anesth. 2008;20:297–299.
107. Mack PF, Perrine K, Kobylarz E, et al. Dexmedetomidine and neurocognitive testing in awake craniotomy. J Neurosurg Anesthesiol. 2004;16:20–25.
108. Frost EA, Booij LH. Anesthesia in the patient for awake craniotomy. Curr Opin Anaesthesiol. 2007;20:331–335.
109. Sokhal N, Rath GP, Chaturvedi A, et al. Anaesthesia for awake craniotomy: a retrospective study of 54 cases. Indian J Anaesth. 2015;59:300–305.
110. Handlogten KS, Sharpe EE, Brost BC, et al. Dexmedetomidine and mannitol for awake craniotomy in a pregnant patient. Anesth Analg. 2015;120:1099–1103.
111. Phan H, Nahata MC. Clinical uses of dexmedetomidine in pediatric patients. Paediatr Drugs. 2008;10:49–69.
112. Wu J, Mahmoud M, Schmitt M, et al. Comparison of propofol and dexmedetomedine techniques in children undergoing magnetic resonance imaging. Paediatr Anaesth. 2014;24:813–818.
113. Ray T, Tobias JD. Dexmedetomidine for sedation during electroencephalographic analysis in children with autism, pervasive developmental disorders, and seizure disorders. J Clin Anesth. 2008;20:364–368.
114. Konig MW, Mahmoud MA, Fujiwara H, et al. Influence of anesthetic management on quality of magnetoencephalography scan data in pediatric patients: a case series. Paediatr Anaesth. 2009;19:507–512.
115. Shukry M, Ramadhyani U. Dexmedetomidine as the primary sedative agent for brain radiation therapy in a 21-month old child. Paediatr Anaesth. 2005;15:241–242.
116. Shukry M, Clyde MC, Kalarickal PL, et al. Does dexmedetomidine prevent emergence delirium in children after sevoflurane-based general anesthesia? Paediatr Anaesth. 2005;15:1098–1104.
117. Erkonen G, Lamb F, Tobias JD. High-dose dexmedetomidine-induced hypertension in a child with traumatic brain injury. Neurocrit Care. 2008;9:366–369.
118. Tobias JD. Bradycardia during dexmedetomidine and therapeutic hypothermia. J Intensive Care Med. 2008;23:403–408.
119. Sanders RD, Xu J, Shu Y, et al. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology. 2009;110:1077–1085.
120. Sanders RD, Sun P, Patel S, et al. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand. 2010;54:710–716.
121. Perez-Zoghbi JF, Zhu W, Grafe MR, et al. Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. Br J Anaesth. 2017;119:506–516.
122. Li J, Xiong M, Nadavaluru PR, et al. Dexmedetomidine attenuates neurotoxicity induced by prenatal propofol exposure. J Neurosurg Anesthesiol. 2016;28:51–64.
123. Duan X, Li Y, Zhou C, et al. Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain. Acta Anaesthesiol Scand. 2014;58:1121–1126.
124. Pancaro C, Segal BS, Sikes RW, et al. Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain. J Matern Fetal Neonatal Med. 2016;29:3827–3833.
125. Mahmoud M, Mason KP. Dexmedetomidine: review, update, and future considerations of paediatric perioperative and periprocedural applications and limitations. Br J Anaesth. 2015;115:171–182.
126. Funai Y, Pickering AE, Uta D, et al. Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: an in vivo patch-clamp analysis of analgesic mechanisms. Pain. 2014;155:617–628.
127. Hayashida K, Eisenach JC. Spinal alpha 2-adrenoceptor-mediated analgesia in neuropathic pain reflects brain-derived nerve growth factor and changes in spinal cholinergic neuronal function. Anesthesiology. 2010;113:406–412.
128. Peng K, Wu S, Liu H, et al. Dexmedetomidine as an anesthetic adjuvant for intracranial procedures: meta-analysis of randomized controlled trials. J Clin Neurosci. 2014;21:1951–1958.
129. Song J, Ji Q, Sun Q, et al. The opioid-sparing effect of intraoperative dexmedetomidine infusion after craniotomy. J Neurosurg Anesthesiol. 2016;28:14–20.
130. Rajan S, Hutcherson MT, Sessler DI, et al. The effects of dexmedetomidine and remifentanil on hemodynamic stability and analgesic requirement after craniotomy: a randomized controlled trial. J Neurosurg Anesthesiol. 2016;28:282–290.
131. Gandhi KA, Panda NB, Vellaichamy A, et al. Intraoperative and postoperative administration of dexmedetomidine reduces anesthetic and postoperative analgesic requirements in patients undergoing cervical spine surgeries. J Neurosurg Anesthesiol. 2017;29:258–263.
132. Peng K, Jin XH, Liu SL, et al. Effect of intraoperative dexmedetomidine on post-craniotomy pain. Clin Ther. 2015;37:1114–1121.e1.
133. Cortinez LI, Hsu YW, Sum-Ping ST, et al. Dexmedetomidine pharmacodynamics: Part II: crossover comparison of the analgesic effect of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology. 2004;101:1077–1083.
134. Hwang W, Lee J, Park J, et al. Dexmedetomidine versus remifentanil in postoperative pain control after spinal surgery: a randomized controlled study. BMC Anesthesiol. 2015;15:21.
135. Yun Y, Wang J, Tang RR, et al. Effects of an intraoperative dexmedetomidine bolus on the postoperative blood pressure and pain subsequent to craniotomy for supratentorial tumors. J Neurosurg Anesthesiol. 2017;29:211–218.
136. Joo YC, Ok WK, Baik SH, et al. Removal of a vertebral metastatic tumor compressing the spinal nerve roots via a single-port, transforaminal, endoscopic approach under monitored anesthesia care. Pain Physician. 2012;15:297–302.
137. Ibraheim OA, Abdulmonem A, Baaj J, et al. Esmolol versus dexmedetomidine in scoliosis surgery: study on intraoperative blood loss and hemodynamic changes. Middle East J Anaesthesiol. 2013;22:27–33.
138. Peng K, Liu HY, Liu SL, et al. Dexmedetomidine-fentanyl compared with midazolam-fentanyl for conscious sedation in patients undergoing lumbar disc surgery. Clin Ther. 2016;38:192–201.e2.
139. Saravana Babu M, Verma AK, Agarwal A, et al. A comparative study in the post-operative spine surgeries: epidural ropivacaine with dexmedetomidine and ropivacaine with clonidine for post-operative analgesia. Indian J Anaesth. 2013;57:371–376.
140. Flexman AM, Ng JL, Gelb AW. Acute and chronic pain following craniotomy. Curr Opin Anaesthesiol. 2010;23:551–557.
141. Reade MC, Eastwood GM, Bellomo R, et al. Effect of dexmedetomidine added to standard care on ventilator-free time in patients with agitated delirium: a randomized clinical trial. JAMA. 2016;315:1460–1468.
142. Zhao LH, Shi ZH, Chen GQ, et al. Use of dexmedetomidine for prophylactic analgesia and sedation in patients with delayed extubation after craniotomy: a randomized controlled trial. J Neurosurg Anesthesiol. 2017;29:132–139.
143. Srivastava VK, Agrawal S, Kumar S, et al. Comparison of dexmedetomidine, propofol and midazolam for short-term sedation in postoperatively mechanically ventilated neurosurgical patients. J Clin Diagn Res. 2014;8:GC04–GC07.
144. Tsaousi GG, Lamperti M, Bilotta F. Role of dexmedetomidine for sedation in neurocritical care patients: a qualitative systematic review and meta-analysis of current evidence. Clin Neuropharmacol. 2016;39:144–151.
145. Erdman MJ, Doepker BA, Gerlach AT, et al. A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients. Crit Care Med. 2014;42:1696–1702.
146. Grof TM, Bledsoe KA. Evaluating the use of dexmedetomidine in neurocritical care patients. Neurocrit Care. 2010;12:356–361.
147. Mirski MA, Lewin JJ III, Ledroux S, et al. Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST). Intensive Care Med. 2010;36:1505–1513.

dexmedetomidine; neurosurgical anesthesia; neuroanesthesia; perioperative care

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