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Table of Contents    
ORIGINAL ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 1  |  Page : 163-168

Neuroprotective role of dexmedetomidine in epilepsy surgery: A preliminary study


1 Department of Neuroanaesthesiology and Critical Care, All India Institute of Medical Sciences, New Delhi, India
2 Department of Anesthesia, AIIMS, Rishikesh, Uttarakhand, India
3 Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India
4 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Neurobiochemistry, All India Institute of Medical Sciences, New Delhi, India
6 Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India
7 National Institute of Medical Malaria Research, New Delhi, India

Date of Web Publication7-Mar-2019

Correspondence Address:
Dr. Ashish Bindra
Room No 710, CN Centre, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.253616

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 » Abstract 


Purpose: Long standing temporal lobe epilepsy (TLE) causes cerebral insult and results in elevated brain injury biomarkers, S100b and neuron specific enolase (NSE). Surgery for TLE, has the potential to cause additional cerebral insult. Dexmedetomidine is postulated to have neuroprotective effects. The aim of this study was to assess the effect of intraoperative dexmedetomidine on S100b and NSE during TLE surgery.
Materials and Methods: 19 consenting adult patients with TLE undergoing anteromedial temporal lobectomy were enrolled and divided into two groups. Patients in Group D (n = 9) received dexmedetomidine whereas patients in Group C (n = 10) received saline as placebo in addition to the standard anaesthesia technique. Blood samples of these patients were drawn, before induction of anaesthesia, at the end of surgery, as well at 24 hours and 48 hours postoperatively, and analysed for serum S100b and NSE.
Results: The demographic and clinical profile was comparable in both the groups. The baseline S100b in group C and group D was 66.7 ± 26.5 pg/ml and 34.3 ± 21.7 pg/ml (P = 0.013) respectively. After adjustment for the baseline, the overall value of S100b was 71.0 ± 39.8 pg/ml and 40.5 ± 22.5 pg/ml (P = 0.002) in the control and study group, respectively. The values of S100b (79.3 ± 53.6 pg/ml) [P = 0.017] were highest at 24 hours postoperatively. The mean value of NSE in the control and study group was 32.8 ± 43.4 ng/ml (log 3.0 ± 0.1) and 13.51 ± 9.12 ng/ml (log 2.42 ± 0.60), respectively. The value of NSE in both the groups was comparable at different time points.
Conclusions: Lower perioperative values of S100b were observed in patients who received intraoperative dexmedetomidine. Dexmedetomidine may play a role in cerebroprotection during epilepsy surgery.


Keywords: Anaesthesia, dexmedetomidine, epilepsy surgery, neuroprotection, neuron specific enolase, perioperative, S100b
Key Message: Intraoperative dexmedetomidine may have a favourable effect on S100b (a marker of astroglial gliosis and proliferation, and a mediator of central nervous system inflammation). Thus, the intraoperative use of the medication may have a possible role in providing neuroprotection during temporal lobe surgery.


How to cite this article:
Bindra A, Kaushal A, Prabhakar H, Chaturvedi A, Chandra PS, Tripathi M, Subbiah V, Sathianathan S, Banerjee J, Prakash C. Neuroprotective role of dexmedetomidine in epilepsy surgery: A preliminary study. Neurol India 2019;67:163-8

How to cite this URL:
Bindra A, Kaushal A, Prabhakar H, Chaturvedi A, Chandra PS, Tripathi M, Subbiah V, Sathianathan S, Banerjee J, Prakash C. Neuroprotective role of dexmedetomidine in epilepsy surgery: A preliminary study. Neurol India [serial online] 2019 [cited 2019 May 23];67:163-8. Available from: http://www.neurologyindia.com/text.asp?2019/67/1/163/253616




Surgery is one of the vital options for drug resistant epilepsy (DRE). Mesial temporal sclerosis (MTS) is one of the well documented and common causes of DRE.[1] The surgical procedure of choice in these patients is anterior temporal lobectomy combined with amygdalohippocampectomy. The underlying pathology of MTS includes gliosis (characterized by initial signal changes especially noticeable on FLAIR sequences of MRI), followed by loss of volume and atrophy of the hippocampus. Additional secondary changes may also include atrophy of the fornix and ipsilateral mamillary body. S100b is a member of the S100 protein multigenic family and participates in an extracellular and intracellular regulation of cellular calcium metabolism.[2] It is mostly present in glial cells of the central (predominantly astrocytes) and peripheral nervous system, but it is also present in chondrocytes, melanocytes, and adipocytes.[3] S100b is a marker of astroglial gliosis and proliferation, and is hypothesized to mediate nuclear factor-κB activation and the release of proinflammatory cytokines.[4],[5] Disrupted astrocytes have been shown to release massive quantities of S100b following cerebral ischemia, which may further aggravate cerebral injury. Since it is a marker of astroglial gliosis and proliferation, it is a biomarker for temporal lobe epilepsy, but lacks specificity. Neuron specific enolase (NSE) is considered more specific due to its predominant neural origin. NSE is a glycolytic pathway isoenzyme of enolase (2-phospho-D-glycerate hydrolase), which catalyses the transition of 2-phosphoglycerate into phosphoenolpyruvate and is neuroectodermal in origin.[6] Haemolysis may result in a high level of NSE because of its presence in erythrocytes.[7]

Both S100b and NSE are known as “biomarkers of brain damage” and are widely used to quantitate and prognosticate neuronal damage.[8] A number of research papers reported altered concentrations of NSE and S100b protein in long standing epilepsy.[9],[10],[11] These biomarkers are also raised after other forms of neurological insults like traumatic brain injury (TBI), brain ischemia, bleeding, Alzheimer disease, or after a cardiac surgery.[9],[10],[12],[13],[14],[15],[16],[17] Studies also indicate raised S100b and NSE in neurosurgical patients with a glioma and other intracranial space occupying lesions.[18],[19] de Vries J et al., investigated the values of S100b, in the cerebrospinal fluid (CSF) and serum of neurosurgical patients with various intracranial disorders intra-operatively before any surgical manipulation of the brain was carried out in them. Intraoperative values of S100b protein were increased in patients with intracranial haemorrhage, benign intracranial mass lesion, and malignant neoplastic disease.[20] There are no studies regarding the perioperative patterns of these biomarkers during the conduction of neurosurgery.

Surgery is a form of iatrogenic insult and results in an inflammatory response.[21] Levels of S100b and NSE are likely to rise further during surgery in these patients with long standing epilepsy. We hypothesised that greater the acute intraoperative cerebral insult, more is the rise in biomarkers. Dexmedetomidine is a sedative analgesic drug with proposed neuroprotective action, and the use of this drug in addition to standard anaesthetic techniques will help to decrease this insult, as measured by S100b and NSE.[22] The aim of this study was to assess the effect of intraoperative dexmedetomidine in addition to the standard anaesthetic technique on the perioperative serum S100b and NSE levels during TLE surgery in patients with DRE.


 » Materials and methods Top


After obtaining clearance from the institute ethical committee, 19 adult consenting patients with mesial temporal sclerosis undergoing anteromedial temporal lobectomy were enrolled. The baseline values of serum S100b and NSE were obtained in these patients. The study included patients operated by a single neurosurgeon. Patients with heart block, hypotension, pregnancy or renal/hepatic disease were excluded from the study. On the morning of surgery, before induction of anaesthesia, venous blood sample (5 ml) was drawn from the patient and sent for analysis of serum levels of S100b and NSE. Computer generated randomization was used to recruit patients to either Group D (n = 9, received dexmedetomidine) or Group C (n = 10, received normal saline). [Figure 1] displays the consort flow diagram for the study.
Figure 1: Summary of the trial design

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Inside the operation theatre, monitoring with 5-lead electrocardiography (ECG), non-invasive blood pressure (NIBP), and pulse oximetry was started and baseline parameters were recorded. After establishing a peripheral intravenous access, general anaesthesia was induced with fentanyl 2 μg/kg and propofol 3-5 mg/kg. After paralysing with intravenous rocuronium 1 mg/kg, tracheal intubation was performed and all patients were mechanically ventilated to maintain end tidal carbon dioxide level of 35 ± 2 mm Hg. Anaesthesia was maintained with isoflurane in air and oxygen (2:1) mixture with a total flow of 2 L/min. All patients received a bolus dose of fentanyl 1 μg/kg/hr and rocuronium 0.5 mg/kg/hr for maintaining intra-operative analgesia and muscle relaxation, respectively. Normal saline was used as maintenance fluid. Normothermia (nasopharyngeal temperature 36-37°C) was maintained using a forced air warming blanket.

Patients in Group D received dexmedetomidine (infusion at a rate of 0.5 mcg/kg/h), whereas patients in group C received normal saline as a placebo at the same rate in addition to standard anaesthesia technique. A constant depth of anaesthesia was maintained and bispectral index (BIS) was kept in the range of 40-60. According to the protocol, we kept the mean heart rate and the mean blood pressure within 20% of baseline values, and for achieving this, we practiced the following set of rules. Hypertension (mean arterial pressure [MAP] ≥ 20% of the baseline values) was managed with an additional analgesic, and if required, esmolol (0.5-1.5 mg/kg) bolus was administered. Hypotension (MAP ≤20% of baseline values) was managed by intravenous fluids, and if required, 3 mg bolus of mephentermine was administered. Tachycardia (heart rate [HR] ≥ 20% of baseline value) was treated with additional fentanyl bolus, intravenous fluids, and if required, esmolol bolus (0.5-1.0 mg/kg). Bradycardia (HR <40 beats per min or ≤20% of baseline with associated hypotension) was treated with incremental doses of atropine. The value of the mean heart rate and the mean blood pressure was recorded every half hour in each group [Figure 2] and [Figure 3]. The muscle relaxant and the study drug/placebo infusion were stopped at the completion of dural closure. Isoflurane was discontinued at completion of skin closure. The time taken for the procedure and the total duration of anaesthesia were recorded. At the end of surgery, neuromuscular blockade was reversed with neostigmine (50-70 μ/kg) and glycopyrrolate (08-10 μ/kg). The tracheal tube was removed only when the patient started obeying simple commands and his/her vital parameters were satisfactory. Thereafter, all patients were shifted to the neurosurgical intensive care unit for observation and further management. A second venous sample was taken at the end of the surgery followed by two more samples at 24 and 48 hours postoperatively.
Figure 2: Graph showing the values of intraoperative heart rate in both the groups

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Figure 3: Graph showing the values of intraoperative MAP in both the groups

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Blood sampling and biochemical analyses

The baseline (0 h) blood samples were collected before the induction of anaesthesia, the second sample was taken at the end of surgery before extubation, and the third and fourth samples were collected at 24 and 48 hours after the surgery. The serum was separated and stored at −80°C prior to analysis. S100b assays were performed using enzyme linked immunosorbent assay (ELISA). The human S100b ELISA is a sandwich immunoassay for the quantitative measurement of human S100b. A standard curve was constructed by plotting absorbance values against concentration standards and the concentration of unknown samples was determined using this standard curve. Immunoenzymatic colorimetric method was used for quantitative determination of NSE. The colour intensity is proportional to the NSE concentration in the sample. NSE concentration in the sample was calculated based on the calibration curve.

The primary endpoint of this study was to measure the level of S100b and NSE at the defined time period in Group C and Group D, whereas the secondary endpoint was to record vitals (HR and MAP) at the defined time period in Group C and Group D.

Statistical analysis

All data were analyzed using the STATA version 12.0 software and were presented as mean (SD) or median (P25-P75). The categorical data were presented as frequency (percentage). The continuous data were compared using unpaired t-test and categorical data were analysed using Fisher's exact test. Generalised estimating equation (GEE) was used to compare the S100b and NSE values between the two groups over different time points. The multivariate GEE was used to adjust for variability in baseline data. Log transformation was applied to normalize the NSE values. Rank-sum test was used to compare S100b and NSE values between controls and cases. Pearson correlation coefficient was used to assess the relation between age, duration of seizure and biomarkers. A value of P < 0.05 was considered significant.


 » Results Top


It is a prospective, double-blind, randomized placebo-controlled study. 19 patients with TLE posted for temporal lobe surgery were enrolled and divided into two groups (Group C and D) by computer generated randomization and analysed for perioperative serum levels of S100b and NSE. [Figure 1] displays the consort flow diagram of the study. 10 patients were recruited in Group C and 9 patients in group D. The demographic profile, duration of seizures and the total number of antiepileptic drugs used were comparable in both the groups [Table 1]. The mean duration of anaesthesia in Group C and Group D was 5.1 ± 0.47 hours and 5.14 ± 1.77 hours, respectively. The mean duration of surgery in Group C and Group D was 4.14 ± 13.18 hour and 4.12 ± 3.13 hour, respectively. The value of mean heart rate and mean blood pressure was recorded every half hour in each group and depicted in [Figure 2] and [Figure 3]. The hemodymanics (HR, MAP, end tidal CO2 concentration and temperature) were constant and comparable in both the groups. In this study, in particular, not many interventions were required to maintain vitals in the normal range. The measured values of perioperative S100b and NSE in Group C and Group D at different time points are shown in [Table 2]. A total of 34 and 23 values of S100b and NSE were analysed in Group C and group D, respectively. The baseline value of S100b in Group C and Group D was 66.7 ± 26.5 pg/ml and 34.3 ± 21.7 pg/ml (P = 0.013), respectively [Table 2]. The value of S100b in Group D was lower as compared to Group C. Since baseline value of S100b was unequal in the two groups, so a multivariate GEE was used to adjust for variability in data. The change in values of S100b over time between the groups adjusted for baseline value using generalized estimating equation are shown in [Table 3]. After adjustment for the baseline, the mean value of S100b was 71.0 ± 39.8 pg/ml and 40.5 ± 22.5 pg/ml (P = 0.002) in group C and group D, respectively [Table 3]. The overall value of S100b was lower in Group D. The overall value of S100b (79.3 ± 53.6 pg/ml) was highest (P = 0.017) at 24 hours [Table 3]. This was applicable for all the patients in both the groups, indicating a rise in biomarkers after surgery. The baseline value of NSE was 22.5 ± 23.4 ng/ml and 12.4 ± 12.1 ng/ml (P = 0.0164), respectively [Table 1]. After adjustment for the baseline, the mean value of NSE in Group C and Group D was 32.8 ± 43.4 ng/ml (log 3.0 ± 0.1) and 13.51 ± 9.12 ng/ml (log 2.42 ± 0.60), respectively [Table 4]. There was no significant difference in the values of NSE at all time points [Table 4]. [Figure 4] and [Figure 5] show the trend of perioperative value of S100b and NSE in both the groups, respectively, at different time points during the study. {The baseline (0 hour), at the end of surgery before extubation, 24 hours and 48 hours after the surgery}.
Table 1: Baseline demographic and clinical data

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Table 2: Measured values of S100B and NSE in group C and group D at different time points

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Table 3: Change in value of S100B over time between groups adjusted for baseline value using generalized estimating equation

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Table 4: Change in value of NSE over time between groups adjusted for baseline value using generalized estimating equation

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Figure 4: Graph showing the perioperative pattern of value of S100b in both the groups

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Figure 5: Graph showing the perioperative pattern of value of NSE in both the groups

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 » Discussion Top


We studied the effect of intraoperative dexmedetomidine on perioperative serum S100b and NSE levels in patients undergoing TLE surgery and also obtained a perioperative cerebral biomarker (S100b, NSE) pattern. TLE has been shown to increase brain biomarkers due to the occurrence of a long standing insult, resulting in increased S100b and NSE.[9],[10],[11] This might be the reason for the elevated baseline values of S-B100 and NSE in the control group. The elevated S100b concentration has been detected in epilepsy animal models and in post-surgery specimens from patients with epilepsy.[23] The elevated serum NSE has been reported in patients with status epilepticus and complex partial status, in addition to TLE.[9] However, very few studies have examined peripheral blood S100b and NSE levels in living epilepsy patients and there is no consensus on this at present. The levels are more consistently raised after the occurrence of generalised or prolonged seizures as compared to partial seizures. There is no direct relation between the duration of seizures and the degree of rise in the biomarkers. There is no literature on the assessement of perioperative biomarkers in TLE surgery at present.

Dexmedetomidine, an alpha 2 agonist, is increasingly used in the practice of neuroanesthesia for analgesia, sedation, hypnosis and sympatholysis. It is a proposed neuroprotectant in various brain injury models. The alpha 2 agonism leads to inhibition of adenyl cyclase and decreased formation of cAMP. cAMP acts as a second messenger for norepinephrine action, inhibits calcium entry into the cells and also the phospholipase c activity, resulting in reduced activity of protein kinase C, thus protecting against oxidative stress and apoptosis.[24] Other mechanisms include decreased release of excitatory neurotransmitters, upregulation of antiapoptosis protein (bcl-2, mdm-2) and downregulation of proapoptotic proteins (Bcx andp53), a preconditioning effect through increase in focal adhesion kinase phosphorylation.[25],[26],[27] In a rat study, it is postulated to restore the reduced/oxidized glutathione ratio and attenuate the levels of malondialdehyde, a marker of lipid peroxidation, and cause downregulation of interleukin-1 (IL-1) on mRNA and protein level after exposure to high oxygen concentration. However, the dose used in animal studies are far more than doses used in the clinical settings.[28] This may account for inability to replicate results in clinical studies.

Sulemanji et al.,[29] studied the neuroprotective effect of clinical doses of dexmedetomidine in patients undergoing cardiopulmonary bypass and found no benefit of using the drug. The different findings may be attributed to the different population studied. Our findings need to be validated on a large scale. However, in a meta-analysis, the use of dexmedetomidine was associated with neuroprotection by supressing inflammatory and neuroendocrine responses. The study found that dexmedetomidine reduced the secretion of S100b in perioperative patients, when comparing its effects with placebo against ischemic brain injury.[30] In a small study in patients with intracranial tumors, dexmedetomidine attenuated the increase of perioperative S100b protein levels.[31] In a retrospective study, the perioperative use of dexmedetomidine was associated with a decrease in the postoperative mortality up to 1 year, and a decreased incidence of postoperative complications and delirium in patients undergoing cardiac surgery.[32] However, no biomarkers were studied.

Patients with chronic seizure/epilepsy disorders are prone to neurological injury. Extensive glutaminergic activation in epileptics causes neuronal damage. Seizure activities in TLE causes dysregulated inflammation, and damage to blood brain barrier and neurons.[33] Brief recurrent seizures lead to cell loss and sprouting in a kindled model.[34] In TLE, both interictal neural as well as glial temporal lobe dysfunction is present.[23] The mesial temporal structures are prone to causing damage than other areas of the brain. Patients with epilepsy have progressive features like increased seizure frequency and cognitive deterioration.[6] Hence, the need for cerebral protection in patients undergoing TLE surgery. Several MRI studies have shown an association between the severity of hippocampal damage and the estimated total seizure number, seizure frequency, and duration of epilepsy.[35] In one study serum S100b and serum NSE levels over 0.2 μg/L and 10 μg/L respectively, were considered pathologic.[36] But this is the value seen in traumatic brain injury and cannot be generalized. DRE may be associated with higher levels of S100b and NSE. Long standing temporal lobe epilepsy causes cerebral insult and results in elevated brain injury biomarkers, S100b and NSE.[9],[10],[11] In addition, surgery on the brain, results in an inflammatory response.[21] The magnitude of clinically significant increase in NSE or S100b levels in terms of brain damage is not well established. As such, there is no cut off value. Changes relative to the baseline levels are noted. Our study showed a favourable effect of the intraoperative use of dexmedetomidine infusion on serum S100b. The overall increase in serum S100b was significantly less in patients who received the drug.

Limitations

This study was a pilot study with a small sample size. The information has a reflection on the anaesthetic technique to be chosen during epilepsy surgery. However, no favourable change in NSE values was seen though NSE is more specific for brain injury. Larger study enrolling more patients may provide a better answer. The effect of the drug on postoperative cognition and seizure control was not assessed in this study. Larger studies are required to confirm the association between intraoperative dexmedetomidine and perioperative biomarkers. The findings of this study call for exploration of the role of this drug in intraoperative and perioperative practice.


 » Conclusion Top


We conclude that the use of intraoperative dexmedetomidine may have a favourable effect on S100b values, suggesting its possible neuroprotective role during TLE surgery. Future studies with larger number of patients and different aetiologies are required to replicate the results and correlate the effects of the medication with clinical outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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