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STUDY PROTOCOL
Asia Pac J Clin Trials Nerv Syst Dis 2017,  2:1

Effects of dexmedetomidine combined with sodium creatine phosphate on inflammation, oxidative stress, and neurological function recovery in patients undergoing intracranial hematoma evacuation: study protocol for a multi-center, prospective randomized parallel-cohort controlled trial


1 Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province; Department of Anesthesiology, Anhui Provincial Hospital, Hefei, Anhui Province, China
2 Department of Anesthesiology, Anhui Provincial Hospital, Hefei, Anhui Province, China
3 Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China

Date of Web Publication30-Jan-2017

Correspondence Address:
Zhong-yuan Xia
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.198958

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  Abstract 

Background: In treating intracranial hematoma, dexmedetomidine (Dex) exhibits neuroprotective effects by preventing cognitive decline, and sodium creatine phosphate (SCP) exhibits neuroprotective effects by reducing cell death, maintaining the blood-brain barrier and improving interstitial cerebral edema. Few studies have examined the effects of Dex combined with SCP on perioperative inflammation and oxidative stress response, or recovery of neurological function.
Methods/Design: Here we propose a multi-center, prospective randomized parallel-cohort controlled trial, to be performed at Anhui Provincial Hospital and Renmin Hospital of Wuhan University, China. After screening against inclusion and exclusion criteria, 80 patients scheduled to receive intracranial hematoma evacuation will be randomly divided into control, Dex, SCP, and Dex + SCP groups, with 20 patients per group. Under general anesthesia, all patients will undergo craniotomy for hematoma removal. In the Dex and Dex + SCP groups, an intravenous bolus of Dex (0.6 μg/kg) will be administered 10 minutes before anesthesia induction and thereafter intravenous administration of Dex (0.4 μg/kg/h) will be given. In the SCP, and Dex + SCP groups, 1.0 g SCP will be administered 10 minutes before anesthesia induction. The primary outcome measure is the difference in postoperative 72-hour Glasgow Coma Scale (GCS) score and postoperative 12-hour GCS score. The secondary outcome measures include differences in postoperative 48-hour and 24-hour GCS scores and postoperative 12-hour GCS score; plasma levels of inflammatory and oxidative stress markers, and pathological changes in brain tissue before anesthesia induction and at the end of surgery; and physiological indices during surgery.
Discussion: We evaluate whether results from the proposed study protocol will provide evidence that the use of Dex combined with SCP in patients undergoing intracranial hematoma evacuation is feasible.
Trial registration: The study protocol was registered at Chinese Clinical Trial Registry (http://www.chictr.org.cn/) on 11 December 2014 (registration number: ChiCTR-IPR-14005656).
Ethics: The study protocol was approved by Ethics Committee, Anhui Provincial Hospital, China on 25 November 2014 (approval No. 2014-ethics-39) and will be performed in accordance with the Declaration of Helsinki formulated by the World Medical Association.
Informed consent: Written informed consent will be obtained from patient's guardians or clients prior to enrollment in the clinical trial.

Keywords: clinical trial; intracranial hemorrhage; dexmedetomidine; sodium creatine phosphate; intracranial hematoma; inflammation response; oxidative stress; neurologic function; multi-center, prospective randomized parallel-cohort controlled trial


How to cite this article:
Tang Cl, Li J, Zhao B, Shi S, Shen H, Xia Zy. Effects of dexmedetomidine combined with sodium creatine phosphate on inflammation, oxidative stress, and neurological function recovery in patients undergoing intracranial hematoma evacuation: study protocol for a multi-center, prospective randomized parallel-cohort controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:1-8

How to cite this URL:
Tang Cl, Li J, Zhao B, Shi S, Shen H, Xia Zy. Effects of dexmedetomidine combined with sodium creatine phosphate on inflammation, oxidative stress, and neurological function recovery in patients undergoing intracranial hematoma evacuation: study protocol for a multi-center, prospective randomized parallel-cohort controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2018 Dec 16];2:1-8. Available from: http://www.actnjournal.com/text.asp?2017/2/1/1/198958


  Introduction Top


History and current related studies

Cerebral hemorrhage is a common and severe type of stroke, with high prevalence, morbidity and mortality. However, with the exception of surgical removal of hematoma and lowering of intracranial pressure by dehydration, there are no effective methods for improving neurological impairment caused by cerebral hemorrhage. During the perioperative period, patients with cerebral hemorrhage often experience acute agitation due to pain (Rajan et al., 2014; Sriganesh et al., 2015). Pain caused by cerebral hemorrhage increases sympathetic activity and causes stress responses, leading to increased blood pressure, intracranial pressure and cerebral oxygen consumption. This can cause excessive release of a range of hormones and inflammatory factors, leading to secondary brain injury, and eventually resulting in severe postoperative complications, such as intracranial hemorrhage (Chi et al., 2011, 2014; Hancı et al., 2012). Dexmedetomidine (Dex) is a highly selective new α2-adrenoceptor agonist that regulates the release of catecholamines to control blood pressure via a sympathetic negative feedback mechanism. It also acts on postsynaptic membrane α2 receptors, hyperpolarizing postsynaptic cells and inhibiting the conduction of pain signals to the brain, exhibiting analgesic, sedative, anti-anxiety and anti-sympathetic effects. Dex, as an anesthetic adjuvant, can motorize the adrenergic receptors in the central and peripheral nervous systems, effectively decrease sympathetic activity, lower abnormally elevated blood pressure and heart rate under stress, maintain hemodynamic stability, and simultaneously reduce the necessary dosages of sedatives and analgesics (Yi et al., 2011). Similar to other α2-adrenoceptor agonists, Dex does not produce respiratory depression; it can greatly alleviate brain edema caused by acute craniocerebral injury (Benggon et al., 2012), exhibit neuroprotective effects and prevent cognitive impairment (Zhu et al., 2013). After cerebral hemorrhage, a strong stress response of the body is triggered, stimulating the excessive release of proinflammatory factors via inflammatory cells at the bleeding site, causing metabolic disorders in the brain tissue. In addition, compression of the hematoma to the adjacent brain tissue can aggravate ischemia/hypoxic brain injury in normal brain tissue. All of these processes can strongly influence the recovery of neurological function after surgery (Zhang et al., 2006). After cerebral hemorrhage, cerebral blood flow in the corresponding brain regions decreases, and the brain tissue rapidly enters the ischemic/hypoxic state, disrupting the energy metabolism of brain cells and leading to brain edema and necrosis of brain tissue (Fallon, 2008; Vallböhmer et al., 2008). Use of anesthetics and surgery can also cause hypotension and low perfusion, leading to ischemia/hypoxia of the brain cells and causing abnormal energy metabolism of brain cells (D'Angelo et al., 2008).

Creatine phosphate is an important component of the tissue antioxidant system and an important substance for cell energy metabolism. There is strong evidence that exogenous creatine phosphate can react with adenosine di-phosphate to generate creatine and adenosine tri-phosphate in the cytoplasmic membrane, cytoplasmic reticulum, mitochondrial membrane space and myofibrils under the catalysis of phosphocreatine creatine kinase (Green et al., 2007; Hazra and Dubinett, 2007; Pan and Takahashi, 2007). This can supplement for adenosine tri-phosphate deficiency caused by cerebral ischemia/hypoxia or glucose deprivation, greatly decreasing cell death. In addition, supplementation of creatine phosphate can increase the anti-hypoxic ability of nerve cells, accelerate the recovery of brain cell membranes, maintain the integrity of brain cells, and progressively maintain the integrity of functionalized vascular walls while strengthening the regulation of anterior sphincter of capillaries to local blood pressure. These processes are conducive to maintaining the blood-brain barrier, improving interstitial brain edema (Al-Joudi et al., 2007; Lu et al., 2008), and exhibiting neuroprotective effects (Samaka et al., 2006; Ducray et al., 2007; Pankova et al., 2007).

Objective

Based on previous research, the proposed study is designed to investigate the effects of Dex combined with sodium creatine phosphate (SCP) on perioperative inflammation, oxidative stress, and neurological function recovery in patients undergoing intracranial hematoma evacuation, which will provide clinical evidence for anesthetic use and neuroprotection during removal of intracranial hematoma.

Novelty of this study

Previously reported studies have mainly focused on the neuroprotective effects of Dex or SCP on intracranial hematoma ([Table 1]). Few studies have examined the effects of Dex combined with SCP on perioperative inflammation and oxidative stress as well as recovery of neurological function in patients with intracranial hematoma.
Table 1: Previous studies on the neuroprotective effects of dexmedetomidine (Dex) or sodium creatine phosphate (SCP) in patients with intracranial hematoma


Click here to view



  Methods/Design Top


Study design

This is a multi-center, prospective randomized parallel-cohort controlled trial, which will be performed at Anhui Provincial Hospital and Renmin Hospital of Wuhan University, China. Eighty patients scheduled to receive intracranial hematoma evacuation will be randomly divided into control, Dex, SCP, and Dex + SCP groups.

In the Dex and Dex + SCP groups, an intravenous bolus of Dex (0.6 μg/kg) will be administered 10 minutes before anesthesia induction, followed by intravenous Dex (0.4 μg/kg/h) administration. In the SCP and Dex + SCP groups, 1.0 g SCP will be administered 10 minutes before anesthesia induction. Under general anesthesia, all patients will undergo craniotomy for hematoma removal. The primary outcome measure is the difference of postoperative 72-hour Glasgow Coma Scale (GCS) score and postoperative 12-hour GCS score. The secondary outcome measures include the differences in postoperative 48-hour and 24-hour GCS scores and postoperative 12-hour GCS score; plasma levels of inflammatory and oxidative stress markers, and pathological changes in brain tissue before anesthesia induction and at the end of surgery; and measurements of physiological indices during surgery. Other outcome measures include dosages of propofol and remifentanil, amount of drainage, operation time, and anesthesia time.

The flowchart of study protocol is shown in [Figure 1].
Figure 1: The flowchart of study protocol.
Note: Dex: Dexmedetomidine; SCP: sodium creatine phosphate; GCS: Glasgow Coma Scale


Click here to view


Study participants

Patients with intracranial hemorrhage scheduled for craniotomy for hematoma removal in the Anhui Provincial Hospital and Renmin Hospital of Wuhan University, China will be considered for admission to this study after screening against the inclusion and exclusion criteria described below.

Inclusion criteria

Patients meeting all of the following criteria will be considered for admission to this study:

  • Patients with intracranial hemorrhage confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) findings who need surgery: (1) Hypertensive cerebral hemorrhage: a) lobar hemorrhage ≥ 30 mL; b) basal ganglia hemorrhage ≥ 30 mL; c) thalamic hemorrhage ≥ 10 mL; d) cerebellar hemorrhage ≥ 10 mL; e) intraventricular hemorrhage, causing obstructive hydrocephalus or molded intraventricular hemorrhage; f) intracranial hemorrhage volumes do not meet the indications for surgery, but patients have severe neurological disorders; (2) traumatic intracranial hemorrhage: a) acute epidural, subdural hematoma, amount of supratentorial hematoma ≥ 30 mL, amount of subtentorial hematoma ≥ 10 mL, unstable disease condition; b) subacute chronic subdural hematoma; c) intracranial hematoma referencing to hypertension indications; d) brain injury complicated by intraventricular hemorrhage and obstructive hydrocephalus (Rao and Wang, 2014)
  • Mode of surgery: craniotomy for hematoma removal
  • Age 18-70 years of age
  • American Society of Anesthesiologists (ASA) grade I-IV


Exclusion criteria

Patients presenting with one or more of the following conditions will be excluded from this study:

  • Coagulation disorder
  • Identified aneurysm or arterial malformation caused by hematoma
  • Previous drug allergy
  • Drug (alcohol, opioids or tranquilizers) addiction
  • Complication with other severe diseases, such as severe hypertension, cardiovascular disease, malignant tumor, autoimmune diseases, mental disorders and patients with diabetes who have poor blood glucose control
  • Liver and kidney dysfunction
  • Long-term use of opioids
  • Advanced brain herniation or brain death
  • Evidence of infection before suffering from cerebral hemorrhage
  • Currently lactating


Sample size

In accord with previous studies (Xu et al., 2011; Yu et al., 2012; Bishnoi et al., 2016; Wang et al., 2016), there will be 20 patients per group. Thus, 80 patients will be included in this study. Data analysis will follow the intention-to-treat principle.

Baseline evaluation

The baseline information is shown in [Table 2].
Table 2: Patient's general information


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Randomization and blinding

Eighty patients will be randomly divided into four groups, with 20 patients per group according to a random digital table, carried out by a statistician blinded to the study protocol. Patients and results evaluators will be blinded to grouping.

Intervention

Venous access will be established for monitoring the patients' vital signs. Under local anesthesia with 0.5 mL 2% lidocaine, radial artery puncture will be performed for direct arterial pressure monitoring. During the surgery, Lactated Ringer's Injection will be administered into the patients according to a 4-2-1 principle (i.e., 4 mL/kg for < body mass < 10 kg, 2 mL/kg for the second 10 kg and 1 mL/kg for the next).

In the Dex and Dex + SCP groups, an intravenous bolus of Dex (0.6 μg/kg; China National Medicines Guorui Pharmaceutical Co., Ltd., China) will be administered 10 minutes before anesthesia induction, followed by intravenous Dex (0.4 μg/kg/h) administration. In the SCP and Dex + SCP groups, 1.0 g SCP (dissolved in 100 mL normal saline; Haikou Kellett Pharmaceutical Co., Ltd., China) will be administered, starting from 10 minutes before anesthesia induction for 30 minutes.

Anesthesia induction: Three minutes after intravenous administration of sufentanil (0.5 μg/kg), atracurium (0.2 mg/kg) and propofol (2 mg/kg), tracheal intubation will be terminated. Anesthesia will be maintained by target-controlled infusion with remifentanil (predicted concentration (Cp) 3.0-4.0 ng/mL) and propofol (Cp 3.0-4.0 μg/mL). Dosages of remifentanil and propofol will be adjusted in accord with changes in the bispectral index. The bispectral index value will be maintained between 45-55. Dex administration will not be terminated until 10 minutes prior to the completion of the surgery. Remifentanil and propofol a dministration will not be terminated until completion of the surgery.

Outcome measures

Primary outcome measure


  • Difference of postoperative 72-hour GCS (Teasdale and Jennett, 1974) score and postoperative 12-hour GCS score.
  • GCS is composed of three tests: eye, verbal and motor responses with scores ranging from 3-15. The GCS is the most widely used assessment of disturbance of consciousness. It is used for evaluation of coma after traumatic brain injury causing various types of impairment in a range of types of consciousness (details of the GCS are shown in Additional file 1 [Additional file 1]).


Secondary outcome measures

  • Differences in postoperative 48-hour and 24-hour GCS scores and postoperative 12-hour GCS score.
  • Plasma levels of inflammatory markers: Prior to anesthesia induction and at the end of the surgery, 3 mL of peripheral venous blood will be collected then preserved at −80°C. Plasma levels of interleukin-6, -8 and -10 and tumor necrosis factor-α will be measured using the enzyme-linked immunosorbent assay (ELISA) method (Welch et al., 2016).
  • Plasma levels of oxidative stress markers: Prior to anesthesia induction and at the end of the surgery, 3 mL of peripheral venous blood will be collected for measurement of plasma levels of malondialdehyde, superoxide dismutase, 4-hydroxynonenal, neurotensin and 8-hydroxydeoxyguanosine. Malondialdehyde is a commonly used peroxidation index for membrane lipids (Gerritsen et al., 2006) and it is determined using the thiobarbituric acid method. Superoxide dismutase is the major antioxidant enzyme produced by the mitochondria (Washio et al., 2008) and is determined with the xanthine oxidase method. 4-Hydroxynonenal is a highly active, diffusible lipid peroxide (Chen and Ran, 2006) determined with the ELISA method. Neurotensin is a biomarker of nitrated protein (Ceriello et al., 2001). 8-Hydroxydeoxyguanosine is a specific product of DNA oxidative damage (Gao et al., 2012) and is a recognized biomarker of oxidative damage to DNA by both endogenous and exogenous factors. Both nitrotyrosine and 8-hydroxydeoxyguanosine are tested with the ELISA method (Welch et al., 2016).
  • Pathological changes of brain tissue: Neuronal specific enolase and CD31 expression will be detected with immunohistochemical staining in the brain tissue surrounding the hematoma of patients to investigate neuronal damage and angiogenesis.
  • Physiological indices: Patient's systolic blood pressure, diastolic blood pressure, and heart rate will be measured at the time of patients entering the operating room, prior to anesthesia induction, 1 minute after tracheal intubation, at the beginning of operation, after removal of the bone flap, after dura mater opening, at the end of surgery and after extubation.


Other outcome measures

The dosages of propofol and remifentanil, amount of drainage, operation time, and anesthesia time will also be recorded.

The schedule of primary and secondary outcome measures is shown in [Table 3].
Table 3: The timing of outcome measures


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Data management

The case report forms will be filled out by the investigators accurately, completely and in time. The written records will be transferred to an electronic format by professional staff using a double-data entry strategy.

All observations and findings in clinical trials will be verified to ensure data reliability, to ensure that the conclusions from clinical trials are derived from the original data, and to ensure that the database is locked by the primary investigator. All relevant data will be stored by Anhui Provincial Hospital and Renmin Hospital of Wuhan University of China.

All data will be statistically analyzed by professional statisticians and anonymized trial data will be published at www.figshare.com.

Statistical analysis

All data will be statistically analyzed using SPSS 23.0 software (IBM, Armonk, NY, USA). Data analysis will follow the intention-to-treat principle. All data will be expressed as the mean ± SD. Independent-sample t-tests will be used for comparison of normally distributed data. Nonparametric two-sample tests (Wilcoxon signed-rank tests) will be used for comparison of non-normally distributed data. A level of P < 0.05 will be considered statistically significant.

Bias control

Possible sources of bias include: (1) diagnosis bias (the choice of criteria for inclusion); (2) admission bias (the tendency to choose hospitalized patients to reduce the lost to follow-up rate and increase compliance); (3) no-response bias (patients failing to respond to the survey, or providing false responses); (4) measurement bias (possible errors because of poor staff performance); (5) confounding bias (sex, age).

Measures that will be taken to control bias include: (1) unified training of investigators; (2) strict inclusion and exclusion criteria; (3) ensuring sample independence; (4) avoiding additional harm to patients in the trial process, increasing the likelihood of compliance; (5) reducing the number of withdrawn cases, and follow-up with withdrawn patients; (6) curative effect evaluation will be performed by designated persons before and after treatment to avoid measurement bias; (7) confounding factors (such as etiology, course of disease and sex) likely to influence the curative effects will be treated as independent variables in a multivariate analysis; (8) to reduce the loss of data, data from withdrawn patients will also be included in an intention-to-treat analysis.

Confidentiality

The results and relevant data from this study will be owned and used without charge by Renmin Hospital of Wuhan University and Anhui Provincial Hospital, China. Patient's baseline information will be password-protected by the Anhui Provincial Hospital, China. Patient identity will not be divulged unless required by law. The findings from this study will be published for scientific purposes without disclosing the patient's identity.


  Trial Status Top


Patient recruitment is currently underway.


  Discussion Top


Significance of this study

Dex, as a promising neurosurgical anesthetic, has unique sedative and analgesic effects, does not produce respiratory depression, has stable hemodynamics, exhibits neuroprotective effects on postoperative re-hemorrhage and promotes the recovery of neurological function. Dex in combination with systemic anesthetics for craniotomy for removal of intracranial hematoma has been found to maintain hemodynamic stability during surgery (Benggon et al., 2012). SCP is an important substance for cell energy metabolism. It can provide energy under conditions of insufficient energy, and protects important organs. Dex in combination with SCP may exhibit stronger neuroprotective effects during the removal of intracranial hematoma in patients with cerebral hemorrhage than monotherapy.

Strengths and limitations of this study

In this study, the addition of Dex and SCP, which are commonly used in the clinic, to conventional systemic anesthetics for craniotomy for removal of intracranial hematoma is a simple and feasible method. In addition, the hospitals at which surgery will be performed are equipped with the relevant capability and equipment. Moreover, the experimental processes will not cause additional harm to patients, increasing the likelihood of compliance. All of these characteristics are likely to facilitate success in surgery. Nevertheless, differences in etiology, disease course and sex exist between the patients with cerebral hemorrhage that will be included in this study. In addition, the included patients are likely to have a history of hypertension. Thus, discrepancies regarding category, usage and dosage of blood pressure-lowering drugs may exist between patients. These limitations should be taken into consideration in future studies.

Evidence for contribution to future studies

The proposed study is designed to provide clinical evidence for the use of Dex in combination with SCP in craniotomy for the removal of intracranial hematoma, enabling new treatment options for improving inflammation, oxidative stress and neurological function recovery in patients with cerebral hemorrhage.

Additional file

Additional file 1: Glasgow Coma Scale.[35]

 
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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
Conception and design of study protocol: CLT and ZYX; trial conduction: CLT, JL, BZ, SS and HS; data management and manuscript writing: CLT; manuscript authorization: ZYX. All authors approved the final version of this paper.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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