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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 1  |  Page : 6-11

Postoperative sedation by intranasal dexmedetomidine in patients with hypertensive cerebral hemorrhage: study protocol for a randomized parallel-cohort controlled trial


Department of Anesthesiology, Southern District of Anhui Provincial Hospital, Hefei, Anhui Province, China

Date of Web Publication31-Dec-2015

Correspondence Address:
Chao-liang Tang
Department of Anesthesiology, Southern District of Anhui Provincial Hospital, Hefei, Anhui Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2455-7765.173000

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  Abstract 

Background: Cerebral hemorrhage is often complicated by conscious disturbance and restlessness regardless of the size or location of the hemorrhage, and sedation is often necessary. Dexmedetomidine has dose-dependent sedative, anxiolytic and analgesic effects. It is suited to patients undergoing mechanical ventilation for traumatic brain injury; however, its sedative effects cannot easily be controlled in patients breathing spontaneously. We will investigate the safety and efficacy of postoperative intranasal dexmedetomidine in patients undergoing craniotomy for hypertensive cerebral hemorrhage.
Methods/Design: A randomized parallel-cohort controlled trial will be performed at the South District of Anhui Provincial Hospital, China. Patients with hypertensive cerebral hemorrhage will be randomly divided into groups treated with 0.9% normal saline (placebo), or dexmedetomidine 1 or 1.5 μg/kg. Study drug, either undiluted dexmedetomidine 1 or 1.5 μg/kg (dexmedetomidine group) or equal volume of 0.9% normal saline (placebo group), will be administered immediately to each naris as drops after craniotomy for evacuation of hematoma. Primary outcomes include systolic blood pressure, diastolic blood pressure, heart rate, peripheral oxygen saturation, intracranial pressure, Glasgow Coma Scale score, the level of inflammatory markers in the cerebrospinal fluid, and the levels of malondialdehyde, superoxide dismutase, 4-hydroxynonenal, neurotensin, 8-hydroxy-2'-deoxyguanosine and corticosteroid in serum. Secondary outcomes are volume of hematoma, body weight, duration of surgery, duration of anesthesia, blood loss, urine output and length of hospital stay.
Discussion: The results of this trial will provide evidence for the safe and effective postoperative use of intranasal dexmedetomidine in patients with hypertensive cerebral hemorrhage who are not mechanically ventilated.
Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) identifier: ChiCTR-IPR-15006668; registered on 30 June 2015.
Ethical issues: The trial was approved by Clinical Research Ethics Committee of Anhui Provincial Hospital, China (permission No. 2015 ethics No. 07).

Keywords: clinical trials; dexmedetomidine; intranasal; sedation; hypertension; cerebral hemorrhage; stress state; randomized controlled trial


How to cite this article:
Tang Cl, Li J. Postoperative sedation by intranasal dexmedetomidine in patients with hypertensive cerebral hemorrhage: study protocol for a randomized parallel-cohort controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2016;1:6-11

How to cite this URL:
Tang Cl, Li J. Postoperative sedation by intranasal dexmedetomidine in patients with hypertensive cerebral hemorrhage: study protocol for a randomized parallel-cohort controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2016 [cited 2018 Dec 19];1:6-11. Available from: http://www.actnjournal.com/text.asp?2016/1/1/6/173000


  Background Top


Cerebral hemorrhage may occur as a result of non-traumatic spontaneous bleeding in the brain. Its causes are diverse, but the most common is rupture of cerebral blood vessels due to hypertensive arteriolosclerosis (Zhang and Ying, 2004). Approximately one third of patients with hypertension will have a cerebral hemorrhage, and about 95% of patients with cerebral hemorrhage suffer from hypertension (Billet et al., 1974; Kurata et al., 1993). There is evidence that prompt intervention can improve clinical outcomes for patients with cerebral hemorrhage (Feldstein, 2014). Although early surgical evacuation of cerebral hematoma can reduce compression and destruction of adjacent brain tissue and address secondary brain injury, early postoperative secondary hemorrhage may cause further neuronal injury and substantially impair outcomes (Zhao et al., 2005). Clinicians must be mindful of the factors that increase the risk of adverse patient outcomes in the postoperative management of cerebral hemorrhage. In patients with cerebral hemorrhage, the sympatho-adreno-medullary system and hypothalamo-hypophyseal-adrenal axis are activated, leading to the paracrine or juxtacrine release of excitatory neurotransmitters by the adrenal medulla (Liu et al., 2010; Xu et al., 2012). The actions of excitatory amino acids at their receptors lead to stress-induced injury of hippocampal function and structure (Collingridge et al., 1983; Deng et al., 2013). Postoperative stress can also increase blood glucose concentration in patients with cerebral hemorrhage, resulting in lactic acidemia, further injury to brain cells, and cell membrane ion pump function impairment; ultimately causing cell swelling and even death (Ribo et al., 2007; Huang et al., 2013). If hemodynamic and pulmonary pathophysiologic changes occur simultaneously, pulmonary dysfunction will occur, leading to hypoxemia, metabolic acidosis and disturbance of the microcirculation. This pathophysiologic disturbance contributes to a vicious cycle of further cerebral edema and intracranial hypertension, the final result of which is likely to be a minimally conscious state or death (Robertson et al., 1999). Surgical stress can also impair immunity, leading to infection, sepsis and further complications (Wu and Zheng, 2000).

Cerebral hemorrhage is often accompanied by conscious disturbance and restlessness regardless of the size or location of the hemorrhage, and sedation is frequently necessary (Molina et al., 2004; Evron et al., 2007). Dexmedetomidine (Dex) is a novel, highly-selective α2-adrenergic agonist that exhibits dose-dependent sedative, anxiolytic and analgesic effects (Yuen et al., 2007; Chrysostomou and Schmitt, 2008; Takimoto et al., 2011; Wujtewicz et al., 2013; Nonaka et al., 2015; Tang et al., 2015b). There is evidence that Dex is ideal for sedating patients with traumatic brain injury undergoing mechanical ventilation (Hao et al., 2013). There have been no reports of the sedative effects of Dex in patients who are not mechanically ventilated. Intranasal Dex reportedly provide more stable breathing and circulation, produce fewer adverse events than intravenous administration, and are considered to be a safer and more effective method of providing anesthesia (Iirola et al., 2011; Han et al., 2014). The abundance and permeability of capillaries and lymphatic vessels in the subcutaneous layer of the nasal mucosa means that the bioavailability of drugs administered by the intranasal route is high, and peak blood concentrations are achieved rapidly (Villa et al., 2012; Tang et al., 2015b). We will undertake a study of intranasal Dex administered immediately after craniotomy in patients with hypertensive cerebral hemorrhage. Patients who are anesthetized, sedated or who have been administered neuromuscular blocking drugs are not able to describe the intensity of pain or distress that they are experiencing; however, pain-related behaviors and physiologic indices, including blood pressure, heart rate and respiratory frequency can also reflect pain intensity (Chawla and Kochar, 1999; Tousignant-Laflamme et al., 2005; Saccς et al., 2013). Therefore, we used blood pressure and heart rate as surrogate outcomes of the sedative effects of Dex.


  Methods/Design Top


Study design

A randomized parallel-cohort controlled trial.

Study setting

The trial will be undertaken at the Department of Anesthesiology, Southern District of Anhui Provincial Hospital, China.

Ethics approval and informed consent

Patients' legal representatives will be invited to give informed consent, as patients will have reduced levels of consciousness and will not be able to provide consent for participation. On recovery of consciousness, the benefits and risks of participation will be explained to each patient, and written informed consent will be obtained. The trial has been approved by Clinical Research Ethics Committee of Anhui Provincial Hospital, China (permission No. 2015, ethics No. 07). The trial will be conducted in accordance with the Declaration of Helsinki.

Study participants

Patients with hypertensive cerebral hemorrhage who receive treatment in the Department of Neurosurgery, South Branch of Anhui Provincial Hospital, China will be enrolled according to the following criteria.

Inclusion criteria

  • Patients with hypertensive cerebral hemorrhage confirmed by computed tomography and/or magnetic resonance imaging
  • Patients who have undergone craniotomy for evacuation of intracranial hematoma
  • Age 18-70 years
  • American Society of Anesthesiologists (ASA) physical status I-IV (Fitz-Henry, 2011)
  • Patients with hypertension, defined as a systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥ 90 mmHg


Exclusion criteria

  • Patients with abnormal blood coagulation
  • Patients with known hypersensitivity to the study drug
  • Severe hypertension (defined as systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg with cardiovascular disease)
  • Hepatic and/or renal insufficiency
  • Sedative drug administered within 2 days of surgery
  • Sinus bradycardia
  • Requirement for postoperative mechanical ventilation


Randomization procedure and intervention measures

Patients will be allocated to groups using a computer-based simple randomization method, then randomly coded and provided with a corresponding emergency envelope. Blind codes will be provided to the drug administrator. If any error or disclosure with regard to randomization occurs, a new randomization sequence will be generated starting from the problematic serial number and applied to subsequent patients. Patients, outcome assessors, and statisticians will be blinded to information regarding grouping. Once severe adverse events occur, the researcher in charge will open the group assignment envelope, and the date and reasons for unblinding will be recorded in the medical records.

Patients will be randomly divided into groups administered 0.9% normal saline (inactive placebo), or 1 μg/kg or 1.5 μg/kg Dex, with 40 patients per group. After craniotomy for hematoma removal, all patients will be immediately transferred to the post-anesthesia care unit and monitored by nurse anesthetists. Study drng, either undiluted Dex 1 or 1.5 μg/kg (Dex group) or the equal volume of 0.9% normal saline (placebo group), was administered to each naris as drops. Thirty minutes later, patients will undergo CT imaging of the brain and then be transferred to the neurosurgical intensive care unit.

A trial protocol flow chart is shown in [Figure 1].
Figure 1: Flow chart of the trial protocol.

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Outcome measures

Primary outcomes will be: (1) systolic blood pressure, diastolic blood pressure, heart rate, intracranial pressure and peripheral oxygen saturation; (2) cerebrospinal fluid concentrations of interleukin-1β, -6, -8, -10 and tumor necrosis factor-α; (3) Glasgow Coma Scale score (Teasdale and Jennett, 1974); and (4) serum concentrations of malondialdehyde, superoxide dismutase, 4-hydroxynonenal, neurotensin, 8-hydroxy-2′-deoxyguanosine and corticosteroid. Secondary outcome measures will be: volume of hematoma drained; body weight; duration of surgery; duration of anesthesia; blood loss; urine output and length of hospital stay. All outcome measures will be recorded by the administrators of the neurosurgical intensive care unit who are blinded to the trial protocol and patient grouping.

The timing of outcome assessment is shown in [Table 1].
Table 1: Timing of outcome assessment

Click here to view


Data management and statistical analysis

The researchers will ensure the accuracy of all data entered and recorded in the case-report forms. After confirmation, the correct information will be input into the database and statistical analysis will be undertaken by the researcher in charge. All data will be analyzed using SPSS software version 12.0 (SPSS, Chicago, IL, USA). Measurement data will be expressed as the mean ± standard deviation. The independent samples t-test will be used to compare normally distributed data between groups, and independent samples non-parametric tests will be used for non-normally distributed data. The chi-squared test will be used to compare categorical data between groups. A P value < 0.05 will be considered statistically significant.

Data preservation

Data collected in the trial will be preserved and managed in accordance with the guidance of Good Clinical Practice. All clinical data will be preserved for 5 years after completion of the trial.

Trial quality assurance and control

All researchers will receive uniform training in the trial methodology, and the same group of assessors will record study parameters and outcomes, and assess the therapeutic effects of the study drug to avoid measurement bias. Factors that might influence the therapeutic effect, such as comorbid disease, disease duration and sex, will be analyzed.


  Discussion Top


Adequate sedation provides anxiolysis, reduces the stress response to surgery and critical illness, and reduces cerebral oxygen consumption and intracranial pressure, providing neuroprotection against secondary brain injury, and reducing the risk of further intracranial hemorrhage caused by elevated blood pressure (Villa et al., 2012). Sedatives also reportedly alleviate the stress response by reducing catecholamine and neuropeptide release (Goldstein et al., 1982). Inadequate sedation is likely to result in substantial fluctuations in blood pressure, heart rate and respiratory frequency, increased oxygen consumption, impaired cerebral perfusion and increased risk of secondary intracranial hemorrhage (Lim et al., 2015). Adequate sedation is therefore beneficial and necessary for patients with cerebral hemorrhage. Excessive sedation may make conscious level difficult to evaluate, mask the manifestations of underlying disease, and increase the risk of death. An ideal sedative should have the following features: (1) patients can be roused in response to voice while being sedated; (2) have analgesic and anxiolytic properties; (3) not impair respiratory drive or hemodynamic function; (4) not have cumulative effects; and (5) have few adverse effects such as nausea, vomiting or constipation (Yuen et al., 2007). Dex exhibits sedative and analgesic effects (Yuen et al., 2007; Chrysostomou and Schmitt, 2008; Takimoto et al., 2011; Wujtewicz et al., 2013; Nonaka et al., 2015), has little influence on hemodynamic or respiratory function (Nishida et al., 2002; Guler et al., 2005; Chen et al., 2014), and patients remain easy to rouse (Yuen et al., 2008). Therefore, Dex can be used for sedation when patients are not mechanically ventilated, and also alleviate inflammation and oxidative stress in the acute period and improve recovery of neurological function after surgery (Tang et al., 2015a).

Results from this randomized parallel-cohort controlled trial will provide objective evidence for the safe and effective use of intranasal Dex for sedation in patients with hypertensive cerebral hemorrhage. Design of the trial will ensure patient safety and compliance, and the straightforward protocol will facilitate its completion.

Trial status

Recruitment of participants is ongoing.

Conflicts of interest

None declared.

Author contributions

CLT and JL conceived and designed experimental procedures, contributed to article writing, and approved the final version of this article.

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.[35]

 
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