Co-administration of Dexmedetomidine in Carotid Endarterectomy (CEA) With Intraoperative SSEP and MEP Monitoring: A Single-centre Prospective Randomized Controlled Trial
Phase: PHASE4
Conditions: Carotid Stenosis
Sponsor: Insel Gruppe AG, University Hospital Bern

 
 
 
 
Study ID: Vetter2017, Version 4.20 of 9.08.2018 
 
Page 1 of 34 
Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
 
 
 
 
 
 
Co-administration of dexmedetomidine in carotid 
endarterectomy (CEA) with intraoperative SSEP and MEP 
monitoring: A single-centre prospective randomised 
controlled trial 
 
 
 
 
  
 
Clinical Study Protocol 
 
 
SHORT TITLE: Dexdor Study, 2018-00220 
 
 
 
Study Type: 
Clinical trial with drugs 
Study Categorisation: 
Risk category A 
Study Registration: 
Clinical trials.org 
Study Identifier: 
Vetter2017 
Sponsor-Investigator:              
Principal Investigator: 
Christian Vetter 
Christian Vetter 
christian.vetter@insel.ch 
Investigational Product: 
Dexmedetomidine 
Protocol Version and Date: 
V4.20, 9.08.2018 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of Christian Vetter. 
The information may not – in full or in part – be transmitted, reproduced, published, or disclosed 
to others than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) 
without prior written authorisation from the sponsor, except to the extent necessary to obtain 
informed consent from those who will participate in the study. 

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
Signature Page(s)  
 
Study 
number 
Study registry and registration number (at clinicaltrials.gov)   
Study Title 
Co-administration of dexmedetomidine in carotid 
endarterectomy (CEA) with intraoperative SSEP and MEP 
monitoring. A single-centre prospective randomized 
controlled trial. 
 
 
The Sponsor-Investigator and trial statistician have approved protocol version 4.20, 09.08.2018, 
and confirm hereby to conduct the study according to the protocol, current version of the World 
Medical Association Declaration of Helsinki, ICH-GCP guidelines or ISO 14155 norm if applicable 
and the local legally applicable requirements. 
 
 
Sponsor: Dr. med. Christian Vetter 
 
Bern, 09th August 2018 
Place/Date 
Signature 
 
 
Principal Investigator  
I have read and understood this trial protocol and agree to conduct the trial as set out in this study 
protocol, the current version of the World Medical Association Declaration of Helsinki, ICH-GCP 
guidelines or ISO 14155 norm and the local legally applicable requirements. 
 
 
Principal investigator:  Dr. med. Christian Vetter 
 
Bern, 09th August 2018 
Place/Date 
Signature 
 
 
 
Study Investigator: PD Dr. med. Vladimir Krejci  
 
Bern, 15th January 2018 
Place/Date 
Signature 
 
 
 
 

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
Table of Contents 
STUDY SYNOPSIS .............................................................................................. 6 
STUDY SUMMARY IN LOCAL LANGUAGE .................................................... 14 
1. 
STUDY ADMINISTRATIVE STRUCTURE ................................................ 18 
1.1 
Sponsor, Sponsor-Investigator ................................................................... 18 
1.2 
Principal Investigator(s) .............................................................................. 18 
1.3 
Statistician ("Biostatistician")....................................................................... 18 
1.4 
Monitoring Institution ................................................................................... 18 
2. 
ETHICAL AND REGULATORY ASPECTS .............................................. 18 
2.1 
Study registration ........................................................................................ 20 
2.2 
Categorisation of study ............................................................................... 20 
2.3 
Competent Ethics Committee (CEC)  ......................................................... 20 
2.4 
Ethical conduct of the study ........................................................................ 20 
2.5 
Declaration of conflicts of interest ............................................................... 20 
2.6 
Patient information and informed consent .................................................. 20 
2.7 
Participant privacy and confidentiality ......................................................... 21 
2.8 
Early termination of the study ..................................................................... 21 
2.9 
Protocol amendments ................................................................................. 21 
3. 
BACKGROUND AND RATIONALE .......................................................... 22 
3.1 
Background and rationale ........................................................................... 22 
3.2 
Investigational product (treatment, device) and indication .......................... 24 
3.3 
Clinical evidence to date ............................................................................. 24 
3.4 
Dose rationale: rationale for the intended purpose in study ........................ 24 
3.5 
Explanation of choice of comparator (or placebo)....................................... 24 
3.6 
Risks/benefits ............................................................................................. 24 
3.7 
Justification of choice of study population ................................................... 25 
4. 
STUDY OBJECTIVES ............................................................................... 26 
4.1 
Overall objective ......................................................................................... 26 
4.2 
Primary objective ........................................................................................ 26 
4.3 
Secondary objectives .................................................................................. 26 
4.4 
Safety objectives......................................................................................... 26 
5. 
STUDY OUTCOMES ................................................................................. 27 
5.1 
Primary outcome......................................................................................... 27 
 Secondary ......................................................................................................... 27 
5.2 
outcomes .................................................................................................... 27 
5.3 
Safety outcomes ......................................................................................... 27 
6. 
STUDY DESIGN ........................................................................................ 27 
6.1 
General study design and justification of design ......................................... 27 
6.2 
Methods of minimising bias ........................................................................ 27 
6.2.1 Randomisation ........................................................................................... 27 
6.2.2 Blinding procedures .................................................................................... 28 
6.3 
Unblinding procedures (code break) ........................................................... 28 

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
7. 
STUDY POPULATION .............................................................................. 28 
7.1 
Eligibility criteria .......................................................................................... 28 
7.2 
Assignment to study groups ....................................................................... 28 
7.3 
Criteria for withdrawal/discontinuation of participants ................................. 28 
8. 
STUDY INTERVENTION ........................................................................... 28 
8.1 
Investigational treatment ............................................................................. 28 
8.1.1 Experimental intervention ........................................................................... 28 
8.1.2 Control intervention (routine treatment) ...................................................... 29 
8.2 
Administration of experimental and control interventions ............................ 29 
8.2.1 Experimental intervention ........................................................................... 29 
8.2.2 Control intervention .................................................................................... 29 
8.3 
Data collection and follow-up for withdrawn participants ............................ 29 
Study flow chart(s) / table of study procedures and assessments: The graphic 
shows the course of the study. The orange fields relate to the study-related 
measures. The light blue fields contain all study-independent procedures. ........ 29 
8.4 
Assessments of outcomes .......................................................................... 29 
8.4.1 Assessment of primary outcome ................................................................ 29 
8.5 
Secondary outcomes .................................................................................. 30 
8.5.1 Assessment of secondary outcomes .......................................................... 30 
8.5.2 Assessment of safety outcomes ................................................................. 30 
8.6 
Procedures at each visit ............................................................................. 30 
9. 
SAFETY .................................................................................................... 31 
10. 
STATISTICAL METHODS ........................................................................ 31 
10.1 
Hypothesis ............................................................................................... 31 
10.2 
Determination of sample size................................................................... 32 
10.3 
Planned analyses .................................................................................... 32 
10.3.1 
Datasets to be analysed, analysis populations ..................................... 32 
10.3.2 
Safety analysis ...................................................................................... 32 
10.3.3 
Deviation(s) from the original statistical plan ........................................ 32 
10.4 
Handling of missing data and drop-outs .................................................. 32 
11. 
QUALITY ASSURANCE AND CONTROL ................................................ 32 
11.1 
Data handling and record keeping/archiving ............................................ 32 
11.1.1 
Case report forms ................................................................................. 32 
11.1.2 
Recordkeeping/archiving ...................................................................... 32 
11.2 
Data management ................................................................................... 33 
11.2.1 
Data management system .................................................................... 33 
11.2.2 
Data security, access and back-up ....................................................... 33 
11.2.3 
Analysis and archiving .......................................................................... 33 
11.2.4 
Electronic and central data validation ................................................... 33 
11.3 
Monitoring: ............................................................................................... 33 

 
 
 
 
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Universitätsklinik für 
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Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
12. 
PUBLICATION AND DISSEMINATION POLICY ...................................... 33 
13. 
FUNDING .................................................................................................. 33 
13.1 
Funding .................................................................................................... 33 
14. 
INSURANCE ............................................................................................. 34 
15. 
REFERENCES  ......................................................................................... 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
STUDY SYNOPSIS  
Sponsor-
Investigator 
Dr. med. Christian Vetter, Dept. of Anaesthesia and Pain Medicine, 
Inselspital Bern University Hospital, University of Bern, Bern, Switzerland 
Study Title: 
Co-administration of dexmedetomidine in carotid endarterectomy (CEA) with 
intraoperative SSEP and MEP monitoring. A single-centre prospective 
randomised controlled trial. 
Short Title / 
Study ID: 
Dexdor 
Protocol 
Version and 
Date: 
Version 4.20 of 09.08.2018  
Trial 
registration: 
Anticipated registry: www.clinicaltrials.gov 
Study 
category and 
Rationale 
Clinical trial with drugs. Risk category A.  
Interventional RCT comparing the effective concentration (Cet) of propofol 
required for EEG burst suppression and maintenance thereof by the co-
administration of dexmedetomidine 
Clinical 
Phase: 
4 
Background 
and Rationale: 
In our institution, as a neuroprotective measure, all neurosurgical patients 
undergoing operation for carotid endarterectomy (CEA) are routinely 
operated on under deep anaesthesia with suppression of the electrical 
activity of the electroencephalogram (EEG). The rationale for BS is to 
decrease oxygen consumption. To achieve this suppression of the EEG 
activity (burst suppression, BS), high effector concentrations (Cet) of 
propofol doses are needed. However, a protracted infusion of large amounts 
of propofol to reach a BS during the operation can lead to accumulation and 
a protracted wake-up phase with poorer neurological assessability.  
 
Somatosensitive evoked potentials (SSEPs) are used to test the functional 
integrity of the nervous system. Standardised surgical and 
anaesthesiological measures at the CEA, with defined EEG endpoints and 
depending on the anaesthetic effect, can – in normal EEG and SSEPs – 
effectively exclude severe global ischaemia. The effects of burst suppression 
and the volatile anaesthetics on SSEPs have also been investigated and 
showed no significant difference. Since 2016, motor-induced evoked 
potentials (MEPs) have also been used, but they may be suppressed even 
by low dose of volatile anaesthetics. On the other hand, dexmedetomidine in 
combination with propofol seems to suppress only insignificantly the 
MEPs10).  
 
Somatosensory evoked potentials (SSEP) and trans-cranial Doppler (TCD) 
flow velocity in the middle cerebral artery are measured to detect ischaemia. 
A significant decrease in TCD velocity and/or SSEP amplitudes during 
cross-clamping of the internal carotid artery (ICA) is treated with an adapted  
Median nerve somatosensory evoked potentials (SEPs) were performed by 
stimulation at the wrist with a pair of needle electrodes (Inomed Germany®). 

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
This is a single pulse stimulation with 0.5 ms pulse duration and a low 
repetition rate ranging from 0.7 - 2.3 Hz. Recording is performed via 
corkscrew electrodes placed according to the 10-20-EEG system on the 
patient’s scalp. SEP C3´/Fz is chosen as standard derivation for the right 
median nerve and SEP C4´/Fz is chosen for the left median nerve. 
Alternatively, Cz’ or the contralateral Cp’ served as a reference to improve 
quality of recording. To improve the signal-to-noise ratio the responses are 
averaged 150-200 times. Latencies and amplitudes as shown in Figure 1 are 
measured and recorded in the protocol at the defined critical events7). 
Figure 1: 
 
Figure 1: Illustration of SEP latencies and amplitudes recorded from the 
corkscrew electrodes on the patient’s head after averaging. Ten consecutive 
recordings are presented. In this example the SEP amplitude changed 
drastically between line 6 and 7, with a complete loss of the signal at time of 
ICA clamping (from Dr. med. K. Seidel, Dept. of Neurosurgery, Inselspital 
Bern). 
 
The indication spectrum for the centrally acting α2-agonist dexmedetomidine 
has been increasingly expanded since its approval in Switzerland. In 
addition to its use in intensive care units, dexmedetomidine is also 
increasingly being used perioperatively up to premedication in children. In 
some studies, an anaesthetic reduction of 40%–60% could be achieved or 
the opioid consumption after the addition of an α2-agonist could be reduced 
by 50%–75%11). The blood pressure response to a dexmedetomidine dose 
depends on the rate of infusion4). In addition, administration of 
dexmedetomidine does not result in respiratory depression or compromise of 
the respiratory tract. It has been shown that dexmedetomidine can cause a 
“sleep-like” sedation state, and this state can be interrupted by verbal 
stimuli2). Huupponen et al. 20083) examined the EEG activity in sedated 
volunteers compared to a control group with physiological sleep patterns. In 
this study, it was shown that the EEG spindle activity in subjects with 
dexmedetomidine infusion was comparable to that of a physiological non-

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
rapid eye-movement (nonREM) sleep stage II in the control tests. The 
authors concluded from their investigations that a "sleep-like state" (stage II 
non-REM) can be achieved by the Dexmedetomidine infusion. However, no 
data currently exist for practical use in carotid endarterectomy with propofol 
and dexmedetomidine in conjunction with electrophysiological studies 
(somatosensory evoked potentials (SSEP) and motor evoked potentials 
(MEP)). 
In addition, there is a high risk of postoperative delirium (POD) in many of 
these patients undergoing CEA. This was examined in a recently published 
Lancet study by Xian Su and colleagues in 700 elderly patients with non-
cardiac interventions8). A reduction of the delirium incidence from 23% to 9% 
was found after a low-dose dexmedetomidine dose of 0.1 μg/kg body 
weight/h. In addition, a neuroprotective effect against ischemic and hypoxic 
influences is attributed to dexmedetomidine5). Other experimental studies in 
animals have indicated neuroprotection in ischemic insult and subsequent 
reperfusion6). 
Objective(s): 
Primary study objectives are to evaluate the maximum dose of propofol 
leading to the attainment of EEG burst suppression (measured and 
interpreted by the anaesthesiologist) for the co-administration of 
dexmedetomidine in combination with propofol compared to propofol alone 
as the standard therapy. 
 
The secondary study objectives are the intraoperative propofol requirement 
and consumption per unit of time, duration from the end of surgery to 
reaching the extubation criteria (extubation), intraoperative 
electrophysiological parameters (latency and amplitude of evoked potentials, 
measured and interpreted by the neurosurgery team), intraoperative 
haemodynamic parameters, vasoactive substances, and fluid management. 
We will also measure vigilance (Glasgow Coma Scale = GCS, Richmond 
Agitation Sedation Scale = RASS) before beginning  of anaesthesia and 
directly before the patient is transferred to the intensive care unit and the 
development of delirium (CAM-ICU) and muscle force measured in the 
extremities as described by Janda (M0-M5) in the first 24 hours after the end 
of the operation in the intensive care unit (ICU). Further measurements will 
include: perioperative urinary output; patients’ use of painkillers; the need for 
rescue analgesics; and postoperative nausea and vomiting (PONV). 
Outcome(s): 
The primary study outcome is to determine whether the intervention reduces 
the effect size concentration of propofol. 
 
Secondary endpoints are the intraoperative propofol requirement or 
consumption per unit of time, duration from the end of surgery to extubation 
(measured by extubation criteria), intraoperative electrophysiological 
parameters (latency and amplitude of evoked potentials), intraoperative 
haemodynamic parameters, vasoactive substances, and fluid management. 
We will also measure vigilance (Glasgow Coma Scale = GCS, Richmond 
Agitation Sedation Scale = RASS), criteria for the development of delirium 
(CAM-ICU) and muscle force of the extremities as described by Janda (M0-

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
M5) in the intensive care unit (ICU) in the first 24 hours after the end of the 
operation at. Furthermore, we will examine the perioperative urinary output 
in these patients during the operation and during their stay in the intensive 
care unit.  Additionally, we want to examine the patients’ use of painkillers 
and the need for rescue analgesics as well as the postoperative nausea and 
vomiting (PONV) direct after the patient has been extubated and once during 
the stay in the intensive care unit. 
Study design: 
Randomised controlled prospective trial in two groups. Group 1 will receive 
anaesthesia with propofol and co-administration of dexmedetomidine in 
conjunction with electrophysiological studies measuring somatosensory 
evoked potentials (SSEPs) and motor evoked potentials (MEPs). Group 2 
will receive standard anaesthesia with propofol alone, in conjunction with 
electrophysiological studies measuring SSEPs and MEPs. 
Inclusion / 
Exclusion 
criteria: 
We will include patients undergoing surgery of carotid endarterectomy 
requiring general anaesthesia at the Inselspital, Bern University Hospital, 
University of Bern, Department of Neurosurgery. 
 
Inclusion criteria are: age ≥18 years, ASA physical status 1-4, and written 
informed consent provided.  
 
Exclusion criteria are: Age <18 years, higher grade atrioventricular block 
without pacemaker, severe hypovolaemia or bradycardia, uncontrolled hyper 
or hypotension, hypersensibility concerning the active substance 
dexmedetomidine or any other component, serve liver disease, known 
malignant hyperthermia, cardiovascular instability or severe heart failure (> 
NYHA III), limited peripheral autonomic activity, pregnancy, rejection or lack 
of consent of the patient or their relatives. 

 
 
 
 
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Universitätsklinik für 
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Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
Measurements 
and 
procedures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The study participants must be undergoing carotid endarterectomy (CEA) of 
the internal carotid artery (ICA). All patients will receive anaesthetic care 
according to the standard operation procedure of the institution. This 
includes preoperative assessment by an anaesthesiologist (premedication) 
before surgery, the NIHSS (National Institutes of Health Stroke Scale) Score 
and obtainment of written informed consent. The patients will not receive any 
sedatives before surgery as premedication. On arrival in the operating room, 
patients are monitored and recorded according to the clinical standards. An 
intravenous catheter is inserted in a peripheral vein and a catheter in the 
radial artery for continuous blood pressure monitoring and for analysis of 
arterial blood gases. Either the Bispectral Index (BIS) or Narcotrend® will be 
used to measure the frontal EEG (brain activity) before and during the 
anaesthesia procedure. The results are measured and interpreted by by the 
treating anesthesiologist. The effects of propofol will be detected with EEG 
burst suppression.  
The study participants are divided into two groups: Group 1 starts with a 
bolus of dexmedetomidine 0.4 µg/kg over 10 minutes, followed by con-
tinuous infusion of dexmedetomidine 0.4 µg/kg/h until the end of burst 
suppression. Group 2 receives the standard anaesthesia management. 
Patients are intubated and ventilated. Inspiratory and end-tidal concen-
trations of oxygen and carbon dioxide are measured. All patients receive 
intravenous propofol as a target-controlled infusion for induction and 
maintenance of general anaesthesia. Remifentanil is given as a continuous 
intravenous infusion and additional boli of fentanyl are administered as 
needed. Neuromuscular blocking agents are given to facilitate endotracheal 
intubation. The effect-site concentration of propofol (Cet) is set based on the 
clinical evaluation and the processed EEG (target BIS of 40-60, 
Narcotrend®, Narcotrend-Gruppe Hannover, Germany, corresponding 25-
65). The data and curves will be analysed and interpreted by the attending 
anaesthesiologist. Before cross-clamping of the internal carotid artery, the 
effect-site concentration of propofol is gradually increased until a burst 
suppression pattern is established in the frontal EEG (max. 1 burst every 10 
seconds, which is approximately 70% of isoelectric EEG). After reperfusion 
of the internal carotid artery, Cet of propofol is decreased and guided by 
clinical appreciation and EEG. At the end of burst suppression, 
dexmedetomidine is discontinued. 
Somatosensory evoked potentials (SSEP) and Doppler flow velocity in the 
middle cerebral artery are measured and interpreted by the neurosurgeon 
team to detect ischaemia. A significant decrease in Doppler velocity and/or 
SSEP amplitudes during cross-clamping of the internal carotid artery (ICA) is 
treated with an adapted increase of arterial blood pressure or placement of a 
shunt. Every patient undergoing CEA median nerve SEPs and MCA flow 
velocity is constantly monitored by an additional technician who has been 
trained and certified in the assessment of intraoperative monitoring. The 
median nerve SEP amplitudes are recorded at least at these time points: 
baseline value before skin incision, EEG burst suppression before cross 
clamping of the internal carotid artery, at the time of ICA cross clamping, 10 
minutes after cross clamping or immediately after placement of a shunt (ICA 
clamping 2), on reperfusion of ICA, and when haemostasis is reached (end 

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
of surgery). The predefined criterion for temporary shunting is the reduction 
of more than 50% of the SEP amplitude. 
Median nerve somatosensory evoked potentials (SEPs) were performed by 
stimulation at the wrist with a pair of needle electrodes (Inomed® Germany). 
This is a single pulse stimulation with 0.5 ms pulse duration and a low 
repetition rate ranging from 0.7 -2.3 Hz. Recording is performed via 
corkscrew electrodes placed according to the 10-20-EEG system on the 
patient’s scalp. For the right median nerve SEP C3´/Fz and for the left 
median nerve SEP C4´/Fz is chosen as standard derivation. Alternatively, 
Cz’ or the contralateral Cp’ served as reference to improve quality of 
recording. To improve the signal-to-noise ratio the responses are averaged 
150–200 times. Latencies and amplitudes as shown in Figure 1 are 
measured and recorded in the protocol at the defined critical events7). 
Figure 1: 
 
Figure 1: Illustration of SEP latencies and amplitudes recorded from the 
corkscrew electrodes on the patient’s head after averaging. Ten consecutive 
recordings are presented. In this example the SEP amplitude changed 
drastically between lines 6 and 7, with complete loss of the signal at the time 
of ICA clamping (from Dr. med. K. Seidel, Dept. of Neurosurgery, Inselspital 
Bern). 
 
Particular attention will be paid to haemodynamic management. The last 
three blood pressure values are averaged and used to determine a baseline. 
During the operation and until clamping, blood pressure is kept in a range of 
baseline +/- 10%. If this value is undershot or exceeded, then vasopressors 
or antihypertensives are used, following the preference of the supervising 
anaesthesiologist. Before clamping of the ICA, arterial blood pressure is 
usually increased to levels slightly above normal systolic values (150-160 
mmHg) and subsequently decreased before reperfusion. Until the end, and 
after the procedure, arterial systolic blood pressure is maintained below 
values of 100-140 mmHg to prevent hyperperfusion oedema. Concentrations 
of intravenous anaesthetics are gradually decreased and discontinued on 

 
 
 
 
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Universitätsklinik für 
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Schmerztherapie  
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Prof. Dr. med. F. Stüber 
completion of skin closure. Patients are extubated and discharged to the 
ICU. A postmedication interview will be performed before ICU discharge with 
a CAM-ICU Test (see appendix) and the medication given at the ICU will be 
registered in our database. 
 
 

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
 
Flow chart: The graphic shows the course of the study. The orange fields relate 
to the study-related measures. The light blue fields contain all study-
independent procedures. 
 
Study 
Intervention
: 
 
 
Group 1: Co-administration of dexmedetomidine and propofol in conjunction 
with electrophysiological studies (somatosensory evoked potentials (SSEPs) 
and motor evoked potentials (MEPs)) 
 
Group 2: Standard anaesthesia with propofol in conjunction with 
electrophysiological studies (somatosensory evoked potentials (SSEPs) and 
motor evoked potentials (MEPs)) 
Control 
Inter-
vention: 
 
Group 2: Standard anaesthesia with propofol in conjunction with 
electrophysiological studies (somatosensory evoked potentials (SSEPs) and 
motor evoked potentials (MEPs)). 
Number of 
Participants 
with 
Rationale: 
We will include 46 patients, 23 patients each group.  
 
Assuming an effect size concentration (Cet) of 6 mg/ml with a SD of +/- 3 
mg/ml in the control arm, a minimal clinically important difference of 3 mg/ml 
and an alpha of 0.05, at least 23 patients per group would be needed to reach 
a power of 90%. 
Study 
Duration: 
24 months 
Study 
Schedule: 
Study begin: July 2018. Study end: July 2020 
Investigator
(s): 
Dr. med. Christian Vetter and PD Dr. med. Vladimir Krejci, both Dept. of 
Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, 
University of Bern 
 
Christian Vetter, Christian.vetter@insel.ch, phone: 031 632 69 78, Address: 
Inselspital Bern, Freiburgstrasse, 3010 Bern 
Vladimir Krejci, vladimir.krejci@insel.ch, phone: 031 632 90 53, Address: 
Inselspital Bern, Freiburgstrasse, 3010 Bern 
Monitoring prior to the 
beginning of  anaesthesia
Group 1: Dexmedetomidine 
as a bolus 0.4µg/kg over 10 
minutes
Group 1: continuous 
infusion of 
dexmedetomidine 0.4 
µg/kg/h, SSEPs and 
MEPs until the end of 
burst supression 
Group 2: no bolus of 
dexmedetomidine
Group 2: no infusion of 
dexmedetomidine, 
SSEPs and MEPs 
start of anaesthesia
Group 1 and 2: Follow-up i
the intensive care unit wit
completion of a 
questionnaire (ICAM-ICU
operation
end of anaesthesia

 
 
 
 
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Universitätsklinik für 
Anästhesiologie und 
Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
Study 
Centre: 
Inselspital Bern, Freiburgstrasse, 3010 Bern 
Statistical 
Considerati
ons: 
Null hypothesis (H0): We will test the null hypothesis that the effect 
concentration (Cet) of propofol (Propofol®, Fresenius, Switzerland) for EEG 
burst suppression and maintenance thereof remains unchanged through the 
co-administration of Dexmedetomidine (Dexdor®, Orion Pharma, Switzerland) 
against a two-sided alternative. 
 
Parametric distribution and equal variances will be confirmed. ANOVA and 
Student's t-test will be used to verify differences between mean, with Tukey’s 
correction factor for multiple comparison where appropriate. No interim analysis 
is planned. 
GCP 
Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as 
applicable) as well as all national legal and regulatory requirements.  
STUDY SUMMARY IN LOCAL LANGUAGE  
Am Inselspital wird als neuroprotektive Massnahme bei allen neurochirurgischen Carotis Endar-
terektomien (CEA) routinemässig die elektrische EEG-Aktivität mit hohen 
Effektortkonzentrationen (Cet) von Propofol unterdrückt (Burst-Suppression; BS). Eine 
protrahierte Infusion grosser Mengen an Propofol zum Erreichen eines BS während der 
Operation kann jedoch zu einer Kumulation und einer protrahierten Aufwachphase mit 
schlechterer neurologischen Beurteilbarkeit führen.  
 
Zur Überprüfung der funktionellen Integrität des Nervensystems werden somatosensensorisch 
evozierte Potentiale eingesetzt (SSEP). Standardisierte Massnahmen aus chirurgischer und 
anästhesiologischer Sicht bei der CEA mit definierten EEG-Endpunkten und in Abhängigkeit von 
der Anästhetikawirkung, können bei normalem EEG und SSEP eine schwere, globale Ischämie 
praktisch ausschliessen. Darüber hinaus werden seit 2016 zusätzlich motorisch evozierte 
Potentiale (MEP) intraoperativ erhoben. Die intraoperative EEG-Aktivität wird durch den 
betreuenden Kaderarzt der Anästhesie beurteilt und interpretiert. Die MEPs und SSEPs werden 
durch das Team der Neurochirurgie erhoben und beurteilt. 
 
Die somatosensorisch evozierte Potenziale (SSEP) und die Fliessgeschwindigkeit in der mittleren 
zerebralen Arterie werden mittels Doppler gemessen, um eine Ischämie zu detektieren. Eine 
signifikante Abnahme der Flussgeschwindigkeit und / oder der SSEPs-Amplitude während dem 
vorübergehendem Verschluss der Arteria carotis interna (ICA) wird mit einer angepassten 
Erhöhung des arteriellen Blutdrucks oder der Platzierung eines Shunts behandelt.  
 
Das Team der Neurochirurgie überwacht und zeichnet die Daten bei jedem Patienten auf, der 
sich einer CEA unterzieht. Die SSEPs und MEPs sowie die Flussgeschwindigkeit der Arteria 
cerebri media werden intraoperativ permanent von einem intraoperativen Monitoring 
(IOM-)Techniker überwacht, der speziell in der Beurteilung der Überwachung der SEPs-Signale 
geschult und zertifiziert wurde.  
 
Die SEP-Amplituden des N. medianus werden kontinuierlich aufgezeichnet. Dies ist insbesondere 
bei folgenden kritischen Ereignissen der Fall: Ausgangswert als Baseline vor Hautinzision, EEG-
Burstunterdrückung vor dem Abklemmen der A. carotis interna, 10 Minuten nach Abklemmung 
der ACI oder unmittelbar nach Platzierung des Shunts (ICA Abklemmung 2), Reperfusion der ICA 
und Hämostase / Ende der Operation. Das vordefinierte Kriterium für den temporären Shunt ist 
eine Reduktion von mehr als 50% der SEP-Amplitude. 
Die somatosensorisch evozierte Potentiale (SEPs) Nervus medianus wurden durch Stimulation 
am Handgelenk mit einem Paar Nadelelektroden (Inomed Germany®) durchgeführt. Hierbei 

 
 
 
 
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Universitätsklinik für 
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Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
erfolgt eine Einzelimpulsstimulation mit einer Pulsdauer von 0,5 ms und einer niedrigen 
Wiederholrate von 0,7-2,3 Hz. Die Aufnahme erfolgt über Korkenzieherelektroden, die 
entsprechend dem 10-20-EEG-System auf der Kopfhaut des Patienten platziert sind. Für den 
rechten Nervus medianus SEP C3' / Fz und für den linken N. medianus wird der SEP C4' / Fz als 
Standardableitung gewählt. Alternativ diente Cz 'oder das kontralaterale Cp' als Referenz, um die 
Aufzeichnungsqualität zu verbessern. Um das Signal-Rausch-Verhältnis zu verbessern, werden 
die Antworten im Mittel 150-200-mal gemittelt. Bei den kritischen Ereignissen werden die 
Latenzen und Amplituden gemessen und aufgezeichnet (vgl. Abbildung 1)7). 
 
 
Abbildung 1:  
 
 
 
Abbildung 1: Darstellung der SEP-Latenzen und -Amplituden, die von Korkenzieherelektroden am 
Patientenkopf nach der Mittelung aufgenommen wurden. Zehn aufeinander folgende Aufnahmen 
werden vorgestellt. In diesem Beispiel änderte sich die SEP-Amplitude drastisch zwischen den 
Zeilen 6 und 7 mit einem vollständigen Verlust des Signals zum Zeitpunkt der ICA-Abklemmung 
(von Dr. med. K. Seidel, Klinik für Neurochirurgie, Inselspital Bern). 
 
 
Der additive Effekt von Propofol und Sevoflurane auf die EEG-Suppression wurde 2009 von 
Schumacher und al. beschrieben und in unserer Klinik angewendet, jedoch unterdrücken volatile 
Anästhetika dosisabhängig MEPs, so dass die volatilen Anästhetika sich nur bedingt bei 
Operationen bei denen die SSEPs bzw. MEPs gemessen werden wie z.B. bei Carotis 
Endarterektomien (CEAs) eigenen. Hingegen scheint Dexmedetomidine in Kombination mit 
Propofol SSEPs und MEPs nur unwesentlich zu unterdrücken. 
 
Das Indikationsspektrum für den zentral wirkenden α2-Agonist Dexmedetomidine wurde seit 
seiner Zulassung in der Schweiz zunehmend ausgeweitet. Neben dem Einsatz von 
Dexmedetomidine auf den Intensivstationen wird Dexmedetomidine zunehmend auch 
perioperativ bis hin zur Prämedikation bei Kindern eingesetzt. In einigen Studien konnte eine 
Anästhetikareduktion von 40-60% erzielt oder der Opioidverbrauch nach Zugabe eines α2-
Agonisten um 50-75% reduziert werden. Die Blutdruckantwort auf eine Dexmedetomidinegabe ist 
abhängig von der Infusionsgeschwindigkeit4). Darüber hinaus führt die Gabe von 
Dexmedetomidine zu keiner Atemdepression oder einer Kompromittierung der Atemwege. 
Nachdem gezeigt werden konnte, dass Dexmedetomidine einen „Schlaf ähn-
lichen“ Sedationszustand herbeiführen und dieser Zustand durch verbale Stimuli unterbrochen 
werden kann2), untersuchte Huupponen et al. 20083) die EEG-Aktivität bei Sedation an freiwilligen 
Probanden im Vergleich zu einer Kontrollgruppe mit physiologischem Schlafmuster. In dieser 
Studie konnte gezeigt werden, dass die EEG-Spindel-Aktivität bei Probanden mit 

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
Dexmedetomidine-Infusion derjenigen eines physiologischem non rapid eye movement 
(nonREM)-Schlafes Stadium II bei den Kontrollprobanden vergleichbar war. Die Autoren folgerten 
aus ihren Untersuchungen, dass durch die Dexmedetomidine-Infusion ein „schlafähnlicher 
Zustand“ (Stadium II Non-REM) erreicht werden kann. Momentan sind jedoch keine Daten zur 
praktischen Anwendung bei Carotis Endarterektomien mit Propofol und Dexmedetomidine in 
Verbindung mit elektrophysiologischen Untersuchungen (somatosensibel evozierten Potentialen 
(SSEPs) und motorisch evozierte Potentialen (MEPs)) bekannt.  
 
Darüber hinaus besteht bei einer Vielzahl dieser Patienten ein hohes Risiko für ein 
postoperatives Delir (POD). Dies wurde in einer kürzlich publizierten Lancet Studie von Xian Su 
und Kollegen an 700 Patienten mit nicht kardialen Eingriffen bei älteren Patienten untersucht8). 
Hierbei zeigte sich eine Reduktion der Deliriumsinzidenz von 23% auf 9% nach einer niedrig 
dosierten Dexmedetomidine-Gabe von 0.1µg/kg/h. Zusätzlich wird Dexmedetomidine ein 
neuroprotektiver Effekt gegenüber ischämischen und hypoxischen Einflüssen zugeschrieben5). 
Weitere tierexperimentelle Studien weisen auf eine Neuroprotektion bei ischämischem Insult und 
anschliessender Reperfusion hin6). 
 
 
Ziel der Studie: 
Durchführung einer prospektiv kontrollierten Studie, welche die Quantität von Propofol mit der 
Co-Administration von Dexmedetomidine im Vergleich zum Propofol alleine untersucht. Hierbei  
sind der intraoperative Propofol-Bedarf und -Verbrauch pro Zeiteinheit, die Dauer vom Ende der 
Operation bis zum Erreichen der Extubationskriterien (Extubation), intraoperative 
elektrophysiologische Parameter (Latenz und Amplitude evozierter Potentiale (SSEPs und 
MEPs), intraoperative hämodynamische Parameter, Quantität an Vasoaktiva, sowie das 
Flüssigkeitsmanagement.  
 
Darüber hinaus wird die Vigilanz mittels GCS (= Glasgow Coma Scale) und RASS (= Richmond 
Agitation Sedation Scale) vor der Narkose und kurz bevor der Patient auf die Intensivstation 
verlegt wird und kurz vor Verlegung von der Intensivstation auf die Normalstation untersucht. 
Kriterien für die Entwicklung eines Delirs gemäss CAM-ICU Fragebogen und Objektivierung der 
Muskelkraft der Extremitäten nach Janda (M0-M5) in den ersten 24 Stunden nach dem Ende der 
Operation und in den ersten 24 Stunden auf der Intensivstation. Darüber hinaus untersuchen wir 
die perioperative Urinausscheidung bei diesen Patienten intra- und während der folgenden 24h 
postoperativ. Darüber hinaus wollen wir den Schmerzmittelbedarf, den Bedarf an 
Reserveanalgetika, sowie das Auftreten von postoperativen Übelkeit- und Erbrechen (PONV) und 
den Antiemetikabedarf während des Aufenthaltes auf der Intensivstation untersuchen. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Universitätsklinik für 
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Schmerztherapie  
Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
Abbreviations 
AE 
Adverse Event  
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
BS 
CEA 
EEG 
Competent Ethics Committee 
burst supression 
carotid endarterectomy 
electro encephalogram 
CRF 
Case Report Form  
Cet 
effector concentrations 
GCP 
Good Clinical Practice  
HFG 
HFNCT 
Humanforschungsgesetz (Law on human research) 
High Frequency Nasal Cannula Therapy 
HMG 
Heilmittelgesetz  
HRA 
Federal Act on Research involving Human Beings 
ICA 
internal carotid artery 
IIT 
Investigator-initiated Trial 
ITT 
Intention to treat 
KlinV 
Verordnung über klinische Versuche in der Humanforschung (in English: 
ClinO) 
PI 
Principal Investigator 
POD 
postoperative delirium 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SSEP 
Somatosensory evoked potentials 
 
 
 
 
 
 
 
 
 
 
Study schedule  
July 2018: Start clinical part of the study, first patient included 
March 2019: last patient included 
Mayr 2019: data analysed and manuscript drafted 
July 2020: end of study 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
1. 
STUDY ADMINISTRATIVE STRUCTURE  
All persons mentioned are members of the Department of Anaesthesiologie and Pain Medicine at 
the Inselspital, Bern University Hospital, Freiburgstrasse, 3010 Bern. Contact details for the PI 
Christian Vetter, Dr. med., christian.vetter@insel.ch; Tel: 031 632 69 78 
1.1 
Sponsor, Sponsor-Investigator  
Dr. med. Christian Vetter will oversee the entire study, drafting and finalisation of the protocol, the 
analysis of the results, and the writing of the manuscript for publication. Contact details: 
christian.vetter@insel.ch, Tel: 031 632 69 78 
1.2 
Principal Investigator(s)  
Dr. med Christian Vetter, christian.vetter@insel.ch; Tel: 031 632 69 78 
1.3 
Statistician ("Biostatistician")  
PD Dr. med. Vladimir Krejci, vladimir.krejci@insel.ch; Tel: 031 632 90 53 
1.4 
Monitoring Institution 
A study nurse from our department who is not involved in the study will control all data for its 
validity and completeness on a weekly basis. External monitoring will not occur, as this is an 
investigator-initiated study with no external funding.  
 
2. 
ETHICAL AND REGULATORY ASPECTS  
Before the study is conducted, the protocol, the proposed patient consent form as well as other 
study-specific documents will be submitted to the Cantonal Ethics Committee Bern. Any 
amendment to the protocol must be approved by this institution as well. 
The decision of the CEC concerning the conduct of the study will be communicated in writing to 
the Sponsor-Investigator before commencement of the study. The clinical study can only begin 
after approval from all required authorities has been received. Any additional requirements 
imposed by the authorities shall be implemented. 
 
Ethical considerations 
a. 
The potential gain of new knowledge obtained with this study, and its meaning for 
patients/society:  
 
 
 
 
 
 
 
 
 
In Switzerland, Stroke is a major cause of mortality and disability, and accounts for a large part of 
healthcare expense, and suffering. One cause of stroke is untreated significant, or symptomatic 
stenosis of the internal carotid artery. Carotid artery endarterectomy may be performed in select 
patients to decrease the risk of stroke. General, as well as loco-regional anaesthesia are equally 
accepted and safe for this type of procedure. While loco-regional anaesthesia allows better 
neurological assessment of the awake patient, general anaesthesia provides more comfort for 
both the surgeon and the patient. In addition, the risk of unexpected complications, such as loss 
of the airway, or sudden movement of the patient are greatly reduced with general anaesthesia. 
However, assessment of neurological function is more difficult. For this reason, in our institution 
the integrity of the nervous system in patients undergoing CEA under general anaesthesia is 
assessed with neurophysiological monitoring. Cross-clamping of the internal carotid artery bears 
the risk of cerebral ischemia and infarction. 
 

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
Although electrophysiological monitoring may detect ischemia, cerebral oxygen consumption is 
decreased to a „maintenance“ level with high doses of anaesthetics for neuroprotection, the end-
point being electroencephalographic burst suppression. High amounts of anaesthetics may result 
in delayed recovery and difficult neurological assessment. While most patients recover from this 
type of general anaesthesia within acceptable limits, in some patients a significant delay of one 
hour and more was observed. The aim of this study is to test a combination of intravenous 
anaesthetics, which may decrease the risk of delayed recovery. Published data from other 
procedures suggest, that electrophysiological monitoring will not be impaired with the type of 
anaesthesia used in the present study. 
 
Arterial hypotension is a known cause of morbidity in patients with cerebrovascular disease. 
Uncontrolled hypertension during emergence may result in complications such as bleeding, or 
brain edema. Our preliminary experience with this anaesthetic regimen suggestes, which it will 
possibly contribute to hemodynamic stability, both at induction, and during emergence. 
 
Delirium is another cause of postoperative morbidity, mortality, and prolonged hospital stay. 
Published data strongly suggest, that Dexmedetomidine, may reduce the risk of postoperative 
delirium. 
 
Overall, CEA is very safe procedure. However, in our experience, CEA is performed the longer 
the more often in patients with very recent stroke, who may be more vulnerable to hemodynamic 
instability and ischemia, and who may benefit from pharmacological prevention of delirium. 
 
 
b. Assessment of the benefit/risk relationship for the patient  
 
Study participants must be undergoing either emergency or elective surgery of the internal carotid 
artery (ICA). All patients will receive anaesthetic care according to their institution’s standard 
operation procedure. This includes preoperative assessment by an anaesthesiologist (premedi-
cation) before surgery, the NIHSS (National Institutes of Health Stroke Scale) Score and written 
informed consent. For this operation, standard operating procedure has been developed and is 
applied regularly.  
Every patient in this study will be monitored according to our clinical standards as well as the 
recommendations of the specialist company. Postoperatively, patients’ blood pressure must be 
closely monitored and managed; invasive blood pressure measurement will provide the 
corresponding values in real time. The treating anaesthesiologist can react promptly and initiate 
necessary measures. All anaesthesiologists who supervise patients in this study are familiar with 
the drug dexmedetomidine and use it regularly. Dexmedetomidine has been approved by 
Swissmedic for the sedation of patients with a dose of up to 1.4 μg/kg/h. The dose we will use in 
this study, 0.4 μg/kg/h, is in the lower third.  
 
Two theoretical risks are involved when dexmedetomidine is used as a bolus or continuous 
infusion. First, severe bradycardia can occur. However, the amount of dexmedetomidine to be 
administered in our study is relatively small. On the other hand, studies with higher 
dexmedetomidine concentrations do not indicate a heightened occurrence of severe bradycardia 
nor has this been described in the literature. Second, there is the possibility of severe 
hypotension, which requires therapy. Since patients will already be receiving invasive blood 
pressure measurement as standard, and the anaesthesiologist can intervene at an early stage, 
this risk is also very small. 
 
We cannot use healthy people or animals as a substitute for this patient group.  

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
 
c. 
The methodology is ethically appropriate to gain new generalizable knowledge 
Our patients will be blinded to the randomisation. The responsible anaesthetist cannot influence 
the bolus of dexmedetomidine started prior to the induction of anaesthesia (very low risk of 
creating bias). The two groups will be statistically and clinically equivalent with regard to age, 
weight, health status and elective or emergency status. The trial method is well suited to study 
the research question, and the participating anaesthesiologists are familiar with all possible side 
effects and comfortable treating them. 
 
2.1 
Study registration  
The study will be registered at www.clinicaltrials.gov and in the database of the Inselspital Bern 
through the University of Bern’s Clinical Trials Unit, as well as with the Swiss Federal Office of 
Public Health’s portal for human research, KOFAM (www.kofam.ch). 
2.2 
Categorisation of study  
Risk category A.  
Rationale: The medications we will use in this study are approved as sedatives by Swissmedic 
(registration number: 62183). We compare two therapeutic strategies in one experimental and 
one standard therapy arm (= propofol is routinely used as an anaesthetic in modern anaesthesia 
procedure). 
2.3 
Competent Ethics Committee (CEC)  
Kantonale Ethikkommission Bern (KEK), Institut für Pathophysiologie, Hörsaaltrakt Pathologie, 
Eingang 43A, Büro H372, Murtenstrasse 31, 3010 Bern. According to Art. 38 KlinV:  completion 
of the study must be reported to the responsible ethics committee within 90 days or interruption 
(including details of reasons) within 15 days. In addition, a final report must be submitted to the 
Ethics Committee within one year after completion or interruption of the study. 
2.4 
Ethical conduct of the study  
The study will be carried out in accordance with the protocol and with principles enunciated in the 
current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) 
issued by ICH , Swiss law, and the Swiss regulatory authority’s requirements. The CEC and 
regulatory authorities will receive annual safety and interim reports and be informed about study 
stop/end in agreement with local requirements. A final report will be sent to the CEC at latest one 
year after the study ends.  
2.5 
Declaration of conflicts of interest  
None of the investigators reports a conflict of interest. 
2.6 
Patient information and informed consent 
The investigators will explain to the patients the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits, and any discomfort it may entail. 
Each patient will be informed that participation in the study is voluntary, that he/she may withdraw 
from the study at any time, and that withdrawal of consent will not affect subsequent medical 
assistance and treatment. Patients must be informed that their medical records may be examined 
by authorised individuals (e.g., CEC) other than their treating physician. 
 
All study participants will receive a consent form along with an information sheet describing the 
study and providing sufficient information to make an informed decision about their participation.  

 
 
 
 
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Prof. Dr. med. F. Stüber 
The study information sheet and consent form will be submitted to the CEC for review and 
approval. In elective patients the formal consent must be obtained from the participant before the 
participant undergoes any study procedures.  
According to our numbers of patients, we assume 13% of emergencies in this patient group each 
year. In case of emergencies, a distinction is made as to whether they are even able to give 
informed consent. If this is the case and the patient has enough time (time to participate in the 
study to the operation > 6 hours) to take a decision, the consent form will be obtained from the 
patient himself. If this is not the case, as the patient is not able to consent at the time of the 
information, the next family members will be informed and the consent of one of the patient family 
members will be obtained in a writing form. In addition, an independent doctor is consulted. Once 
the patient is able to consent, the informed consent is obtained retrospectively. 
 
Study participants should read before signing and dating the informed consent form and should 
be given a copy of the signed document. The consent form must also be signed and dated by the 
investigator (or his designee) and retained as part of the study records. 
2.7 
Participant privacy and confidentiality  
The investigators affirm and uphold the principle of the participant’s right to privacy and agree that 
they will comply with applicable privacy laws. In particular, anonymity of the participants shall be 
guaranteed when presenting the data at scientific meetings or publishing them in scientific 
journals.  
Medical information about individual subjects obtained through this study is considered 
confidential, and disclosure to third parties is prohibited. Subject confidentiality will be further 
ensured by utilising subject identification codes to correspond to treatment data in the computer 
files. 
The codes will be stored in the lockable office of the principal investigator in a lockable cupboard 
where no one else has access.   
For data verification purposes, authorised representatives of a competent authority (e.g. 
Swissmedic) or the cantonal ethics committee may require direct access to parts of the medical 
records relevant to the study, including participants’ medical history. 
2.8 
Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely under certain circumstances, for 
example: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is in doubt or at risk, 
 
when alterations in accepted clinical practice make the continuation of a clinical trial unwise,  
 
when there is early evidence of harm of the intervention  
2.9 
Protocol amendments 
Substantial amendments can only be implemented after approval of the CEC. Under emergency 
circumstances, deviations from the protocol to protect the rights, safety and well-being of the 
study participants may proceed without prior approval of the sponsor and the CEC. Such 
deviations shall be documented and reported to the sponsor as soon as possible. 
All non-substantial amendments are communicated to the CEC within the Annual Safety Report 
(ASR).  

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
3. 
BACKGROUND AND RATIONALE  
3.1 
Background and rationale 
In our clinic, as a neuroprotective measure, all neurosurgical patients undergoing operation for 
carotid endarterectomy (CEA) are routinely operated on under deep anaesthesia with 
suppression of the electrical activity of the electroencephalogram (EEG). To achieve this 
suppression of the EEG activity (burst suppression, BS), high effector concentrations (Cet) of 
propofol doses are needed. However, a protracted infusion of large amounts of propofol to reach 
a BS during the operation can lead to accumulation and a protracted wake-up phase, with poorer 
neurological assessability. Somatosensory evoked potentials (SSEPs) are used to verify the 
functional integrity of the nervous system. Intraoperative monitoring and recording of data 
in every patient undergoing CEA median nerve SEPs and MCA flow velocity is constantly 
monitored by an additional intraoperative monitoring (IOM) technician who has been trained and 
certified in the assessment of intraoperative monitoring.  
 
The median nerve SSEP amplitudes are recorded at least at these events: 
 
Baseline value before skin incision 
 
EEG burst suppression before cross clamping of the internal carotid artery 
 
At time of ICA cross clamping 
 
10 minutes after cross clamping or immediately after placement of shunt (ICA clamping 2) 
 
Reperfusion of ICA  
 
Haemostasis/end of surgery 
 
The predefined criterion for temporary shunting is the reduction of more than 50% of the SEP 
amplitude. 
 
Median nerve SSEPs are measured by stimulation at the wrist with a pair of needle electrodes 
(Inomed® Germany). This is a single pulse stimulation with 0.5 ms pulse duration and a low 
repetition rate ranging from 0.7 -2.3 Hz. Recording is performed via corkscrew electrodes placed 
according to the 10-20-EEG system on the patient’s scalp. For the right median nerve SEP 
C3´/Fz and for the left median nerve SEP C4´/Fz is chosen as standard derivation. Alternatively, 
Cz’ or the contralateral Cp’ served as reference to improve quality of recording. To improve the 
signal-to-noise ratio the responses are averaged 150-200 times. Latencies and amplitudes as 
shown in Figure 1 are measured and recorded in the protocol at the defined critical events7). 
 
 

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
 
 
Figure 1: Illustration of SEP latencies and amplitudes recorded from the corkscrew electrodes on 
the patient’s head after averaging. Ten consecutive recordings are presented. In this example the 
SEP amplitude changed drastically between lines 6 and 7, with complete loss of the signal at the 
time of ICA clamping (from Dr. med. K. Seidel, Neurosyrgery, Inselspital Bern). 
 
Standardised surgical and anaesthesiological measures at the CEA with defined EEG endpoints 
and depending on the anaesthetic effect can, in normal EEG and SSEPs, effectively exclude 
severe global ischaemia. The effects of burst suppression and volatile anaesthetics on SSEPs 
have also investigated and showed no significant difference. Since 2016, motor-induced evoked 
potentials (MEPs) have also been used, but they are suppressed by volatile anaesthetics in a 
dose-dependent manner. On the other hand, dexmedetomidine in combination with propofol 
seems to suppress only insignificantly. 
 
The indication spectrum for the centrally acting α2-agonist dexmedetomidine has been 
increasingly extended since the drug’s approval in Switzerland. In addition to being used in 
intensive care units, dexmedetomidine is also increasingly being used perioperatively up to 
premedication in children. In some studies, an anaesthetic reduction of 40-60% could be 
achieved, or opioid consumption after the addition of an α2-agonist could be reduced by 50-75%. 
The blood pressure response to a dexmedetomidine dose depends on the rate of infusion4). In 
addition, administration of dexmedetomidine does not result in respiratory depression or 
compromise of the respiratory tract. It has been shown that dexmedetomidine can cause a 
“sleep-like” sedation state, and this state can be interrupted by verbal stimuli2). 
 
Huupponen et al. 20083) examined the EEG activity in sedated volunteers compared to a control 
group with physiological sleep patterns. In this study, it was shown that the EEG spindle activity in 
subjects with dexmedetomidine infusion was comparable to that of a physiological non-rapid-eye-
movement (nonREM) sleep stage II in the control tests. The authors concluded from their 
investigations that a “sleep-like state” (stage II non-REM) can be achieved with dexmedetomidine 
infusion. However, no data are currently available for practical use in carotid endarterectomy with 
propofol and dexmedetomidine in conjunction with electrophysiological studies (somatosensory 
evoked potentials and motor-evoked potentials). 

 
 
 
 
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Universitätsklinik für 
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Direktor und Chefarzt  
Prof. Dr. med. F. Stüber 
In addition, there is a high risk of postoperative delirium (POD) in many of these patients. This 
was examined in a recently published Lancet study by Xian Su and colleagues in 700 elderly 
patients with non-cardiac interventions. A reduction of the delirium incidence from 23% to 9% was 
found after a low-dose dexmedetomidine dose of 0.1 μg/kg body weight/h. In addition, a 
neuroprotective effect against ischaemic and hypoxic influences has been attributed to 
dexmedetomidine5). Other experimental studies in animals indicate neuroprotection in ischemic 
insult and subsequent reperfusion6).  
 
3.2 
Investigational product (treatment, device) and indication  
Dexmedetomidine (Dexdor®).  
3.3 
Clinical evidence to date  
All relevant available evidence is summarized under 3.1 
3.4 
Dose rationale: rationale for the intended purpose in study  
The drug dexmedetomidine is approved by Swissmedic for the sedation of patients. The most 
common dose in the previously published studies is between 0.5 and 0.7 μg/kg/h. Since patients 
usually have relevant comorbidities and thus belong to ASA class III and higher, and due to the 
substantial exclusion of side effects, we have a bolus of 0.4 μg/kg over 10 minutes followed by a 
continuous infusion of 0.4 μg/kg/h until the end of the operation. The dose of 0.4 μg/kg/h we plan 
to use in this study is in the lower third of the maximum dosage approved by Swissmedic. The 
Risk for adverse events is very little. 
3.5 
Explanation of choice of comparator (or placebo)  
We will not use a placebo for this study, as the current standard for treating patients undergoing 
carotid endarterectomy (CEA) is propofol. We will test whether co-administration of 
dexmedetomidine and propofol is superior to the standard therapy with propofol alone.   
3.6 
Risks/benefits  
The study participants must undergo either an emergency or elective surgery on the internal 
carotid artery (ICA). Standard operating procedure has been developed for this operation and is 
applied regularly.  
 
Every patient in this study will be monitored according to our clinical standards as well as the 
recommendations of the specialist company. Postoperatively, patients’ blood pressure must be 
closely monitored and managed; invasive blood pressure measurement will provide the 
corresponding values in real time. The treating anaesthesiologist can react promptly and initiate 
necessary measures. All anaesthesiologists who supervise patients in this study are familiar with 
the drug dexmedetomidine and use it regularly. Dexmedetomidine has been approved by 
Swissmedic for the sedation of patients with a dose of up to 1.4 μg/kg/h. The dose we will use in 
this study, 0.4 μg/kg/h, is in the lower third. According to the product information of 
dexmedetomidine, there is currently no adequate experience with the use of dexmedetomidine in 
pregnant women. Therefore, a pregnancy test must be performed on women of childbearing 
potential prior to enrolment. 
 
Two theoretical risks are involved when dexmedetomidine is used as a bolus or continuous 
infusion. First, severe bradycardia can occur. However, the amount of dexmedetomidine to be 
administered in our study is relatively small. On the other hand, studies with higher 
dexmedetomidine concentrations do not indicate a heightened occurrence of severe bradycardia 
nor has this been described in the literature. Second, there is the possibility of severe 

 
 
 
 
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hypotension, which requires therapy. Since patients will already be receiving invasive blood 
pressure measurement as standard, and the anaesthesiologist can intervene at an early stage, 
this risk is also very small. 
 
 
All patients undergoing general anaesthesia have at least a small risk of perioperative 
complications. Although this risk is multifactorial, it depends on the clinical condition of the patient 
as well as the type of intervention. But these conditions have a great influence on the 
perioperative outcome. High effector concentrations (Cet) of propofol suppress the electrical EEG 
activity up to burst suppression (BS). However, protracted infusion of large amounts of propofol to 
reach BS during a carotid endarterectomy (CEA) can lead to accumulation and a protracted 
wake-up phase, with poorer neurological assessability.  
 
With this study, we hypothesize that the spearing effect of propofol caused by the co-
administration of dexmedetomidine will reduce the dose of anaesthetics required to achieve and 
sustain anaesthesia without influencing the SSEPs and MEPs during the operation. If we can 
show with this study both that patients awaken faster from anaesthesia and that neurological 
assessability improves with a lower risk of postoperative complications – such as postoperative 
delirium (POD) – we will greatly improve patient safety. 
 
3.7 
Justification of choice of study population  
The study participants must undergo either an emergency or elective surgery on the internal 
carotid artery (ICA). Standard operating procedure has been developed for this operation and is 
applied regularly. 
 
 
Every patient in this study will be monitored according to our clinical standards as well as the 
recommendations of the specialist company. Postoperatively, patients’ blood pressure must be 
closely monitored and managed; invasive blood pressure measurement will provide the 
corresponding values in real time. The treating anaesthesiologist can react promptly and initiate 
necessary measures. All anaesthesiologists who supervise patients in this study are familiar with 
the drug dexmedetomidine and use it regularly. Dexmedetomidine has been approved by 
Swissmedic for the sedation of patients with a dose of up to 1.4 μg/kg/h. The dose we will use in 
this study, 0.4 μg/kg/h, is in the lower third.  
 
Two theoretical risks are involved when dexmedetomidine is used as a bolus or continuous 
infusion. First, severe bradycardia can occur. However, the amount of dexmedetomidine to be 
administered in our study is relatively small. On the other hand, studies with higher 
dexmedetomidine concentrations do not indicate a heightened occurrence of severe bradycardia 
nor has this been described in the literature. Second, there is the possibility of severe 
hypotension, which requires therapy. Since patients will already be receiving invasive blood 
pressure measurement as standard, and the anaesthesiologist can intervene at an early stage, 
this risk is also very small. 
 
We cannot use healthy people or animals as a substitute for this patient group. 

 
 
 
 
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Prof. Dr. med. F. Stüber 
4. 
STUDY OBJECTIVES  
4.1 
Overall objective 
This study investigates the co-administration of dexmedetomidine and propofol for carotid 
endarterectomy under controlled conditions. In our clinic, as a neuroprotective measure, all 
neurosurgical patients undergoing operation for carotid endarterectomy (CEA) are routinely 
operated on under deep anaesthesia with suppression of the electrical activity of the electroence-
phalogram (EEG). To achieve this suppression of the EEG activity (burst suppression, BS), high 
effector concentrations (Cet) of propofol doses are needed. However, a protracted infusion of 
large amounts of propofol to reach a BS during the operation can lead to accumulation and a 
protracted wake-up phase with poorer neurological assessability. 
 
 
With the co-administration of dexmedetomidine and propofol during anaesthesia we will try to 
show that both the outcome and the complication rate can be improved, resulting in improved 
safety and better patient management during the operation. 
 
4.2 
Primary objective 
The primary study objective is to determine whether the intervention reduces the effect size 
concentration of propofol. 
  
4.3 
Secondary objectives 
The secondary study objectives are the intraoperative propofol requirement and consumption per 
unit of time, duration from the end of surgery to reaching the extubation criteria (extubation), 
intraoperative electrophysiological parameters (latency and amplitude of evoked potentials), 
intraoperative hemodynamic parameters, vasoactive substances, fluid management. We also 
measure the vigilance (Glasgow Coma Scale = GCS, Richmond Agitation Sedation Scale = 
RASS) before anaesthesia and directly before the patient is transferred to the intensive care unit. 
Criteria for the development of delirium (CAM-ICU) and muscle force of the extremities as it was 
described by Janda (M0-M5) in the first 24 hours after the end of the operation at the intensive 
care unit (ICU). Furthermore, we examine the perioperative urinary output in these patients.  
Additionally, we want to examine the patient's use of painkillers and the need for rescue 
analgesics as well as the postoperative nausea and vomiting state (PONV). 
 
4.4 
Safety objectives 
According to the recommendations of the SGAR (Schweizerische Gesellschaft für 
Anästhesiologie und Reanimation), all patients are monitored and a radial artery for continuous 
blood pressure monitoring and for analysis of arterial blood gases, electrolytes and metabolites is 
inserted prior starting with the induction of anaesthetics. The brain activity is monitored by 
Bispectral Index or Narcotrend®. Both are assessed and analysed by the treating 
anesthesiologist. The SSEPs, MEPs and MCA flow velocity Doppler are analysed and assessed 
by the treating neurosurgery team. 

 
 
 
 
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5. 
STUDY OUTCOMES  
5.1 
Primary outcome 
The primary study outcome is to determine whether the intervention reduces the effect size 
concentration of propofol. 
 
5.2 
Secondary outcomes 
 
Secondary endpoints are the intraoperative propofol requirement or consumption per unit of time, 
duration from the end of surgery to extubation (measured by extubation criteria), intraoperative 
electrophysiological parameters (latency and amplitude of evoked potentials), intraoperative 
haemodynamic parameters, vasoactive substances, and fluid management. We will also measure 
vigilance (Glasgow Coma Scale = GCS, Richmond Agitation Sedation Scale = RASS), criteria for 
the development of delirium (CAM-ICU) and muscle force of the extremities as described by 
Janda (M0-M5) in the intensive care unit (ICU) in the first 24 hours after the end of the operation 
at. Furthermore, we will examine the perioperative urinary output in these patients during the 
operation and during their stay in the intensive care unit.  Additionally, we want to examine the 
patients’ use of painkillers and the need for rescue analgesics as well as the postoperative 
nausea and vomiting (PONV) direct after the patient has been extubated and once during the 
stay in the intensive care unit. 
5.3 
Safety outcomes 
Presence of severe refractory hypotension and bradycardia during surgery will be identified by 
the continuous blood pressure measurement and treated immediately. 
 
6. 
STUDY DESIGN  
6.1 
General study design and justification of design  
Single-blinded randomised controlled prospective trial (Co-administration of dexmedetomidine in 
carotid endarterectomy with intraoperative SSEP and MEP monitoring. A single-centre 
prospective randomised controlled trial).  
 
In total we will include 46 patients; at least 23 patients in each group. Patients will be blinded as 
to their group allocations.  
 
Double-blinding is not intended. The sequence is described above. 
6.2 
Methods of minimising bias  
6.2.1 
Randomisation  
Patients will be assigned to their respective groups using a computer-generated randomisation 
list. Randomisation will be stratified according to use of propofol alone as standard therapy (group 
2) and propofol with the co-administration of dexmedetomidine (group 1), with 23 patients in each 
group. Group allocation will be kept in a sealed opaque envelope opened before induction of 
anaesthesia until the patient is motorised. The Patients won’t be informed about this result. 
Patients excluded from the study before opening of the randomisation envelope will be replaced, 
as if they were not eligible for the study. 

 
 
 
 
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Prof. Dr. med. F. Stüber 
6.2.2 
Blinding procedures  
Patients are under general anaesthesia and therefore blinded to the treatment group, but 
personnel in the operating room are not blinded. 
6.3 
Unblinding procedures (code break) 
Unblinding procedure: The randomization code is placed in a locked drawer in the office of the 
study sponsor from Dr. med. C. Vetter. Only the study leader has a key for it. 
7. 
STUDY POPULATION  
7.1 
Eligibility criteria  
To be included are all patients undergoing elective and emergency carotid endarterectomy under 
general anaesthesia with intubation in the neurosurgery clinic at the Inselspital, Bern University 
Hospital.  
 
Additional inclusion criteria are: Age ≥18 years, ASA physical status 1-4, a pregnancy test must 
be performed on women of childbearing potential prior to enrolment, provision of written informed 
consent.  
 
Exclusion criteria are: Age <18 years, higher grade atrioventricular block without pacemaker, 
severe hypovolaemia or bradycardia, uncontrolled hyper or hypotension, hypersensibility 
concerning the active substance dexmedetomidine or any other component, serve liver disease, 
known malignant hyperthermia, cardiovascular instability or severe heart failure (> NYHA III), 
limited peripheral autonomic activity, pregnancy, rejection or lack of consent of the patient or their 
relatives. 
 
Patients will be screened and asked to participate in the study during the pre-anaesthesia visit 
before surgery. If they are willing to take part they will sign the informed consent form, there. 
7.2 
Assignment to study groups  
Patients will be randomly assigned to their respective groups using www.randomisation.com.  
7.3 
Criteria for withdrawal/discontinuation of participants  
The patient will be withdrawn from the study if there is no surgical intervention or if a decision is 
made to change the anaesthesia procedure (i.e., general anaesthesia is not needed). A therapy-
refractory hypotension and/or bradycardia which does not respond to vasoactive or 
sympathomimetic drugs will also lead to exclusion of the patient from the study. 
A pregnancy test must be performed on women of childbearing potential prior to enrolment, if its 
possitiv, we will exclude the patient from this study. 
8. 
STUDY INTERVENTION  
8.1 
Investigational treatment  
8.1.1 
Experimental intervention  
The effect-site concentration of propofol (Fresenius Kabi, Switzerland) (Cet) in co-administration 
with dexmedetomidine (Dexdor®, Orion Pharma, Switzerland) was set based on the clinical 
evaluation and the processed EEG. 

 
 
 
 
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Prof. Dr. med. F. Stüber 
8.1.2 
Control intervention (routine treatment)   
Comparator: The effect-site concentration of propofol (Fresenius Kabi, Switzerland) (Cet) was set 
based on the clinical evaluation and the processed EEG. 
8.2 
Administration of experimental and control interventions  
8.2.1 
Experimental intervention  
The effect-site concentration of propofol (Fresenius Kabi, Switzerland) (Cet) in co-administration 
with dexmedetomidine (Dexdor®, Orion Pharma, Switzerland) was set based on the clinical 
evaluation and the processed EEG. 
8.2.2 
Control intervention 
Comparator: The effect-site concentration of propofol (Fresenius Kabi, Switzerland) (Cet) was set 
based on the clinical evaluation and the processed EEG. 
8.3 
Data collection and follow-up for withdrawn participants  
No further data will be collected after withdrawal from the study. Data already collected will be 
analysed and after data evaluation anonymised   
 
Study flow chart(s) / table of study procedures and assessments: The graphic shows the 
course of the study. The orange fields relate to the study-related measures. The light blue fields 
contain all study-independent procedures. 
 
 
 
8.4 
Assessments of outcomes  
8.4.1 
Assessment of primary outcome  
The primary study outcome is to determine whether the intervention reduces the effect size 
concentration of propofol. 
 
Monitoring prior to the 
beginning of  anaesthesia
Dexmedetomidine as a bolus 
0.4µg/kg over 10 minutes
continuous infusion of 
Dexdemeditine 0.4 
µg/kg/h, SSEPs and 
MEPs until the end of 
burst supression
no bolus of Dexmedetomidine
no infuson of 
Dexdemeditine, SSEPs 
and MEPs 
start of anaesthesia
Follwo up at the intenisve care 
unit with completing a 
questionnaire (ICAM-ICU)
operation
end of anaesthesia

 
 
 
 
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Direktor und Chefarzt  
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8.5 
Secondary outcomes 
The secondary study outcomes are the intraoperative propofol requirement and consumption per 
unit of time, duration from the end of surgery to reaching the extubation criteria (extubation), 
intraoperative electrophysiological parameters (latency and amplitude of evoked potentials), 
intraoperative haemodynamic parameters, vasoactive substances, and fluid management. We 
will also measure vigilance (Glasgow Coma Scale = GCS, Richmond Agitation Sedation Scale = 
RASS) before starting anaesthesia and directly before the patient is transferred to the intensive 
care unit and the development of delirium (CAM-ICU) and muscle force measured in the 
extremities as described by Janda (M0-M5) in the first 24 hours after the end of the operation in 
the intensive care unit (ICU). Further measurements will include: perioperative urinary output; 
patients’ use of painkillers; the need for rescue analgesics; and postoperative nausea and 
vomiting (PONV). 
 
8.5.1 
Assessment of secondary outcomes 
This is a standard procedure used very often in the anaesthesia and intensive care units.  
 
8.5.2 
Assessment of safety outcomes 
According to the product information of dexmedetomidine, there is currently no adequate 
experience with the use of dexmedetomidine in pregnant women. Therefore, a pregnancy test 
must be performed on women of childbearing potential prior to enrolment. 
 
Possible hypotension and bradycardia will be monitored as described before. 
 
8.5.2.1 
Adverse events  
Any adverse events during the study period will be recorded. 
All SAEs will be reported immediately or within a maximum of 24 hours to the Sponsor-
Investigator of the study. 
SAEs resulting in death should be reported to the local ethics committee within 7 days. 
SUSARs will be reported to the local ethics committee within 15 days. 
 
8.5.2.2 
Laboratory parameters 
We will not draw blood for testing in this study. 
8.5.2.3 
Vital signs 
During anaesthesia, standard non-invasive and invasive monitoring of vital signs will be recorded, 
as defined by the American Society of Anaesthesiologists and the Swiss Society for Anaesthesia 
and Reanimation. This includes: ECG, end-tidal CO2, invasive blood pressure, pulse oximetry, 
heart frequency, and body temperature and urinary output. 
8.6 
Procedures at each visit 
The first visit will take place during the pre-anaesthesia visit. A follow-up visit will be performed 
(structured post-medication interview) before the patient leaves the ICU, including completion of 
an ICAM-ICU form. 

 
 
 
 
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9. 
SAFETY  
Adverse events during the anaesthesia procedure will be treated according to current 
departmental guidelines at the discretion of the attending anaesthesia consultant. If severe, 
therapy-refractory problems persist, the study can be stopped at any time points without delay 
and the study patient will be treated according to the departmental guidelines. 
 
 
Adverse event (AE):  
Any unintentional medical incident in a patient or subject who is has received pharmaceutical 
preparation. The undesirable event does not have to necessarily be causally related to treatment. 
Thus, an undesirable event may be any unwanted or unintended sign, symptom or any illnesses 
that are temporary with the administration of the investigational medicinal product is independent 
whether a causal link with the investigational medicinal product is being considered. 
 
Serious Adverse Event (SAE):  
Every AE, that 
• leads to death 
• is life threatening 
• Hospitalization or extension of existing hospitalization 
• leads to permanent and significant disability 
• is a hereditary deviation / birth defect 
• requires medical intervention to avert the above consequences 
Fatal SAEs will be sent to the responsible ethics committee within 7 days. SAEs without fatal 
outcome will be reported as part of the annual safety report. 
 
Suspected unexpected serious adverse reaction (SURAS):  
As SUSAR are called such side effects that are unexpected at the same time and serious. 
SURAS with death must be reported to the ethics committee within 7 days, all other SURAS 
within 15 days 
10. STATISTICAL METHODS  
10.1 Hypothesis 
Null hypothesis: We will test the null hypothesis that the effect concentration (Cet) of propofol 
(Propofol®, Fresenius, Switzerland) for EEG burst suppression and maintenance thereof remains 
unchanged through the co-administration of Dexmedetomidine (Dexdor®, Orion Pharma, 
Switzerland) against a two-sided alternative. 
  
Second outcome hypothesis: secondary outcome hypothesis are the intraoperative Propofol 
requirement and consumption per unit of time, duration from the end of surgery to reaching the 
extubation criteria (extubation), intraoperative electrophysiological parameters (latency and 
amplitude of evoked potentials), intraoperative hemodynamic parameters, vasoactive 
substances, fluid management. We also measure the vigilance (GCS = Glasgow Coma Scale, 
RASS = Richmond Agitation Sedation Scale) before the anaesthesia and directly before the 
patient will be transferred to the intensive care unit, Criteria for the development of a delirium 
(CAM-ICU) and muscle force of the extremities as it was described by Janda (M0-M5) in the 
first 24 hours after the end of the operation at the intensive care unit (ICU). Furthermore, we 
examine the perioperative urinary output in these patients.  Additionally, we want to examine 
the patient's use of painkillers and the need for rescue analgesics as well as the postoperative 
nausea and vomiting state (PONV). 

 
 
 
 
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10.2 Determination of sample size  
Assuming an effect size concentration of 6 mg/ml with a SD of +/- 3 mg/ml (Ref) in the control 
arm, a minimal clinically important difference of 3 mg/ml and an alpha of 0.05, at least 23 
patients per group would be needed to reach a power of 90%. 
 
10.3 Planned analyses  
10.3.1 Datasets to be analysed, analysis populations 
The main analysis set will include all randomized patients. Parametric distribution and equal 
variances confirmed, ANOVA and Student's t-test will be used to verify differences between mean 
with Tukey’s correction factor for multiple comparison where appropriate, no interim analysis is 
planned. 
 
10.3.2 Safety analysis 
According to the product information of dexmedetomidine, there is currently no adequate 
experience with the use of dexmedetomidine in pregnant women. Therefore, a pregnancy test 
must be performed on women of childbearing potential prior to enrolment. 
 
Presence of severe refractory hypotension or bradycardia during surgery will be identified 
immediately by the continuous blood pressure and heart frequency measurement and will be 
compared with known results from the literature. 
10.3.3 Deviation(s) from the original statistical plan  
Any deviation from the planned analyses will be listed and justified in the study report. 
10.4 Handling of missing data and drop-outs  
Any missing data or drop-outs will be listed and justified in the study report. With the rather 
small sample size we will take care to have no missing data or drop-outs in the study. 
11. QUALITY ASSURANCE AND CONTROL  
11.1 Data handling and record keeping/archiving  
11.1.1 Case report forms  
Demographic data (age, weight, sex, type of surgery) will be obtained from the departmental 
electronic anaesthesia information system (AIS). Consent forms will be obtained at the pre-
anaesthesia visit. All study data will be directly recorded in the CRF, which should also be 
considered as source data. These data will be transferred into the departmental research 
documentation system – LabKey. 
11.1.2 Recordkeeping/archiving  
All study data will be archived for a minimum of 10 years after study termination or premature 
termination of the clinical trial. 
Data will be transferred to a secure, web-based data integration platform (LabKey, LabKey 
Software, Seattle, WA, USA, Version 14.3) and controlled independently by two members of 
the study team. Additionally, data will be double-checked by comparing the screening records 
with the digital anaesthesia documenting system of the hospital. 

 
 
 
 
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Prof. Dr. med. F. Stüber 
11.2 Data management  
11.2.1 Data management system  
11.2.2 Data security, access and back-up  
The LabKey Server provides web application security. It can be configured for Secure Socket 
Layer (SSL) encrypted data transfer if needed. 
The application has a group-based and a role-based security model. Each user belongs to 
one or more security groups with specific sets of permissions in relation to folders or projects 
in the system. Only dedicated site administrators have access to the admin console enabling 
user management and changes to security settings. 
Data are stored and visualised in data grids either in the format of datasets, lists or assays. 
Each change of data is tracked and documented in corresponding audit log files. 
The system can only be accessed by entering a user name and password. All events are 
recorded in the user event list of the audit log files. 
The application runs on a productive server with an image on a backup server. In addition, a 
regular backup of the whole database is implemented using storage servers (darwinnas0001 
and darwinnas0002) hosted at the darwin.insel.ch domain. 
11.2.3 Analysis and archiving 
The LabKey server provides data analysis by integrated tools for creating filtered views and 
charts. 
All data can be exported in various formats (excel, text, queries) suitable for transfer to a 
preferred statistical software package. In addition, data can be analysed by creating R views. 
All data will be archived and secured in the database if required by legislation. 
11.2.4 Electronic and central data validation  
Data are validated by the primary investigator and the sponsor when evaluating the results. 
11.3 Monitoring: 
A study nurse from our department who is not involved in the study will control all data for its 
validity and completeness on a weekly basis. External monitoring will not occur, as this is an 
investigator-initiated study with no external funding.  
12. PUBLICATION AND DISSEMINATION POLICY  
The results will be published in a peer-reviewed journal. The final decision on publishing the 
results will be made by the project leaders. Authors of the publication are team members who 
contributed to the design, conduct or analysis of the study and who approved the final version of 
the manuscript. 
13. FUNDING  
13.1 Funding  
This study is solely financed by a departmental research grant from the departmental anaesthesia 
research fund. There is no funding or financial influence through any other company. 

 
 
 
 
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14. INSURANCE  
Insurance will be provided by the Inselspital Bern through Zürich Versicherungs-Gesellschaft AG. 
15. REFERENCES  
1. Liang C, Ding M, Du F et al: J Anesth 2014; 28:721–6: Compared to sevoflurane 
maintenance, co-administration of Propofol and sevoflurane provides faster awakening and 
extubation with a low incidence of emergence coughing and agitation 
 
2. Nelson LE, Lu J, Guo T et al: Anesthesiology 2003; 98:428-36: The α2-Adrenoreceptor 
Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert 
Its Sedative Effects 
 
3. Huupponen E, Maksimow A, Lapinlampi P et al: Acta Anaesthesiol Scand 2008; 52:289-294: 
Electroencephalogram spindle activity during Dexmedetomidine sedation and physiological 
sleep  
 
4. Giovannitti JA Jr, Thoms SM, Crawford JJ.: Anesth Prog 2015; 62:31-38: Alpha-2 Adrenergic 
Receptor Agonists: A Review of Current Clinical Applications 
 
5. Mahmoud M, Mason KP: Britsh J. of Anaesthesia, 2015, 171-82: Dexmedetomidine: review, 
update, and future considerations of pediatric perioperative and procedural applications and 
limitations 
 
6. Luo C, Ouyang MW, Fang YY, et al: Front Cell Neurosci. 2017, 11:197: Dexmedetomidine 
Protects Mouse Brain from Ischemia-Reperfusion Injury via Inhibiting Neuronal Autophagy 
through Up-Regulating HIF-1α  
 
7. Raabe A, Seidel K: Journal of Neurosurgical Siences 2016, 60(1): 95-103: Prevention of 
ischemic complication during aneurysm surgery 
 
8. Su X, Meng ZT, Wu XH et al: The Lancet 2016, 388 (15): 1893 – 1902: Dexmedetomidine for 
prevention of delirium in elderly patients after non-cardiac surgery: a randomized, double 
blind, placebo-controlled trial  
 
9. Bala E, Sessler DI, Nair DR et al: Anaesthesiology 2008, 109: 417 – 425: Motor and 
somatosensory evoked potentials are well maintained in patients given Dexmedetomidine 
during spinal surgery 
10. Brown M, Kinney G, Vavilala MS: Anesthesia and Analgesia 2015, 121(2), 492–501: 
Dexmedetomidine Does Not Affect Evoked Potentials During Spine Surgery 
 
11. Song J, Ji Q, Sun Q, et al: Journal of Neurosurgical Anesthesiology 2016: 28(1):14-20 The 
Opioid-sparing Effect of Intraoperative Dexmedetomidine Infusion After Craniotomy.