Clinical trial NCT03996148
Conditions: Carotid Artery Stenosis
Sponsor: The Cooper Health System
Start date: 2017-09-29; Completion date: 2018-09-19
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this pilot study is to analyze the differences in time to first postoperative neurological examination (cranial nerve XII - tongue movement, movement of extremities) and intraoperative hemodynamic stability with three different general anesthetic techniques that are used for carotid endarterectomy. Carotid endarterectomy surgery removes the plaque and stenosis but has a 1-3% risk of periprocedural stroke or death. The ability to detect neurological abnormalities early after surgery is vital in this patient population to facilitate timely additional diagnostics or interventions if a potential stroke is detected. Anesthetic techniques that facilitate an earlier reliable neurological exam will thus greatly benefit this surgical patient population. The primary objective of this pilot study is to determine the time difference from end of surgery to first neurologic exam between three commonly used anesthetic methods for carotid endareterectomy.

Detailed description:
Carotid endarterectomy reduces the incidence of stroke in people with symptomatic, severe carotid artery stenosis. However, there are risks associated with this procedure such as stroke from carotid clamping with poor collateral brain circulation or embolization of carotid plaque debris (Sheth, 2017). Few surgeons monitor the brain during the procedure using SSEP or EEG, as most rely on intraoperative blood pressure management, shunting, and postoperative neurological exam (De Santis, 2016; Kobayashi, 2011).

A Cochrane review of regional versus general anesthesia for carotid endarterectomy reveals no significant difference in outcomes (Vaniyaping, 2013). It is common practice at Cooper Hospital to deliver general anesthesia. The general anesthetic given may affect the length of time to first post-operative neurological response and the hemodynamic stability, though this is not well studied.

A search in PubMed in April 2017 for "carotid endarterectomy AND (general anesthesia OR total intravenous anesthesia OR regional anesthesia) AND neurologic exam" ("endarterectomy, carotid"\[MeSH Terms\] OR ("endarterectomy"\[All Fields\] AND "carotid"\[All Fields\]) OR "carotid endarterectomy"\[All Fields\] OR ("carotid"\[All Fields\] AND "endarterectomy"\[All Fields\])) AND (("general anaesthesia"\[All Fields\] OR "anesthesia, general"\[MeSH Terms\] OR ("anesthesia"\[All Fields\] AND "general"\[All Fields\]) OR "general anesthesia"\[All Fields\] OR ("general"\[All Fields\] AND "anesthesia"\[All Fields\])) OR (total\[All Fields\] AND ("intravenous anaesthesia"\[All Fields\] OR "anesthesia, intravenous"\[MeSH Terms\] OR ("anesthesia"\[All Fields\] AND "intravenous"\[All Fields\]) OR "intravenous anesthesia"\[All Fields\] OR ("intravenous"\[All Fields\] AND "anesthesia"\[All Fields\]))) OR ("regional anaesthesia"\[All Fields\] OR "anesthesia, conduction"\[MeSH Terms\] OR ("anesthesia"\[All Fields\] AND "conduction"\[All Fields\]) OR "conduction anesthesia"\[All Fields\] OR ("regional"\[All Fields\] AND "anesthesia"\[All Fields\]) OR "regional anesthesia"\[All Fields\])) AND (neurologic\[All Fields\] AND exam\[All Fields\]) revealed no studies comparing anesthetic types and time to first post-operative neurological response in this surgical population. Through anecdotal experience at Cooper Hospital, patients are noted to emerge faster and follow commands sooner when not given preoperative midazolam and given a combined Total Intravenous Anesthetic (TIVA) and volatile inhalational anesthetic technique titrated to a bispectral index (BIS) of 50-60.

Ruling out anesthetic causes of abnormal neurological function is vital in this patient population. Neurological dysfunction that is surgical in nature may require early intervention such as surgical reexploration or CT scan. "Time is brain", and a few minutes difference is enough to cause permanent neurological damage if a progressing stroke is not quickly identified. Anesthetic techniques that demonstrate a quicker return to baseline neurological function will greatly benefit this surgical patient population.

Arms: arm 1: Study group A: no midazolam given; maintenance drugs started immediately after induction and airway is secured. arm 2: Study group B: no midazolam given; maintenance drugs started immediately after induction and airway is secured. arm 3: Study group C (control group): no midazolam given; maintenance drugs started immediately after induction and airway is secured.
Interventions: intervention 1: Remifentanil, Propofol, and Desflurane intervention 2: Remifentanil, Dexmedetomidine, and Desflurane intervention 3: Remifentanil and Desflurane
Intervention descriptions: intervention 1: Remifentanil - titratable; initial starting dose 0.05 mcg/kg/min Propofol - titratable; initial starting dose 75 mcg/kg/min Desflurane 0.5 MAC intervention 2: Remifentanil - titratable; initial starting dose 0.05 mcg/kg/min Dexmedetomidine - titratable; initial starting dose 0.5 mcg/kg/hr Desflurane 0.5 MAC intervention 3: Remifentanil - titratable; initial starting dose 0.05 mcg/kg/min Desflurane - titratable

Protocol documents:
Prot_SAP_002.pdf: 
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COVER PAGE 
 
 
 
 
 
Official Title of Study: Time to Post-Anesthesia Neurological Evaluation With Three Different 
Anesthetic Techniques 
 
Clinicaltrials.gov number: NCT03996148 
 
Date of Document: April 3rd, 2019 
 
 
 
 


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Investigator-Initiated Protocol Template     
 
Title Of Project: Postoperative Neurological Function And 
Hemodynamic Stability In Carotid Endarterectomy 
Comparing Three General Anesthetic Techniques: A Pilot 
Study.  
 
 
Principal Investigator and Department: 
Rhea Temmermand, CRNA, MSN; Anesthesiology 
 
Co-investigators and Departments/Institution: 
 
Dejan Vuckovic, MD; Anesthesiology 
Jonathan Rost, MD; Anesthesiology 
Ludmil Mitrev, MD; Anesthesiology 
Frank Caputo, MD; Vascular Surgery 
Dean Roberts, CRNA, MSN; Anesthesiology 
John Gaughan, PhD; Biostatistics 
 
 
 
 
A 
Objectives/Purpose 
 
The objective of this pilot study is to analyze the differences in time to first postoperative 
neurological response (cranial nerve XII – tongue movement, movement of extremities) and in 
hemodynamic stability when three different general anesthetic techniques are used for carotid 
endarterectomy.  Patients who emerge from general anesthesia, follow commands, and meet 
extubation criteria sooner reassure the surgical team they have returned to their baseline 
neurological status. Failure to return to baseline neurologic status may require early intervention 
through surgical re-exploration or CT scan.  
 
 
 
 
B 
Hypotheses 
 
Our hypothesis is that there is a clinical and statistically-significant difference in time to first 
post-operative neurologic response between subjects undergoing carotid endarterectomy with 
three anesthetic techniques where the depth of anesthesia is titrated to a bispectral index (BIS) 
of 50-60. 
 
 
 


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C 
Background 
 
 
 
Carotid endarterectomy reduces the incidence of stroke in people with symptomatic, severe 
carotid artery stenosis.  However, there are risks associated with this procedure such as stroke 
from carotid clamping with poor collateral brain circulation or embolization of carotid plaque 
debris (Sheth, 2017).  Few surgeons monitor the brain during the procedure using SSEP or 
EEG, as most rely on intraoperative blood pressure management, shunting, and postoperative 
neurological exam (De Santis, 2016; Kobayashi, 2011).   
 
A Cochrane review of regional versus general anesthesia for carotid endarterectomy reveals no 
significant difference in outcomes (Vaniyaping, 2013). It is common practice at Cooper Hospital 
to deliver general anesthesia.  The general anesthetic given may affect the length of time to first 
post-operative neurological response and the hemodynamic stability, though this is not well 
studied.  
 
A search in PubMed in April 2017 for “carotid endarterectomy AND (general anesthesia OR total 
intravenous anesthesia OR regional anesthesia) AND neurologic exam” ("endarterectomy, 
carotid"[MeSH Terms] OR ("endarterectomy"[All Fields] AND "carotid"[All Fields]) OR "carotid 
endarterectomy"[All Fields] OR ("carotid"[All Fields] AND "endarterectomy"[All Fields])) AND 
(("general anaesthesia"[All Fields] OR "anesthesia, general"[MeSH Terms] OR ("anesthesia"[All 
Fields] AND "general"[All Fields]) OR "general anesthesia"[All Fields] OR ("general"[All Fields] 
AND "anesthesia"[All Fields])) OR (total[All Fields] AND ("intravenous anaesthesia"[All Fields] 
OR "anesthesia, intravenous"[MeSH Terms] OR ("anesthesia"[All Fields] AND "intravenous"[All 
Fields]) OR "intravenous anesthesia"[All Fields] OR ("intravenous"[All Fields] AND 
"anesthesia"[All Fields]))) OR ("regional anaesthesia"[All Fields] OR "anesthesia, 
conduction"[MeSH Terms] OR ("anesthesia"[All Fields] AND "conduction"[All Fields]) OR 
"conduction anesthesia"[All Fields] OR ("regional"[All Fields] AND "anesthesia"[All Fields]) OR 
"regional anesthesia"[All Fields])) AND (neurologic[All Fields] AND exam[All Fields]) revealed no 
studies comparing anesthetic types and time to first post-operative neurological response in this 
surgical population. Through anecdotal experience at Cooper Hospital, patients are noted to 
emerge faster and follow commands sooner when not given preoperative midazolam and given 
a combined Total Intravenous Anesthetic (TIVA) and volatile inhalational anesthetic technique 
titrated to a bispectral index (BIS) of 50-60. 
 
 
 
D 
Significance of the research 
 
Ruling out anesthetic causes of abnormal neurological function is vital in this patient population. 
Neurological dysfunction that is surgical in nature may require early intervention such as 
surgical reexploration or CT scan.  “Time is brain”, and a few minutes difference is enough to 
cause permanent neurological damage if a progressing stroke is not quickly identified. 
Anesthetic techniques that demonstrate a quicker return to baseline neurological function will 
greatly benefit this surgical patient population. 
 


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E 
Study Design 
 
This is a prospective, randomized, single-blind (patient only) pilot study. Patients coming to 
Cooper Hospital to have a carotid endarterectomy and are enrolled in this study will be 
randomized into one of three groups. No group will be administered midazolam or other 
benzodiazepines. Study group A will receive a maintenance anesthetic consisting of propofol, 
remifentanil, and 0.5 minimum alveolar concentration (MAC) desflurane.  Study group B will 
receive a maintenance anesthetic consisting of dexmedetomidine, remifentanil, and 0.5 MAC of 
desflurane.  Study group C will receive a maintenance anesthetic consisting of only propofol and 
remifentanil.  The control group will receive only remifentanil and desflurane for maintenance of 
anesthesia.  
 
In all three groups, the depth of anesthesia will be titrated to a BIS of 50 to 60. The titration in 
group A and B will occur by first varying the propofol or dexmedetomidine infusion dose while 
maintaining the dose of desflurane at 0.5 MAC for as long as possible. Only if it proves difficult 
to maintain the BIS between 50-60, and after adjustment of the intravenous anesthetic, will the 
anesthesiologist, at his or her discretion, titrate the dose of desflurane up or down as needed to 
maintain BIS in the prescribed range.  
 
Induction will be achieved by using propofol or etomidate, with or without fentanyl, in the usual 
doses. Lidocaine 100mg IV will be used in all subjects to pretreat the patient’s vein and avoid 
the pain of propofol injection. Fentanyl or any other narcotic with the exception of remifentanil 
will not be re-administered until after the first post-operative neurological exam. The surgeon will 
be asked to infiltrate the surgical field (incision, area around the carotid bulb) with 1-2% 
lidocaine and/or 0.25% bupivacaine for achievement of local analgesia. 
 
Rocuronium, vecuronium or cisatracurium will be used for muscle relaxation. Other agents with 
known hypnotic or psychotropic effects, such as, for example, diphenhydramine, will be avoided 
and only used if required as rescue medications. All other required drugs will be used in 
standard-of care doses in all 3 groups (reversal agents, vasoactive or cardiac drugs) and titrated 
at the discretion of the anesthesia provider. No group will receive ketamine. 
 
All subjects shall have an arterial line placed for blood pressure monitoring and titration of 
vasoactive agents. This is standard of care and not for purposes of the study. 
 
F 
Research Plan 
 
IRB-approved informed consent will be obtained from subjects presenting for carotid 
endarterectomy.  Study consent will be obtained by the investigators in person no later than the 
morning of surgery.  Patients will then be randomized consecutively to one of the three 
treatment groups using a randomized allocation schedule. The anesthesia provider (co-
investigators) for the case will be informed of the anesthetic group and will deliver anesthesia 
per study protocol.  
 


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1 
Subjects 
a 
Number of Subjects: there is insufficient historical data in the literature to 
estimate potential differences in the time until an adequate neurological 
response among the treatment groups.  For this reason we plan to 
include up to 10 patients in each group to determine differences that can 
be used for planning a larger definitive study with appropriate power. 
 
b 
Exclusion and Inclusion criteria 
 
Inclusion: patients receiving carotid endarterectomy, at least 18 years 
old, must be able to give consent, must be able to undergo a preoperative 
neurological exam. 
 
Exclusion: pregnant patient; prisoners; dementia or reduced mental 
status for any reason, acute or chronic; known brain tumor or head 
trauma; known severe CAD (uncorrected); EF < 15%; IABP or other 
mechanical circulatory assist device; severe COPD; uncontrolled/severe 
anxiety requiring benzodiazepine administration; history of difficult airway; 
sedation other than propofol, dexmedetomidine or volatile anesthetic 
agent (VAA) is needed for patient (i.e. ketamine in patients with a history 
of neuropathic pain); intubated or unconscious patients; patients on 
methadone or fentanyl patch; known unusual or extreme anesthetic 
requirements, unusual amount of narcotic needed to control pain; 
surgeon requests local-regional anesthesia only (not general anesthesia); 
known history of prolonged emergence; morbidly obese patients (BMI > 
40); inability to apply BIS monitor strip (scalp or forehead defects). 
 
c 
Recruitment Methods:  Subjects will be recruited through the OR 
schedule.  A co-investigator may speak with the patient via phone before 
the surgery to describe the study and obtain study consent in person the 
morning of surgery. The patients will usually be same-day admits, but 
inpatients are not excluded from consideration. 
 
d 
Informed Consent Process: All prospective subjects will be approached 
concerning participation in this study by a co-investigator from the 
Department of Anesthesiology no later than the morning of surgery.  
 
e 
Vulnerable Subjects:  excluded per the exclusion criteria 
 
f 
Compensation to Subjects:  No compensation 
 
g 
Treatment for Research-Related Injuries: Research related injuries are 
not anticipated but will be dealt with using standard procedures at Cooper 
University Hospital. The expenses will be billed to the subjects’ insurance 
provider. 
 
2 
Research Methods and Procedures 
 


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After receiving informed consent, subjects will be randomized into one of 3 groups: 
 
Study group A: no midazolam given; maintenance drugs started immediately after 
induction and airway is secured.  
 
 
Remifentanil - titratable; initial starting dose 0.05 mcg/kg/min  
 
 
Propofol – titratable; initial starting dose 75 mcg/kg/min 
 
 
Desflurane 0.5 MAC 
 
Study group B: no midazolam given; maintenance drugs started immediately after 
induction and airway is secured. 
 
 
Remifentanil - titratable; initial starting dose 0.05 mcg/kg/min  
 
Dexmedetomidine – titratable; initial starting dose 0.5 mcg/kg/hr 
 
Desflurane 0.5 MAC 
 
Study group C: no midazolam given; maintenance drugs started immediately after 
induction and airway is secured. 
 
Remifentanil - titratable; initial starting dose 0.05 mcg/kg/min 
 
Desflurane – titratable 
 
 
Postoperative: Anesthesia providers will note the “surgical end” time which is when the surgical 
site is closed and the final sterile dressings are placed. Upon emergence, CN XII and gross 
motor neurological exam will be performed every minute (or less) until extubation, or every 3 
minutes (or less) in the PACU until a normal neurological response is achieved or a decision is 
made for some form of further intervention (observation, CT scan, or surgical re-exploration).  
The time to the first adequate neurologic response will be noted and will be the main outcome 
variable.  
 
Surgical fellows/residents and attendings, anesthesia providers and PACU nurses who have 
been trained in the neurological exam may administer it and note the time.  
 
Study participation will end when the subject is discharged from the hospital or 48 hours post-
op, whichever occurs first. Patients will be followed during this time by bedside visit and/or EPIC 
chart review. Any postoperative complications during the first 48 hours or until discharge will be 
noted. Length of PACU and hospital stay will be recorded.  
 
3 
Data Analysis Plan, Statistical Tests, and Sample Size Rationale 
 
In order to carry out a pilot study of the alternative anesthesia options, up 
to 10 subjects per group (3 groups) will be included in the study to 
determine differences that can be used for planning a larger definitive 
study with appropriate power. 
 
 
Variables to be collected: 
• 
Age 
• 
Gender 
• 
Height 


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• 
Weight 
• 
Preoperative and postoperative responses to neurological exam (intact vs. deficits) 
• 
3-minute Confusion Assessment Method (3D-CAM) and Short Blessed Test (SBT). The 
former will be re-administered daily until the second postoperative day or discharge, whichever 
occurs first. The SBT will be re-administered 1 week postoperatively via telephone interview. 
• 
Postoperatively will collect time from ‘surgery end’ until following any command, sticking 
out tongue, squeezing both hands, moving both feet 
• 
Preoperative, intraoperative and postoperative hemodynamic measures: blood pressure, 
heart rate 
• 
Intraoperative use of cardiac drugs: vasopressors, vasodilators, beta blockers, calcium 
channel blockers or any other drugs used to control blood pressure and heart rate – total dose 
• 
Intraoperative arterial blood pressure at intervals no less than every 5 minutes 
• 
Intraoperative fluid administration (total) 
• 
Intraoperative blood loss (EBL) 
• 
Carotid clamp time 
• 
Use of carotid shunt (yes/no) 
• 
Use of SSEPs requested by surgeon (yes/no) 
• 
Surgery end time to extubation time 
• 
Surgery end time to first adequate neurologic response: MAIN OUTCOME VARIABLE 
• 
BIS throughout the intraoperative portion of the case no less than at 15 minute intervals 
• 
Hospital length of stay 
• 
PACU length of stay in hours 
• 
Post-operative complications experienced by subject (e.g. stroke, seizure, MI, sepsis, 
prolonged hospitalization >48 hours, respiratory failure requiring prolonged mechanical 
ventilator support, prolonged awakening from anesthesia (>30 min), pneumonia, DVT, PE, post-
operative nausea and vomiting) 
 
Statistical analysis 
 
Categorical data will be summarized as N (%), continuous variables as mean ± standard 
deviation (SD) or median ± interquartile range (IQR), depending on the distribution of the 
data. Normality of the data will be assessed using the Kolmogorov-Smirnov test. 
Categorical data will be compared using chi-squared tests and continuous variables 
using ANOVA. Post-hoc testing using Holm-Sidak tests or Dunn’s tests will be performed 
if a difference exists among the 3 groups to assess pairwise differences. A p-value of < 
0.05 will be considered statistically significant.   
 
Since no effect size data exists in prior literature, no power calculation will be done. We 
estimate that 5-6 subjects per group will be sufficient to get an impression of differences to first 
neurological exam, since the aim of the study was to facilitate potential larger subsequent trials. 
 
G 
Risks and Benefits 
 
1 
Potential Risks to Subjects and How They Will Be Minimized 
 
 
 
All of the described anesthetic methods in the three study groups are commonly used in 


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practice and can be considered standard of care. Participation in this study therefore 
does not add any study-related risk to patients.  These drugs are currently being used to 
deliver general anesthesia to patients for this procedure.  This is not an off-label use of 
these drugs and these drugs are being given at acceptable dosages for general 
anesthesia. If for some unexpected and unforeseen reason the patient does not appear 
to tolerate the prescribed anesthetic regimen, the anesthesiologist will be allowed to 
modify the regimen as needed to keep the patient safe. The intention to treat principle 
will be used in the subsequent analysis. 
 
 
 
2 
Potential Benefits 
 
Patients may theoretically emerge faster and follow commands sooner in the study 
groups, but in the absence of prior data, this is unknown. Ruling out anesthetic causes of 
delayed normal neurological function may alert the surgical team sooner if there is a 
possibility of a stroke.  Faster recognition of a stroke will allow the surgical team to place 
the patient back under anesthesia for surgical re-exploration or send the patient to CT 
scan sooner.  This unique surgical population can benefit neurologically from a few 
minutes difference in recognition time.  Furthermore, this study will assess the general 
anesthetic type and the hemodynamic stability during CEA. 
 
 
3 
Risk:Benefit Ratio 
 
The aforementioned potential benefits outweigh the potential risks. There are no 
potential risks specific to the study procedures that are different from, or exceed, 
the risk of the surgery and the anesthesia, which are well-known and not related 
to the study procedures.  
 
 
H 
Plans for Monitoring Subject Safety 
 
 
 
Patients will undergo standard monitoring for general anesthesia which includes certified 
anesthesia providers, preoperative and postoperative nurses, and other trained surgical 
staff (surgical attending, fellow and resident) during the perioperative period.  Standard 
monitors will be applied including EKG, blood pressure (arterial line and NIBP), pulse 
oximetry, end-tidal CO2 monitoring and BIS monitoring. Any additional drugs or 
treatments not mentioned in this protocol but required to care for the patient will be given 
without restriction at the discretion of the anesthesiologist and surgeon.  
 
I 
Procedures to Maintain Privacy and Confidentiality  
 
Co-investigators will only use subject numbers on data sheets.  Identifying data will be 


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kept in a study patient shortlist in EPIC and a separate password-protected, encrypted 
Excel file maintained on the anesthesia drive on the Cooper network. The study folder 
with original consent forms and regulatory documents will be kept in a locked cabinet on 
4 Dorrance in the anesthesia research office.  
 
J 
References 
 
De Santis, F., et al. (2016). A Prospective Nonrandomized Study on Carotid Surgery Performed 
under General Anesthesia without Intraoperative Cerebral Monitoring. J Stroke Cerebrovasc Dis 
25(1): 136-143. 
 
Kobayashi, M., et al. (2011). Intentional hypertension during dissection of carotid arteries in 
endarterectomy prevents postoperative development of new cerebral ischemic lesions caused 
by intraoperative microemboli. Neurosurgery 69(2): 301-307. 
 
Sheth, K. & Nourollahzadeh, E. (2017). Neurologic complications of cardiac and vascular 
surgery. Handb Clin Neurol 141: 573-592. 
 
Vaniyapong, T., Chongruksut, W. & Rerkasem, K. (2013). Local versus general anesthesia for 
carotid endarterectomy. Cochrane Database of Systematic Reviews. 12: 1-3.