A Prospective Study Comparing Total Intravenous Anesthesia With Propofol and Remifentanil vs. Propofol and Dexmedetomidine in Adolescent Idiopathic Scoliosis Patients Undergoing Posterior Spinal Fusion and Instrumentation
Phase: PHASE2
Conditions: Adolescent Idiopathic Scoliosis, Multimodal Analgesia, Opioid Induced Hyperalgesia, Remifentanil, Dexmedetomidine, Posterior Spinal Fusion
Sponsor: Cedars-Sinai Medical Center

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A Prospective Study Comparing a Multimodal Anesthetic using Total 
Intravenous Anesthesia (TIVA) with Propofol and Remifentanil vs. Propofol and 
Dexmedetomidine in Adolescent Idiopathic Scoliosis Patients undergoing 
Posterior Spinal Fusion and Instrumentation 
Version Date: 08/23/2023 
Principal Investigator: Glenn Tan, M.D. 
Cedars-Sinai 
 
 
 
 
 
Sponsor/Funder 
Internal Cedars-Sinai funding. 
 
Collaborating 
Institutions and 
Researchers  
Not Applicable 
 
 
 
 

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Table of Contents  
 
1.0 Protocol Summary .............................................................................................................. 3 
2.0 Background, Rationale ....................................................................................................... 4 
3.0 Study Purpose and Objectives ........................................................................................... 7 
4.0 Study Population ................................................................................................................ 9 
Subject Identification, Recruitment, and Consent ......................................................... 10 
5.0 Study Design and Procedures .......................................................................................... 11 
5.1 Schedule of Events and Procedures ...................................................................... 11 
5.2 Study Design and Duration ..................................................................................... 13 
5.3 Description of Study Procedures ........................................................................ 1413 
6.0 Data Collection and Management .................................................................................... 15 
6.1 Data Procurement .................................................................................................. 15 
6.2 Time Period of Data under Review ......................................................................... 15 
6.3 Data Elements ........................................................................................................ 15 
7.0 Data and Safety Monitoring .............................................................................................. 16 
7.1 Data and Safety Monitoring Plan ............................................................................ 16 
7.2 Quality Control and Quality Assurance ................................................................... 17 
8.0 Sample Size and Statistical Considerations ..................................................................... 17 
8.1 Statistical Sample Size Justification ....................................................................... 17 
8.2 Statistical Analysis Methodologies ......................................................................... 17 
9.0 References ....................................................................................................................... 18 
 
 
 
 

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1.0 Protocol Summary  
 
Study Purpose 
• The purpose of the study is to compare two different total 
intravenous anesthesia (TIVA) techniques as part of a multimodal 
anesthetic in pediatric patients with adolescent idiopathic 
scoliosis undergoing posterior spinal fusion (PSF) and 
instrumentation for correction of their scoliosis. 
• TIVA group I is Propofol+ Remifentanil, and TIVA group II is 
Propofol + Dexmedetomidine (DEX). 
• The primary outcome to be studied is postoperative opioid 
consumption for pain control measured in morphine milligram 
equivalents (MME). 
• The secondary outcomes are time from skin closure to patient 
being able to move their feet to command, time from skin 
closure to extubation, and postoperative visual analog (VAS) pain 
scores. 
Research Procedures 
 
The primary research procedures are: 
• Medical record review 
• Recruitment of study subjects 
• Screening of subjects to ensure subjects meet all inclusion 
criteria and have no exclusion criteria. 
• Randomization of patients into the two study groups 
• Data collection intraoperatively 
• Data collection postoperatively in the EMR  
Subject Population 
• The study will enroll randomized patients with the following 
inclusion criteria: 
• Age 12-21 years old 
• ASA 1 and 2 
• Have diagnosis of AIS 
• Undergoing PSF with instrumentation for scoliosis 
correction 
• Matched on age, sex, and the number of vertebral levels 
fused 
Duration of Subject’s 
Participation 
• The duration of subject’s participation is the length of their 
hospitalization for the surgery (2-3 days).  

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2.0 Background, Rationale  
 
Our institution is a major pediatric spine center performing posterior spinal fusion 
and instrumentation for the correction of Adolescent Idiopathic Scoliosis (AIS). AIS 
patients are usually in their teens and are healthy, without other medical 
problems. They generally do not have significant chronic pain and are opioid-
naïve. Scoliosis surgery is painful, so these patients receive a multimodal analgesia 
regimen as a standard of care (1,2). Our intraoperative regimen uses intrathecal 
(IT) morphine (3-7) given pre-incision, IV ketamine at induction, and IV 
acetaminophen at conclusion of case. Postoperatively, patients receive Morphine 
or Hydromorphone PCA which is quickly transitioned to PO Opioids and NSAIDs. 
The most common intraoperative anesthetic technique for pediatric scoliosis 
surgery at our institution is total intravenous anesthesia (TIVA) with Propofol and 
Remifentanil. TIVA avoids the use of inhalational anesthetic gases and so does not 
interfere with intraoperative neurophysiological monitoring such as SSEP and 
MEP. Remifentanil is a popular choice because of its rapid onset, small volume of 
distribution (Vd), rapid clearance, and brief half-time (1.0-1.5 min) for 
equilibration between plasma and the effect compartment. Remifentanil’s unique 
hallmarks are its extremely short context-sensitive half-life (3-5 min), its potency 
(100-200 times more potent than Morphine), and its rapid recovery from drug 
effect. Remifentanil’s ultra-short-acting duration is independent of dose, allowing 
rapid offset after continuous infusion (8-11). Thus, in the event of intraoperative 
loss of neurophysiological signals, remifentanil can be turned off to allow for a 
quick wake up test to be performed.  
 
However, an important concern with intraoperative remifentanil infusion is the 
possible development of acute opioid tolerance or hyperalgesia. In adults, opioid-
induced hyperalgesia (OIH) is a well-documented feature linked to intraoperative 
remifentanil administration, manifesting as increased postoperative analgesic 
requirement and paradoxical increase in sensitivity to painful stimuli (12-18). In 
pediatric patients, the phenomenon is not as well characterized. In one study, a 
continuous intraoperative infusion of remifentanil, when compared with 
intermittent morphine boluses, significantly increased postoperative morphine 
consumption in adolescents undergoing scoliosis surgery (16). The use of 

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intraoperative remifentanil infusion was shown to increase cumulative 
postoperative morphine requirements by 30% in the first 24 hours compared to 
patients not receiving intraoperative remifentanil (16). These findings support the 
hypothesis that intraoperative remifentanil infusion is associated with the 
development of clinically relevant acute opioid tolerance or hyperalgesia as seen 
in adult studies. However, in another study, no association was found between 
the dose of intraoperative remifentanil and postoperative opioid consumption in 
the context of a propofol-based TIVA and multimodal analgesia (19). 
 
An alternative TIVA that is very commonly used for adult spine surgery at our 
institution is propofol + dexmedetomidine (DEX). Notably, pediatric patients 
undergoing scoliosis correction surgery have also safely received propofol + DEX 
TIVA at our institution. DEX is a highly selective alpha2-adrenergic receptor 
agonist with sedative, analgesic and sympatholytic properties. Its sedative effects 
are dose-dependent. The locus ceruleus of the brain stem is the principal site for 
its sedative action, and the spinal cord is the principal site for its analgesic action, 
both acting through alpha2-adrenergic receptors. Side effects are mainly 
hypertension, hypotension and bradycardia as a result of vasoconstriction, 
sympatholysis, and baroreflex-mediated parasympathetic activation (20, 21). A 
meta-analysis of randomized placebo-controlled trials testing systemic alpha2 
agonists like clonidine or dexmedetomidine administered in surgical patients 
showed that perioperative systemic alpha2 agonists decreased postoperative 
opioid consumption, pain intensity, and nausea, and did not prolong recovery 
time (22). 
 
Despite the lack of FDA approval for pediatric use, DEX is widely used off-label in 
pediatric patients and has previously been shown to be safe and efficacious for 
various clinical indications including procedural sedation, craniotomy-awake-
surgery, cardiac surgery, and posterior spinal fusion for scoliosis (23-30). A meta-
analysis of 11 randomized controlled pediatric trials revealed a lower risk for 
postoperative pain and the need for postoperative opioids following 
intraoperative DEX in comparison with placebos or opioids in children undergoing 
surgery; however, the influence of DEX on postoperative opioid consumption was 

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less clear (31). The most common adverse event in patients treated with DEX was 
intraoperative bradycardia (32). DEX does not affect intraoperative 
neurophysiologic monitoring (33,34). The use of DEX has been shown to not affect 
the intraoperative wake up time in patients undergoing spine surgery (35-38).  
 
Are there studies comparing remifentanil to DEX? A recent meta-analysis of 21 
randomized trials comparing intra-operative analgesia with remifentanil and DEX 
demonstrated that intra-operative DEX for general anesthesia was superior to 
remifentanil administration, with lower pain scores during the first 24 hours and 
with less hypotension, shivering, and postoperative nausea and vomiting (39). 
However, time to extubation and length of stay in the recovery room were 
significantly longer in the DEX group by a mean difference (95% CI) of 4.9 min 
(0.8-9.1), I² = 99%, p=0.02, and 8.9 min (4.4-13.4), I² = 97%, p<0.0001, 
respectively. Though statistically significant, the authors viewed the differences as 
clinically negligible. Of note, most of the operations in this meta-analysis were 
laparoscopic surgery and ENT surgery.  
 
There is a paucity of studies comparing TIVA with propofol + remifentanil and 
propofol + DEX in spine patients. In one study of adult patients having posterior 
lumbar interbody fusion (PLIF) surgery under propofol-based TIVA, DEX was 
demonstrated to lower the VAS pain score and reduce PCA requirement 
compared to remifentanil for the first 48 hours (40).  
 
Our study proposes to compare these two TIVAs in the setting of pediatric AIS 
patients having posterior spinal fusion and instrumentation to see if the use of 
DEX instead of remifentanil will result in less hyperalgesia, lower opioid 
consumption, and lower VAS pain scores in the post-operative period. We also 
hope to demonstrate that the use of DEX will not significantly prolong extubation 
time when used appropriately. 
 

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In an age where ERAS protocols seek to improve post-operative pain control, 
decrease opioid consumption, and achieve quick discharge home after posterior 
spinal fusion for pediatric scoliosis patients, we believe our study could have a 
positive societal impact. 
3.0 Study Purpose and Objectives  
 
The proposed study is a prospective, randomized comparison of propofol + 
remifentanil TIVA vs. propofol + DEX TIVA on postoperative opioid requirements 
and pain in AIS patients undergoing PSF and instrumentation for scoliosis 
correction. All other perioperative anesthetic management, including post-
anesthesia care and pain management, are standardized.  
Two intervention groups will include: 
1. Propofol + Remifentanil group: Maintenance TIVA will be started after 
induction using propofol at standard doses (100-200 mcg/kg/min) and 
remifentanil (0.2-0.5 mcg/kg/min); TIVA is titrated to keep BIS < 55-60 to 
ensure patient is asleep. 
2. Propofol + Dexmedetomidine group: Maintenance TIVA will be started after 
induction using propofol at standard doses (100-200 mcg/kg/min) and DEX 
(02-0.7 mcg/kg/hr); TIVA is titrated to beep BIS < 55-60 to ensure patient is 
asleep. 
 
The following persons are blinded: 
a. Surgeon 
b. PICU staff (attending MD, NP, RN) 
c. Patient and family 
The following persons are unblinded: 
a. Patient’s anesthesiologist 
b. This same anesthesiologist will accurately record the time from skin closure 
to patient moving feet to command, and the time from skin closure to 
extubation. (Note: the anesthesia spine team comprises a small core group 

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of pediatric anesthesiologists who work exclusively with the spine surgeons  
and will be trained on the accurate collection of these data.) 
c. Investigator accessing EMS to collect the following patient data: 
i. 
MME 
ii. 
VAS Pain scores 
 
 
Summary of Perioperative Multimodal Analgesia 
Propofol + Remifentanil Group 
Propofol + DEX Group 
At Induction 
 
Ketamine 1 mg/kg (max 50 mg) at induction 
 
Same 
 
 
TIVA to maintain BIS < 55-60 
 
Remifentanil + Propofol  
(remifentanil dose 0.2-0.5mcg/kg/min) 
 
Dexmedetomidine + Propofol 
(DEX dose  0.2-0.7 mcg/kg/hr) 
Pre-Incision 
 
Intra-thecal (IT) Morphine pre-incision 4 – 5 
mcg/kg (max 250 mcg) 
 
Same 
Conclusion of Case 
 
IV Acetaminophen 15 mg/kg (max 1000 mg) 
 
Same 
Post-op (Peds ICU) 
 
Per multimodal analgesia Protocol 
Same 
 
 
 
The primary outcome to be measured is the total opioid consumption (IV and PO 
in MME) on POD 0 and 1 because this is when our patients experience the most 
acute postoperative pain.  By POD 2, most of our patients are discharged home. 
The secondary outcomes to be measured are time from skin closure to patient 
being able to move their feet to command (mins), time from skin closure to 
extubation (mins), average VAS pain scores on POD 0,1 and 2, and total MME on 
POD 0,1 and 2. Skin closure is defined as when the last stich is placed by the 
surgeon thus concluding the surgery. POD 0 = first 24 hours after surgery, POD 2 = 
48 hours after surgery, POD 3 = 72 hours after surgery. 

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Primary Outcome 
 
Opioid Consumption on POD 0 and 1 
 
MME 
Secondary Outcomes 
 
Time from skin closure to patient 
being able to move their feet to 
command 
Time from skin closure to extubation  
Average VAS Pain scores on days 0,1 
and 2 
Opioid consumption on POD 0,1 and 2 
Mins 
 
 
Mins 
Numerical rating scale 
 
MME 
 
 
 
Patients will be sent directly from the OR to the pediatric ICU for their post-
operative recovery. They will be continued on a multi-modal analgesia regimen 
including opioid PCA and oral opioids as needed (PRN) based on the Visual Analog 
Scale (VAS) pain scores.  
4.0 Study Population  
 
The study population will be randomly drawn from AIS patients of spine surgeons 
Dr David Skaggs and Dr Kenneth Illingworth undergoing PSF and instrumentation 
for scoliosis correction. 
Enrollment numbers: A total of 120 patients randomly assigned to one of two 
study groups.  
 
TIVA Group I 
Propofol + Remifentanil TIVA (n=60) 
TIVA Group II 
Propofol + Dexmedetomidine (n=60) 
 
a. Inclusion criteria include: 
i. Age 12-21 years old 

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ii. ASA 1 and 2 
iii. Have diagnosis of adolescent idiopathic scoliosis 
iv. Undergoing posterior spinal fusion with instrumentation for 
scoliosis correction 
v. Matched on age, sex, and the number of vertebral levels fused. 
 
b. Exclusion criteria include: 
i. Neuromuscular scoliosis 
ii. Allergy to any of the multi-modal analgesia regimen drugs 
iii. Use of serotonergic drugs, MAOIs, mixed agonist/antagonist 
opioid analgesics 
 
c. Withdrawal criteria include: 
i. Intraoperative loss of motor evoked potentials necessitating a 
wake up test to monitor for neurological deficits 
ii. Allergic reaction to any medications administered during the 
surgery. 
 
Subject Identification, Recruitment, and Consent 
 
I. 
Subject Identification and Recruitment 
a. Medical records of upcoming preoperative visits at APEC will be 
reviewed for the purposes of recruitment. 
d. At APEC, Eligible patients and parents will be provided introductory 
study material packet by APEC staff. The study material packet 
contains a study recruitment letter, an informed consent form, and a 
child assent form. There is no need to explain the study at this stage, 
but the intent is for parents and potential subjects to be able to read 
the information in the comfort of their home in an unrushed manner. 
Parents will be told that a study investigator will call them to tell 
them about the study and give them an opportunity to participate.  
e. If patients are seen virtually at APEC, staff will provide parents of 
potential subjects with introductory study material packet via email 
or via mail, and a study investigator will call them about the study. 
f. A study investigator will call these patients and their parents after 
their APEC appointment and before the surgery to explain the study 

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protocol including the potential risks, benefits, and alternatives, and 
address any questions/concerns.  
 
II. 
Day of Surgery 
a. Preoperative evaluation by the Anesthesiologist 
i. In the preoperative holding area, patients and their parents 
will provide a detailed medical history, demographic 
information, anesthetic complications such as postoperative 
nausea and vomiting, baseline VAS pain scores, and current 
pain medication regimen.  
b. Consenting performed by the Anesthesiologist 
i. Only patients indicating that they have been introduced to the 
study prior to meeting with the anesthesiologists on the day of 
surgery will be able to participate, undergo screening, and be 
consented. 
ii. Screening will ensure subjects meet all inclusive criteria. 
After consents have been signed, patients will be randomized to one of two 
study groups according to a computer-generated randomization number 
table.  
5.0 Study Design and Procedures 
5.1 Schedule of Events and Procedures 
 
Legend  
• R = Research item/procedure done only for research purposes and their costs are 
covered by the study.  
• S = Standard of care item/procedure that is part of regular care and billed to the 
patient/insurance. 
• sBNA = item/procedure is not billable separately. It is a bundled service. 
 
 
Procedures 
Recruitment  
 
Treatment 
 
Follow 
Up 
Follow 
Up 
Follow 
Up 
 
3-15 days 
before 
Surgery 
Day of 
Surgery 
POD #1 
POD 
#2 
POD 
#3 

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Introductory Study material packet  R 
 
 
 
 
Written Parental Consent 
 
R 
 
 
 
Randomization 
 
R 
 
 
 
Inclusion/Exclusion criteria 
 
R 
 
 
 
Complete Medical History 
 
S(BNA) 
 
 
 
Demographics 
 
S(BNA) 
 
 
 
Weight 
 
S(BNA) 
 
 
 
BMI 
 
S(BNA) 
 
 
 
Preoperative Cobb Angle 
 
R 
 
 
 
Number of levels fused 
 
R 
 
 
 
Number of osteotomies 
 
R 
 
 
 
Anesthetic complications 
 
R 
 
 
 
Visual Analog Pain Scores (VAS) 
 
R 
R 
R 
R 
Current pain medication regimen 
 
R 
 
 
 
Physical Exam 
 
S 
 
 
 
Dexmedetomidine/Remifentanil 
dispensing IV 
 
S 
 
 
 
Dexmedetomidine/Remifentanil 
administration IV 
 
S 
 
 
 
Propofol dispensing IV 
 
S 
 
 
 
Propofol administration IV 
 
S 
 
 
 
Midazolam IV 
 
S 
 
 
 
3-lead EKG 
 
S(BNA) 
 
 
 
 
 
 
 
 
 
NIBP 
 
S(BNA) 
 
 
 
Pulse Oximeter 
 
S(BNA) 
 
 
 
EtCO2 capnography 
 
S(BNA) 
 
 
 
Urinary Temp 
 
S(BNA) 
 
 
 
Bispectral index (BIS) monitor 
 
S(BNA) 
 
 
 
Radial Arterial 
 
S 
 
 
 
Scoliosis Correction Surgery 
 
S 
 
 
 
Ketamine IV 
 
S 
 
 
 
Morphine IT 
 
S 
 
 
 
Acetaminophen IV 
 
S 
 
 
 
Rocuronium IV 
 
S 
 
 
 
Dexamethasone IV 
 
S 
 
 
 
Cefazolin 
 
S 
 
 
 
Gentamycin 
 
S 
 
 
 
Tranexamic acid (TXA) 
 
S 
 
 
 
Deliberate hypotensive anesthesia 
(using nitroglycerin) 
 
S 
 
 
 
Vasopressor (using phenylephrine)  
S 
 
 
 

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Glycopyrrolate IV 
 
S 
 
 
 
Atropine IV 
 
S 
 
 
 
Ephedrine IV 
 
S 
 
 
 
Fentanyl IV 
 
S 
 
 
 
Diazepam IV 
 
S 
 
 
 
Ketorolac 
 IV 
 
S 
S 
S 
 
Patient controlled analgesia (PCA) 
 
 
S(BNA) 
 
 
Oxycodone PO 
 
 
S 
S 
S 
Diazepam PO 
 
 
S 
S 
S 
Acetaminophen PO 
 
S 
S 
S 
S 
Ibuprofen PO 
 
 
 
 
S 
Type of Narcotic given on 
transport to PICU (Fentanyl IV, 
Morphine IV, Dilaudid IV. If 
applicable) 
 
S 
 
 
 
Dose of Narcotic given on 
transport to PICU (As clinically 
applicable) 
 
S 
 
 
 
Type of PCA Medication (Dilaudid 
IV PCA, if applicable) 
 
S 
S 
S 
 
Total dose of PCA Medication (As 
clinically indicated) 
 
S 
S 
S 
 
Type of PO Narcotic (Oxycodone 
PO) 
 
R 
S 
S 
 
Dose of PO Narcotic (As clinically 
indicated) 
 
S 
S 
S 
 
Type of IV rescue narcotic 
(Morphine IV, Diaudid IV, if 
applicable) 
 
S 
S 
S 
 
Dose of IV rescue narcotic (As 
clinically indicated) 
 
S 
S 
S 
 
Total MME 
 
R 
R 
R 
 
Time from skin closure to moving 
feet on command 
 
R 
 
 
 
Time from skin closure to 
Extubation 
 
R 
 
 
 
 
5.2 Study Design and Duration 
 
The total study duration for the subject’s participation is the length of their hospital stay at 
Cedars-Sinai Medical Center (2-3 days).  
 

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5.3 Description of Study Procedures 
The study involves the study procedures listed below. The timepoints of the procedures are 
outlined in the previous section 5.1 Schedule of Events. 
 
Study Procedures 
Description 
Introductory Study Material 
Packet 
Parents of potential study subjects will be handed the 
introductory study material packet during their child’s 
preoperative visit at APEC, or mailed if preoperative visit 
was virtual. Parents are informed that a study 
investigator will call them to tell them about the study 
and give them an opportunity to participate. 
Written Parental Consent 
The anesthesiologist will answer any outstanding 
questions and address any concerns subjects and their 
parents may have about the study in the preoperative 
area on day of surgery. Written parental consent is 
obtained at this time.  
Randomization 
After consents have been signed, patients will be 
randomized to one of two study groups according to a 
computer-generated randomization number table. The 
anesthesiologist will open the sealed envelope containing 
the subject’s randomized group assignment, and 
instructions for drawing up the study drugs. From this 
information, the anesthesiologist will prepare the study 
TIVA medications. Both remifentanil and DEX are within 
the standard of care and routinely used in anesthetic 
care at our institution. Remifentanil is obtained by the 
anesthesiologist ordering the medication from the 
pharmacy, and DEX is obtained by the anesthesiologist 
from the core Pyxis. 
Monitors  
Standard ASA monitors include 3-lead ECG, non-invasive 
BP, pulse oximetry, end-tidal CO2 capnography, 
temperature. In addition, bispectral index (BIS) and radial 
arterial BP are routinely used for all spine cases. 
Multimodal Analgesia 
Multimodal analgesia is used intraoperatively and 
postoperatively as standard of care to help improve pain 
management. It prescribes the use of more than one 
pharmacological class of analgesia medication targeting 
different receptors along the pain pathway with the goal 
of improving pain management while reducing individual 
drug-related side effects. Medications used are listed in 
previous section 5.1. 
Data Collection and Management See section 6 below 
 

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5.4 Medical Record/Clinical Record Review:  
This study involves an electronic medical record review. Data will be abstracted from the 
electronic medical record perioperatively and within 3 months of surgery. The data points to be 
abstracted are outlined in Section 6 of the protocol.  
 
6.0 Data Collection and Management 
6.1 Data Procurement 
• Identification/Access/Abstraction 
☒ Members of the study team will require access to the electronic medical record 
(clinical data source) to identify eligible data and to conduct data abstraction. 
 
• Source(s) of Data: 
The source of the data to be analyzed is the electronic medical record which includes 
pertinent medical information, demographics, anesthesia record, operative note, 
flowsheets for postoperative opioid use, and visual analog scale (VAS) pain scores. 
 
6.2 Time Period of Data under Review  
• Data will be collected from/at the following timepoints: Perioperatively, Day of Surgery 
(DOS), 1-week to 3 month postoperative.  
• Information will be kept indefinitely. 
6.3 Data Elements  
• Age 
• Sex 
• Weight 
• Body Mass Index (BMI) 
• Preoperative Cobb Angle 
• Current pain medication regimen 
• Number of levels fused 
• Number of osteotomies 
• Anesthetic complications 
• Postoperative opioid MME (DOS, POD#1, POD#2, POD#3) 
o PCA opioids IV 
o Rescue opioids IV 
o PO opioids 
• Visual analog scale (VAS) pain scores (DOS, POD#1, POD#2, POD#3) 

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• Time from skin closure to moving feet on command 
• Time from skin closure to extubation 
 
 
6.4 Confidentiality 
 
HIPAA Identifiers 
 
Name 
Medical Record Number 
Age in years 
Date of Surgery 
 
Confidentiality will be maintained in the following manner: 
• Secure Storage: Data will be housed in a HIPAA-compliant secure storage system, like 
Box, within the Cedars-Sinai network with access restricted to approved members of the 
research team.  
• 
Limited Access: Private identifiable information will be accessible only to IRB approved 
study team members with current IRB training. 
• 
Unique ID Numbers and Coding: Each patient will be assigned a unique ID number. The 
linking list will be kept secure. Direct identifiers listed in section 8 will be separated from 
the study materials (data and/or specimens) as soon as possible. During data 
abstraction, name and/or MRN are required for data verification purposes. After data 
abstraction is complete and data have been verified, the name will be removed (if 
collected). Only the MRN will be used to link the study ID/code to the individual after 
that point until the linking list is destroyed. 
• 
Destroying Identifiers: The identifiers and the linking list will be destroyed as soon as 
scientifically possible and maintained only as long as necessary to abstract, analyze and 
verify data. 
• 
Storage of Physical Records: Physical records will be maintained for this study at a 
secure location where access is limited to approved personnel. The records will not be 
removed from Cedars-Sinai premises. 
7.0 Data and Safety Monitoring  
7.1 Data and Safety Monitoring Plan 
The study will be monitored by the PI to ensure appropriate study conduct, including obtaining 
proper access to data/specimens, compliance with the HIPAA Privacy Rule, compliance with 
Cedars-Sinai policy, and adhering to the plans outlined in the protocol for all study procedures, 

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abstracting and recording data, data and/or specimen security and maintenance, and data 
accuracy and integrity. Any adverse events, deviations, protocol exception requests, potential 
unanticipated problems involving risks to subjects or others, or other events will be submitted 
to the IRB in accordance with IRB reporting policy. All study procedures will be conducted in 
accordance with standard clinical practice.] 
 
7.2 Quality Control and Quality Assurance 
• The PI will delegate a study team member to conduct QC/QA activities on a quarterly 
basis who will be responsible for the evaluation of data quality. Data will be evaluated 
for adherence with the protocol and for accuracy in relation to source documents.  
8.0 Sample Size and Statistical Considerations 
8.1 Statistical Sample Size Justification  
The main hypothesis to be tested is whether the primary outcome of Mean Total MME for POD 0 and 
POD 1 is different between the Propofol + Remifentanil group and the Propofol + DEX group.  For sample 
size, we performed a pilot study of 15 AIS patients who underwent PSF with instrumentation by our 
study surgeons at our institution using Propofol + Remifentanil TIVA in the last two years. We performed 
a power analysis with the following assumptions: Power of 80%, estimated SD of 33.3, and level of 
significance (alpha) of 0.05. We considered a difference of 17.2 as an important Group Difference in 
Mean Total MME for POD0 and POD1. The sample size necessary after the power analysis was 60 per 
group using a two-sided two sample t-test.  
8.2 Statistical Analysis Methodologies 
The primary outcome variable (total MME) will be summarized using mean and SD and using 
median and IQR (interquartile range). Differences between the two groups at each time point 
will be analyzed by t test or Wilcoxon rank sum test. The normality assumption will be verified 
by the Shapiro-Francia test[ref] and homogeneity of variance by the Levene test[ref].  
 
The secondary outcome variables are VAS pain score (scale of 1-10), time from skin closure to 
moving feet to command, time from skin closure to extubation, and total MME for POD 0, 1 and 
2. VAS pain score is an ordinal variable that generally is treated as a continuous variable in 
analysis. We considered an important difference in a pain scale of 1-10 to be 2 units, VAS will 
be compared between groups on POD 0, 1 and 2 using t test and/or Wilcoxon tests. Time from 
skin closure to moving feet to command and time from skin closure to extubation will be 
compared between groups on POD 0, 1 and 2 using t test and Wilcoxon rank sum test.  
 
A spaghetti plot will be presented for MME across all time points (POD0,1,2). We will then 
perform multivariable generalized linear mixed effects regression for the continuous MME 
outcome with treatment group, time point, and the interaction between treatment group and 
time point as fixed effects. In addition, relevant demographic and baseline variables will be 
considered as candidate covariates. Adequacy of assumptions will be assessed by the analysis 

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and visualization of residuals. All tests of hypotheses will be two-sided with a significance level 
of 5%. All calculations will be performed using R, version 4.3.0. 
 
9.0 References 
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