Clinical trial NCT03263117
Conditions: Stroke
Keywords: Acute stroke Cerebral Stroke
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2018-07-01; Completion date: 2023-04-22
Enrollment: 260 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Objectives:

This study aims to estimate overall treatment benefit (improvement in disability) among acute ischemic stroke patients that are randomized to General Anesthesia (GA) compared with Sedation (CS) during endovascular therapy. Assess safety (as measured by incidence of symptomatic intracranial hemorrhage); rates of Endovascular therapy (EVT) procedural complications, reperfusion; and quality of life.

Hypothesis:

GA during EVT for acute ischemic stroke improves functional outcomes at 90 days compared to sedation.

Detailed description:

Arms: arm 1: The protocol does not specify a particular combination of drugs that must be used for sedation. The choice of specific drugs and dosages for achieving sedation will be up to the anesthesiologist. arm 2: The protocol does not specify a particular combination of drugs that must be used for general anesthesia. The choice of specific drugs and dosages for achieving general anesthesia will be up to the anesthesiologist.
Interventions: intervention 1: Sedation intervention 2: General Anesthesia (GA) intervention 3: Intra-arterial Thrombectomy
Intervention descriptions: intervention 1: The protocol does not specify a particular combination of drugs that must be used for sedation.

The most common drugs utilized for sedation and wide dosing ranges are included in the protocol (i.e., sedation will be provided under the supervision of an anesthesiologist and may use a combination of fentanyl, midazolam, dexmedetomidine infusion (with or without loading dose), and/or low-dose propofol by intermittent bolus or infusion); however, the choice of specific drugs and dosages for achieving conscious sedation or general anesthesia will not be specified by the protocol but will be up to the anesthesiologist. intervention 2: The protocol doesn't specify drugs that must be used for GA, the choice of drugs and dosages for achieving general anesthesia will not be specified by the protocol but will be up to the anesthesiologist.

The most common drugs utilized for GA and wide dosing ranges included in the protocol are (GA will be provided under the supervision of an anesthesiologist and induction of anesthesia may be achieved with propofol and/or etomidate; muscle paralysis may be achieved with succinylcholine or non-depolarizing paralytic (rocuronium or vecuronium); and adjuvant lidocaine and fentanyl; if intravenous maintenance of anesthesia is used, it may be achieved by propofol infusion at 50 to 150 mcg/kg/min with redosing of non-depolarizing paralytic and fentanyl as needed; if inhalational maintenance of anesthesia is used it will be achieved with sevoflurane 1% to 2% or desflurane 3% to 6% end-tidal concentration with redosing of non-depolarizing paralytic and fentanyl as needed) intervention 3: The first line therapeutic embolectomy device should be a stent retriever. Additional Endovascular therapies including, but not limited to, intra- or extracranial angioplasty ± stenting; antithrombotics (oral, IV or IA antiplatelets or anticoagulants) intra-arterial thrombolytics; are left to the decision of the local treatment team.

Protocol documents:
Prot_SAP_000.pdf: 
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SEGA - SEdation versus General Anesthesia for Endovascular Therapy in Acute Ischemic Stroke 
– a Randomized Comparative Effectiveness Trial. 
 
NCT03263117 
 
Version Date: 02/03/2021 
 
 


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SEGA CLINICAL TRIAL PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17-0436 
PROTOCOL 
NUMBER 
HSC-MS-17-0436 
PROTOCOL TITLE 
SEGA - SEdation versus General Anesthesia for Endovascular Therapy in Acute 
Ischemic Stroke – a Randomized Comparative Effectiveness Trial. 
VERSION / DATE 
1.8 January 8, 2021 
AMENDMENTS / 
DATE 
- / - 
SPONSOR 
McGovern Medical School at The University of Texas Health Science Center at 
Houston (UTHealth), Department of Neurosurgery (Weatherhead Foundation) 
STUDY CHAIR 
STUDY Co-CHAIR 
Peng Roc Chen, MD 
Associate Professor 
Department of Neurosurgery 
McGovern Medical School at UTHealth 
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Andrew Barreto, MD MS 
Associate Professor 
Department of Neurology 
McGovern Medical School at UTHealth | | | | | | 
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STUDY Co-CHAIR 
UTH SITE PI 
STEERING 
COMMITTEE 
Carlos A. Artime, MD 
Associate Professor 
Department of Anesthesiology 
McGovern Medical School at UTHealth 
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Sunil A. Sheth, MD 
Assistant Professor 
Department of Neurology 
McGovern Medical School at UTHealth | | | | | | 
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STATISTICIAN 
COMMITTEE MEMBER 
Claudia Pedroza, PhD 
Associate Professor 
Center for Clinical Research and Evidence- 
Based Medicine, McGovern Medical School 
at UT Health 
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Sean I. Savitz, MD 
Professor 
Department of Neurology 
McGovern Medical School at UTHealth 
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IRB NUMBER: HSC-MS


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PROTOCOL SYNOPSIS 
 
Title 
SEGA: Sedation versus General Anesthesia for Endovascular Therapy in Acute Ischemic 
Stroke – a Randomized Comparative Effectiveness Trial. 
Study Purpose 
Background: Endovascular therapy (EVT) with stent retrievers improve functional outcome 
in acute stroke patients. Although both are routinely performed as usual care during EVT, 
controversy remains regarding the optimal type of anesthesia during EVT – general anesthesia 
(GA) vs. sedation (CS). Retrospective case-control studies found an association between better 
clinical outcomes with the latter. However, one small, single-center randomized trial 
suggested no significant differences in early outcomes. 
Primary Objective: To estimate overall treatment benefit (improvement in disability) among 
acute ischemic stroke patients that are randomized to GA compared with CS during 
endovascular therapy. 
Secondary Objectives: Assess safety (as measured by incidence of symptomatic intracranial 
hemorrhage); rates of EVT procedural complications, reperfusion; and quality of life. 
Design 
Multicenter, randomized, comparative effectiveness trial with un-blinded caregivers but 
blinded assessors (PROBE – Prospective Randomized Outcome Blinded Endpoint). 
Study Population 
Overview 
260 total acute ischemic stroke patients with proximal intracranial arterial occlusions treated 
with endovascular therapy within 16 hours of symptom onset. Patients must not require 
intubation for any clinical indication. Arterial occlusion must be demonstrated by either CT- 
angiogram (CTA) or MR-angiogram (MRA). 
Intervention 
Time of randomization is study time=0. Patients will be randomized 1:1 to receive during 
endovascular therapy either: 
1) General anesthesia (balanced for equal randomization into intravenous vs. inhalational) 
or 
2) Sedation 
Both GA and CS delivered and managed by anesthesiologist. 
Primary Outcome 
Independent functional outcome as measured by the modified ordinal Rankin Scale (mRS) at 
90 days assessed by study personnel blinded to treatment. 
Secondary 
Outcomes 
1) Dichotomized mRS at 90 days (0-2 vs 3-6) 
2) Safety as measured by rates of symptomatic intracerebral hemorrhage within 24-36 hours 
after endovascular therapy. 
3) Angiographic reperfusion defined as modified TICI score ≥ 2b. 
4) Peri-procedural complications. 
5) Difference in 24-36-hour NIHSS scale. 
6) Proportion of independent functional outcome at 90 days in GA patients treated with 
inhalational vs. intravenous medications. 
7) Difference in quality of life at 90-days. 
IRB NUMBER: HSC-MS-17-043


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Study Duration 
Total trial duration: 24 ± 4 months 
a. Enrollment – approximately 18 months with 6 months of data-monitoring and statistical 
analysis 
b. Patient participation - 90 days 
Statistics 
• Planned number of sites (US + international): 10-15. 
• Sample size: 260 patients randomized 1:1 (130 per group). 
• Final analysis uses a Bayesian approach to obtain odds ratio (OR) of good functional 
outcome at 90-days. Bayesian prior assumes treatment equipoise and uses a neutral, 
informative prior (OR=1.0; 95% credible intervals of 0.3-3.0). 
• Trial success is defined as a >80% posterior probability that GA is superior (OR >1.0 of 90- 
day mRS) to CS. 
Assessments 
• Baseline: History & physical exam; vital signs; laboratory tests; non-contrast CT head, 
arterial vessel imaging – CTA or MRA, NIHSS, pre-stroke mRS, home medications. 
• Endovascular Procedure: Continuous vital signs (Blood pressure, pulse, oxygen 
saturation, PETCO2 in general anesthesia [GA] patients);anesthesia medications; monitor 
for device-specific malfunction and serious adverse events; cross-over (e.g., CS to GA). 
• 24-36 hours post EVT: Non-contrast head CT or MRI brain as per local usual care; 
NIHSS 
• 7-days or discharge (whichever occurs first): Vital signs, physical examination, mRS, 
NIHSS, Blinded assessment of mRS and NIHSS; Stroke etiology. 
• 90 ± 15 days: Blinded assessment of mRS and Quality of Life; Stroke etiology. 
Significance 
Data generated will inform the optimal anesthesia management of EVT-treated ischemic 
stroke patients and would be expected to result in significant change of medical practice. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-17-0436 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................................................. 5 
1.0 BACKGROUND AND RATIONALE .............................................................................................................................................. 7 
1.1 RETROSPECTIVE STUDIES OF ANESTHESIA DURING ENDOVASCULAR THERAPY .................................................................................................. 7 
1.2 RANDOMIZED TRIALS OF CONSCIOUS SEDATION VS. GENERAL ANESTHESIA DURING ENDOVASCULAR THERAPY .................................... 7 
2.0 STUDY OBJECTIVES .................................................................................................................................................................... 10 
2.1 PRIMARY OBJECTIVE ............................................................................................................................................................................................................. 10 
2.2 SECONDARY OBJECTIVES ..................................................................................................................................................................................................... 10 
3.0 STUDY ENDPOINTS ...................................................................................................................................................................... 10 
3.1 PRIMARY ENDPOINT ............................................................................................................................................................................................................... 10 
3.2 SECONDARY CLINICAL ENDPOINTS ................................................................................................................................................................................... 10 
3.3 SECONDARY SAFETY ENDPOINTS ...................................................................................................................................................................................... 10 
3.4 EXPLORATORY ANALYSES ................................................................................................................................................................................................... 11 
4.0 STUDY DESIGN .............................................................................................................................................................................. 11 
4.1 OVERVIEW ................................................................................................................................................................................................................................. 11 
4.2 ENROLLMENT AND RANDOMIZATION ............................................................................................................................................................................... 11 
5.0 STUDY POPULATION .................................................................................................................................................................. 12 
5.1 INCLUSION CRITERIA ............................................................................................................................................................................................................. 12 
5.2 EXCLUSION CRITERIA ............................................................................................................................................................................................................ 12 
5.3 CROSSOVER CRITERIA ........................................................................................................................................................................................................... 13 
5.4 NPO STATUS ................................................................................................................................................................................................. 18 
6.0 STUDY PROCEDURES.................................................................................................................................................................. 14 
6.1 INFORMED CONSENT .............................................................................................................................................................................................................. 14 
6.2 TREATMENT PERIOD .............................................................................................................................................................................................................. 15 
6.2.1 Endovascular Procedure and Time Metrics ........................................................................................................................... 15 
6.2.2 Angiographic measures of arterial perfusion and collaterals ................................................................................................ 16 
6.3 90-DAY (± 15 DAYS) FOLLOW-UP....................................................................................................................................................................................... 17 
7.0 ANESTHETIC PROTOCOL .......................................................................................................................................................... 16 
7.1 SEDATION .................................................................................................................................................................................................................................. 16 
7.2 GENERAL ANESTHESIA .......................................................................................................................................................................................................... 18 
7.3 BLOOD PRESSURE MANAGEMENT ....................................................................................................................................................................................... 18 
7.4 ANESTHESIA MONITORING ................................................................................................................................................................................................... 18 
7.5 ANESTHETIC DATA COLLECTION ............................................................................................................................................................. 19 
8.0 SAFETY ............................................................................................................................................................................................ 19 
8.1 ADVERSE EVENTS ................................................................................................................................................................................................................... 19 
8.2 SERIOUS ADVERSE EVENTS (SAES) ............................................................................................................................................... 20 
8.2.1 Reporting of Serious Adverse Events ..................................................................................................................................... 20 
8.3 FOLLOW-UP OF ADVERSE EVENTS .................................................................................................................................................................................... 20 
9.0 STATISTICAL METHODS ........................................................................................................................................................... 21 
9.1 SAMPLE SIZE JUSTIFICATION ............................................................................................................................................................................................... 21 
9.2 STATISTICAL ANALYSES ....................................................................................................................................................................................................... 21 
9.3 MISSING DATA ......................................................................................................................................................................................................................... 22 
10.0 DATA MANAGEMENT ............................................................................................................................................................... 22 
10.1 DATA COLLECTION .............................................................................................................................................................................................................. 22 
11.0 STUDY COMMITTEES AND CORE LABS .............................................................................................................................. 23 
11.1 STEERING COMMITTEE ........................................................................................................................................................................................................ 23 
11.2 DATA SAFETY MONITORING COMMITTEE .................................................................................................................................................................... 23 
11.3 IMAGING CORE LABS ........................................................................................................................................................................................................... 23 
12.0  REFERENCES ............................................................................................................................................................................. 25 
13.0 APPENDICES ................................................................................................................................................................................ 27 
APPENDIX I.   RICHMOND AGITATION SEDATION SCALE (RASS) ..................................................................................................................................... 28 
APPENDIX II.   MONTE CARLO SIMULATION RESULTS OF BAYESIAN POWER ................................................................................................................................................ 29 
APPENDIX III  NPO GUIDELINES…………..…………………….…………………………… 
…IR…B…N…UM
…B…E…R…: H…S…C-…M…S-…17…-0.34136 


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List of Abbreviations 
 
A1 
1st segment of anterior cerebral artery 
A2 
2nd segment of anterior cerebral artery 
ACA 
Anterior Cerebral Artery 
AE 
Adverse event 
AHA 
American Heart Association 
A-line or Aline 
Arterial Line 
ASA 
American Stroke Association 
aICH 
Asymptomatic intracerebral hemorrhage 
aPTT 
Activated partial thromboplastin time 
aOR 
Adjusted Odds Ratio 
aRR 
Adjusted Relative Risk 
ASPECTS 
Alberta Stroke Program Early CT Score 
BA 
Basilar Artery 
BP 
Blood Pressure 
CABG 
Coronary artery bypass graft 
CAS 
Carotid Artery Stenting 
CBC 
Complete blood count 
CEA 
Carotid Endarterectomy 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CK 
Creatine kinase 
CrCl 
Creatinine clearance 
CrI 
Credible Interval 
CO2 
Carbon dioxide 
CRF 
Case Report Form 
CS 
Conscious Sedation 
CT 
Computed tomography 
CTA 
Computed tomography-Angiogram 
CTP 
Computed tomography-Perfusion 
CVA 
Cerebrovascular accident 
DBP 
Diastolic blood pressure 
DTN 
Door to needle 
DTG 
Door to groin 
ECG 
Electrocardiogram 
EDH 
Epidural Hematoma 
eGFR 
Estimated Glomerular Filtration Rate 
ESCAPE 
Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke 
EQ-5D 
European Quality of Life-5 Dimensions 
EVT or ET 
Endovascular Therapy 
EXTEND-IA 
Extending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial 
GA 
General Anesthesia 
GI 
Gastrointestinal 
H, h or hr, hrs 
Hour(s) 
HCG 
beta-human chorionic gonadotropin 
HERMES 
Highly EffectiveReperfusion evaluated in Multiple Endovascular Stroke 
HT1 or HT-1 
Hemorrhagic Transformation Type-1 
HT2 or HT-2 
Hemorrhagic Transformation Type-2 
ICA 
Internal carotid artery 
IRB NUMBER: HSC-MS-17-0436 


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ICH 
Intracranial hemorrhage 
IRB 
Institutional Review Board 
IV 
Intravenous 
IV-tPA 
Intravenous recombinant tissue plasminogen activator 
IVH 
Intraventricular Hemorrhage 
kg 
Kilogram 
LFT 
Liver function test 
LMWH 
Low molecular weight heparin 
LOS 
Length of stay 
M1 
1st segment of middle cerebral artery 
M2 
2nd  segment of middle cerebral artery 
M3 
3rd  segment of middle cerebral artery 
mmHg 
Millimeters of mercury 
MAP 
Mean arterial pressure 
MCA 
Middle cerebral artery 
MR CLEAN 
Multicenter Randomized Clinical trial of Endovascular Treatment in the Netherlands 
mRS 
Modified Rankin Scale 
mTICI 
Modified Thrombolysis In Cerebral Ischemia 
NA 
Not available or Not applicable 
ND 
Not done 
NIHSS 
National Institute of Health Stroke Scale 
NNH 
Number needed to harm 
NNT 
Number needed to treat 
OR 
Odds Ratio 
pH 
Hydrogen ion concentration 
PH1 or PH-1 
Parenchymal Hematoma Type-1 
PH2 or PH-2 
Parenchymal Hematoma Type-2 
Q or q 
Every 
rt-PA or tPA 
Recombinant tissue plasminogen activator 
RCT 
Randomized Clinical Trial 
REVASCAT 
Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior 
Circulation Stroke Within 8 Hours 
SAE 
Serious adverse event 
SAH 
Subarachnoid hemorrhage 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SDH 
Subdural Hematoma 
sICH 
Symptomatic Intracerebral Hemorrhage 
SIESTA 
Sedation vs. intubation for endovascular stroke treatment 
SWIFT-PRIME 
Solitaire with the intention for thrombectomy as primary endovascular treatment trial 
tICA or TICA 
Terminal Internal Carotid Artery 
TICI 
Thrombolysis In Cerebral Ischemia 
VA 
Vertebral artery 


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1.0 BACKGROUND AND RATIONALE 
Stroke is the fourth leading cause of death in developed nations. Each year in the US, approximately 795,000 people 
experience a new or recurrent stroke. On average, every 40 seconds, someone in the United States has a stroke.1 
Representing approximately 30-40% of all ischemic strokes, proximal intracranial arterial occlusions result in the most 
disabling types of ischemic strokes, and are closely associated with poor neurological outcomes at hospital discharge.2 
Recent randomized clinical trials conclusively demonstrated that early endovascular therapy (EVT) with stent-retrievers 
(i.e., embolectomy) significantly improves functional outcomes in patients with acute ischemic stroke up to 6 hours after 
onset and are recommended by the American Heart Association/Stroke Association (AHA/ASA).3-6 However, controversy 
remains regarding the optimal type of anesthesia that should be used during in EVT.7-10 The AHA/ASA guidelines do not 
support a recommended choice of anesthesia as the selection should be individualized to the patient (Class IIb; Level of 
Evidence C).11 Further, the guidelines state that randomized trials are needed. 
 
 
1.1 Retrospective Studies of Anesthesia during Endovascular Therapy 
Many retrospective case-control studies, propensity score analyses and post-hoc analyses of EVT trials have suggested, 
compared to CS, an association between GA and worse stroke outcomes including mortality – see table 1.12-19 In these 
studies, GA compared to conscious sedation (CS) in EVT reduced the odds of 90-day good functional outcome (mRS ≤ 
2). 
 
Following 1:1 matching using propensity score analysis, 507 general anesthesia and 507 CS patients, the outcome of 
thrombectomy patients receiving CS had decreased in-hospital mortality, pneumonia, and lower hospital costs and lengths 
of stay when compared with patients who received general anesthesia.12 This study suffered significant selection bias, 
which compromised its conclusion. A post-hoc analysis of the thrombectomy patients in MR CLEAN (Multicenter 
Randomized Clinical trial of Endovascular Treatment in the Netherlands) showed better functional 90-day outcome in the 
absence of general anesthesia, but again, patients were not randomized to the type of anesthesia.17 
 
 
1.2 Randomized Trials of conscious sedation vs. general anesthesia during Endovascular Therapy 
 
Until the recent publication of the first randomized trial testing general anesthesia vs. CS, 20 none of these studies 
randomized patients to a particular anesthesia approach – see table 1. The SIESTA trial randomized 150 (1:1) EVT 
treated stroke patients to either GA or CS at a single institution in Germany. The primary outcome, improvements in 24- 
hour mean NIHSS scores were nearly identical (3.2 vs. 3.6 points in GA vs. CS, respectively). The mean difference 
between the two groups was 0.4 and not statistically significant, P=0.82. Both arms demonstrated similar rates of 
successful angiographic reperfusion (TICI 2b or 3): 89%-GA vs. 81%-CS. More GA patients had prolonged intubation, 
incidence of pneumonia and hypothermia. Despite the increased incidence of adverse events and lack of clinical 
improvement at 24 hours, GA patients were more likely to be functionally independent (mRS ≤2) at 90 days: 37% GA vs. 
18% CS, P=0.01 (see table 1). Both in-hospital and 90-day mortality were nearly identical in the two study arms. 
Authors concluded SIESTA results did not support superiority of CS over GA and they recommended a larger, 
multicenter RCT powered to address longer-term outcomes. 


 
 
 
Table 1. Summary of clinical studies of ET and anesthesia. Shaded row indicates the lone RCT of EVT patients randomized to GA versus CS. 
 
REF 
Design 
Anesthesia 
Preferred 
Benefit 
Harm 
Comments 
 
12 
Retrospective 
Propensity 
Analysis 
Sedation 
• Sedation associated with: 
↓hospital mortality; 
↓pneumonia; 
↓hospital costs/LOS 
GA associated with: 
↑ in-hospital mortality (25% v 12%) OR=2.4, 95%CI 
1.7-3.4, p<0.001. 
↑pneumonia 17% v 9% OR=2, 95%CI 1.4-2.96, p<0.001. 
• ICH/SAH rates similar: 11% v 12%, p=0.62. 
- 1:1 propensity score matching 507 GA & 
507 CS patients 
- Usage rate of GA decreased from 83.8% in 2006 
to 74% in 2013. 
 
13 
Post-Hoc 
analysis of 
Multicenter 
RCT (IMS-3) 
Sedation 
No significant difference in: 
- Adjusted risk of SAH (P=0.32) or sICH 
P=0.37 
• GA associated with: 
↑ in-hospital mortality - aRR 2.8; 95%CI, 1.7- 
4.9,P<0.001 
• ↓ 90d mRS ≤2, RR 0.68; 95%CI 0.5-0.9; P=0.006 
Sedation – 269 (62%) 
GA – 147 (33.9%) 
Undetermined – 18 (4%) 
 
14 
Retrospective 
analysis 
(n=126) 
Sedation 
• Intra-procedural complications lower in 
patients who received Sedation 6% v GA 
15% P=0.13 
• Sedation assoc with good outcome (OR 3.06, 
P=0.04) 
GA associated with ↑ICU LOS: 6.5 days v 3.2 days, 
P<0.00) 
Sedation – 73 (58%); GA – 53 (42%) 
 
15 
Retrospective 
analysis 
(n=109) 
Sedation 
Duration of procedure & time to 
revascularization was significantly lower in 
Sedation 
GA 18% greater mortality rate compared with the CS 
group (P=0.045) 
- CS – 74; GA - 35 
- GA & post procedure glucose significant 
predictors of mortality 
 
16 
Retrospective 
pre-trial 
Cohort of 
MR-CLEAN 
(n=348) 
Sedation 
• Sedation better clinical outcomes - (OR 2.1, 
95% CI, 1.02–4.31) 
• After adjusting for pre-specified prognostic 
factors, statistical significance was lost 
(OR1.9, 95% CI, 0.89–4.24). 
No difference in sICH or Asymptomatic ICH 
Mortality 
- GA group (21%) vs. Sedation (17%) 
No difference in device dissection or device-related 
complications 
CS - 278 
GA – 70 
 
17 
Post-Hoc 
analysis of 
RCT (MR- 
CLEAN) 
Sedation 
mRS in favor of non-GA compared to control 
group (adjusted common OR 2.2, 95%CI 1.5- 
3.2. 
GA associated with significant (p = 0.011) effect 
modification, resulting in estimated ↓of 51% (95%CI 
31%-86%) in EVT effect compared to CS. 
Treatment without GA was associated with a 
significant treatment benefit in MR CLEAN. 
18 
Retrospective 
Case-Control 
Sedation 
• No difference in hemorrhage 
GA associated with ↑mRS >2 at 90 days (OR 2.33) and 
also ↑mortality (OR 1.7) 
Older study (2005 – 2009); 
n=980 
19 
Post-Hoc 
Meta-Analysis 
of 9 studies 
Sedation 
• No difference in treatment times between the 
two groups 
GA associated with: 
↑mortality OR 2.6, ↑respiratory complications OR 2.1 
↓good clinical outcomes (OR = 0.43) 
- GA patients with higher NIHSS presenting 
scores. 
- n=1956 
 
20 
RCT 
Monocentric 
GA - no 
support for 
CS 
advantage 
• No significant difference (P=0.82) in primary 
outcome (24 hour NIHSS) between groups. 
• ↑ mRS ≤2 at 90d 37%-GA v. 18% CS 
without mortality diff. 
GA had more: 
- hypothermia (32%, P<0.001) 
- delayed extubation (49.3%, P<0.001) 
- pneumonia (13.7%, P=0.03) 
Only RCT that randomized EVT patients to 
either GA or CS. 
Sedation – 77; GA - 73 
Campbell 
(ISC 
2017) 
Post-Hoc 
Meta-Analysis 
5 RCTs 
Sedation 
• Both CS & GA superior compared to usual care 
• Equivalent procedure complications 
↑good outcomes in non-GA group (OR 1.6). 
↑ pneumonia in GA group (16% v 9%), 
- Randomization to treatment time prolonged in GA 
HERMES collaboration; n=1287; 
NIHSS, age, 
onset to random. times comparable CS v. GA 
 
 
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A recent retrospective study of a multi-hospital administrative database between 2006-2013, found 80% of 2515 EVT 
patients received GA, whereas 20%, received CS.21 These findings suggest the majority of neuro-interventionists 
preferred GA. Since that time, multiple retrospective studies have been published (detailed in table 1) that suggest CS 
may be preferable to GA. We recently sent a questionnaire to vascular neurologists and both neurology and neurosurgery 
trained neuro-interventionalists. The aim was to determine the state of anesthesia equipoise among physicians who 
perform or direct care for EVT stroke patients. Notably, the questionnaire was sent 4 months after publication of the 
SIESTA trial. EVT specialists were asked if a randomized trial was still needed – Figure 1. Out of 97 respondents, the 
responses were similar. 
 
Figure 1. Results of questionnaire from comprehensive stroke center’s opinion for a current randomized trial of 
anesthesia in EVT. 
 
For thrombectomy following acute stroke, any delay will likely result further brain infarction. Relative to CS, general 
anesthesia may result in more delays to recanalization time.7 On the other hand, patients who receive CS are more likely 
to suffer agitation and move while on the treatment table, potentially delaying recanalization as well, and increasing 
procedural risk. Iatrogenic arterial rupture and inability to catheterize the occluded vessel are key concerns. There has also 
been speculation of potential anesthetic-related worsening ischemic volume due to a vasodilatory “steal phenomenon”.7 
The cumulative dose of norepinephrine during general anesthesia was considered a predictor of an unfavorable outcome.22 
 
GA for EVT can be administered using intravenous anesthetics, inhaled anesthetics, or a combination. There is no clear 
standard of care as to the type of GA for this procedure: the various retrospective and prospective studies investigating 
this issue have used both. Lacking evidence of the superiority of one type of anesthetic over the other in EVT, the 
decision of which type to administer is based on anesthesiologist preference and/or common local practice. Different 
anesthetic techniques have differential effects on cerebral blood flow, which may affect flow to the penumbra either 
directly, or by increasing flow to unaffected regions (“steal phenomenon”). One retrospective study found that outcomes 
were better in patients administered an inhaled general anesthetic compared to intravenous or combination techniques.9 
 
As expected secondary to study design, previous retrospective studies comparing the utilization of the CS vs. GA are 
severely limited by probable selection bias. The “sicker” patients with cardiovascular instability or respiratory distress, 
agitation, aphasia from dominant hemispheric stroke location, and the inability to protect their airway were typically 
treated under general anesthesia. These patients remained intubated for the same reasons after the procedure as well; 
whereas patients who were otherwise conscious and cooperative at baseline, without airway issues, with stable 
cardiovascular and pulmonary status were selected for EVT under CS. Intuitively, patients within the former group had 
longer ICU and hospital stay, higher hospital mortality, and worse neurological and functional outcomes. 
The soundest mechanism for reducing selection bias remains randomization with allocation concealment. Most 
importantly, randomization balances all the known and unknown patient characteristics. Therefore, a randomized study 
comparing CS and GA during EVT is needed to evaluate the objective outcomes to help determine the future treatment 
paradigm. 
IRB NUMBER: HSC-MS-17-0436 
QUESTION: 
Do you think there is a need for a randomized 
study to evaluate the choice of anesthesia 
(sedation vs. general anesthesia) for EVT, in 
light of the published retrospective data 
suggesting better outcomes of patients 
undergoing EVT under sedation instead of 
general anesthesia, and the latest publication 
of SIESTA (a randomized study)? 


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2.0 STUDY OBJECTIVES 
 
2.1 Primary Objective 
 
To evaluate the hypothesis that GA during EVT for acute ischemic stroke improves functional outcomes at 90 days 
compared to sedation. 
 
 
 
2.2 Secondary Objectives 
 
Evaluate safety, reperfusion, early neurological improvement, effect modification by type of GA, and quality of life in 
EVT patients randomized to GA versus sedation. 
 
 
3.0 STUDY ENDPOINTS 
3.1 Primary Endpoint 
 
The primary endpoint is a comparison of independent clinical outcome, defined as a modified ordinal Rankin Scale (mRS) 
at 90 days (scores 5 and 6 combined) among patients randomized to GA versus sedation. Primary analysis will be 
intention to treat (ITT) and adjusted for stratification variables. 
 
 
 
3.2 Secondary Clinical Endpoints 
1) As treated analysis of primary outcome adjusted for stratification variables 
a. Patients will be analyzed according to the type of anesthesia received (e.g., a patient randomized to 
Sedation that crosses-over to GA will be analyzed in the GA group). 
2) Dichotomized mRS at 90-days (0-2 vs 3-6) adjusted for stratification variables. 
3) Angiographic reperfusion defined as modified TICI score ≥ 2b. 
4) Early clinical improvement measured by difference in 24-36 hour NIHSS scale. 
5) Proportion of independent functional outcome at 90 days in GA patients treated with inhalational vs. intravenous 
medications. 
6) Difference in quality of life at 90-days. 
 
 
3.3 Secondary Safety Endpoints 
1) Symptomatic intracerebral hemorrhage within 18-36 hours. 
1. Defined as the SITS-MOST definition: Increase in NIHSS of ≥4 points and PH-2/rPH-2.23 
2) All-cause mortality. 
3) Rates and types of peri-procedural or device-related complications. 


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3.4 Exploratory Analyses 
 
1) Ordinal ITT and as-treated analysis of primary outcome comparing three groups (CS, GA IV, GA inhalational) 
adjusting for stratification variables. 
2) Multivariable adjusted analysis (including stratification variables) for both primary (mRS 0-2) and ordinal 
analysis of 90-day mRS outcomes, to include (but not limited to) baseline variables known to be clinically 
associated with stroke outcomes: 
a. Age 
b. NIHSS 
c. Time from stroke onset-to-EVT groin puncture 
d. IV-tPA treatment before EVT 
e. Atrial Fibrillation 
3) Duration of time during EVT spent below a systolic blood pressure of 140mmHg. 
4) Total ICU and ventilator days. 
5) Subgroup analyses to test for heterogeneity in patient benefit and Provider Skill: 
a. Proximal vs. Distal occlusion location (ICA+M1-MCA vs. others) 
b. High-volume vs. low-volume centers 
6) Costs from a health system perspective 
 
 
 
4.0 STUDY DESIGN 
 
4.1 Overview 
 
This trial is a multicenter, randomized, parallel-group, open-label treatment with blinded end point adjudication (PROBE). 
Patients with acute stroke who meet endovascular therapy criteria for large arterial vessel occlusion will be randomized 
1:1 to Sedation or GA. Patients randomly assigned to GA will then be randomized to either inhalational or IV anesthesia 
using a 1:1 ratio. 
 
The total estimated duration for trial completion is 2 years (18 months for enrollment, 6 months for data collection, data 
cleaning and statistical analysis); subject participation is expected for 90 days from onset of acute stroke event 
 
 
4.2 Enrollment and Randomization 
 
Enrollment in this study is defined as the moment when the randomization process is completed and the subject is 
assigned to a study arm. After randomization, no crossover is permitted unless either the neurovascular interventionalist 
or anesthesiologist determines the patient meets criteria as described in section 5.0 
Randomization will occur via a secure, password-protected, web-based system. Subjects will be randomized 1:1 to GA or 
Sedation using permuted blocks and stratified by center, terminal ICA occlusion (yes/no), and time of stroke 
symptom onset (≤ 6 hours or 6-16 hours). Patients randomized to GA will subsequently be randomly assigned in a 1:1 
ratio to either inhalational or IV anesthesia. 
 
Stroke management and endovascular therapy procedures will occur as per local site usual care. Only FDA-approved 
thrombectomy devices should be used with first line use of stent retriever. Both general anesthesia and Sedation should 
be delivered and managed by an anesthesiologist. 


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5.0 STUDY POPULATION 
 
5.1 Inclusion Criteria 
 
1. Acute ischemic stroke due to large intracranial vessel occlusion demonstrated on CT-angiography in the 
following anterior circulation locations that will be treated by endovascular therapy (EVT): 
a. Internal Carotid Artery (terminal “T” or “L-type”- occlusion) 
b. Middle Cerebral Artery (MCA) M1 or proximal M2 
c. Anterior Cerebral Artery (ACA) A1 or proximal A2 
• Patients who receive IV-tPA thrombolysis are eligible provided the drug was delivered within 4.5 hours of 
stroke onset or last seen normal and in accordance with local hospital standard of care. 
2. 
Ages 18-90. 
3. National Institute of Health Stroke Scale (NIHSS) score 6-30 
4. Time of stroke symptom onset of last seen normal to start of EVT (defined as groin puncture) ≤ 16 hours. 
5. Limited infarct core, as defined below and adapted from the 2018 American Heart Association guidelines 28 
a. For patients presenting ≤ 6 hours from time of symptom onset or last seen normal, Alberta Stroke 
Program Early Computed Tomography Score (ASPECTS) ≥ 6 
b. For patients presenting > 6 hours and ≤ 16 hours from time of symptom onset or last seen normal, they 
must satisfy EITHER ONE of the two following criteria: 
i. Ischemic core by CT Perfusion or MRI/MR Perfusion < 70 mL, a ratio of volume of penumbral 
tissue to infarct core of ≥ 1.8, and and absolute volume of penumbral tissue of ≥ 15 mL 29 
 
OR 
 
ii. For patients with NIHSS ≥ 10, infarct core of < 31 mL by CT Perfusion or MRI; For patients with 
NIHSS ≥ 20, infarct core < 51 mL.30 
6. Subject willing/able to return for protocol required follow up visits. 
7. No significant pre-stroke disability (modified Rankin Score must be ≤ 2). 
8. Females of childbearing potential must have a negative serum or urine pregnancy test. 
9. Patient or patient’s legally authorized representative has given Informed Consent according to Good Clinical 
Practices (GCP) and/or local IRB policies. 
 
 
5.2 Exclusion Criteria 
 
1. Coma on admission (Glasgow Coma Scale <8), need for intubation upon ED arrival, or transferred patients who 
present previously intubated. 
2. Severe agitation or seizures on admission that preclude safe vascular access. 
3. Loss of airway protective reflexes and/or vomiting on admission. 
4. Predicted or known difficult airway. 
5. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, 
e.g. dementia. 
6. Presumed septic embolus, or suspicion of bacterial endocarditis 
7. Currently participating or has participated in any investigational drug or device study within 30 days. 
8. Inability to follow-up for 90-day assessment. 
9. Known history of allergy to anesthesia drugs. 
10. Known history or family history of malignant hyperthermia 


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5.3 Crossover Criteria 
 
1. Severe agitation or seizures. 
2. Loss of airway protective reflexes, vomiting, or aspiration. 
3. Inability to maintain airway. 
4. Loss of consciousness. 
5. Hemodynamic instability. 
6. Determination by anesthesiologist and/or neurointerventionalist that randomized method of anesthesia is 
contraindicated for some other reason (see section 5.4) 
 
5.4 NPO Status 
 
Lack of confirmation of duration of fasting status (nil per os; NPO) shall, in and of itself, not be considered a 
contraindication to moderate sedation for the purposes of this study. Patients should not be excluded from the study or 
crossed-over from sedation to GA solely due to NPO status. 
 
Rationale: 
NPO status is often unknown in patients presenting with acute ischemic stroke. Despite this, the recommendation by the 
AHA/ASA is that moderate sedation is preferred over general anesthesia for EVT 31 and this is routinely practiced at 
stroke centers across the country. The determination of a potential subject’s eligibility for sedation should be based on the 
overall clinical picture, other risk factors for pulmonary aspiration, and consideration of the target depth of sedation for 
this procedure (moderate sedation). 
 
EVT for acute ischemic stroke is an emergency procedure. The American Society of Anesthesiologists’ guidelines for pre- 
procedural fasting are intended for elective procedures32, and the guidelines for procedural sedation state that “the 
literature does not provide sufficient evidence that pre-procedure fasting results in a decreased incidence of adverse 
outcomes in patients undergoing either moderate or deep sedation,” leading the task force to conclude that “in urgent, 
emergent, or other situations in which gastric emptying is impaired, the potential for pulmonary aspiration of gastric 
contents must be considered in determining (1) the target level of sedation, (2) whether the procedure should be delayed, 
or (3) whether the trachea should be protected by intubation.” 33 The American College of Emergency Physicians has 
developed specific guidelines that support the use of extended-duration moderate sedation for standard-risk patients 
undergoing urgent procedures, and for high-risk patients undergoing emergency procedures.34 See Appendix III. 


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6.0 STUDY PROCEDURES 
 
All subjects who are enrolled into the trial will be followed for 90 days (± 10) unless they withdraw early from the trial, 
expire before the 90 day follow up window is reached, or are lost to follow up. The study event schedule is illustrated in 
Table 2. 
 
 
6.1 Informed Consent 
 
Written informed consent Written informed consent or electronic consent will be obtained for all subjects who are 
screened and meet the trial inclusion/exclusion criteria. If sites choose to utilize electronic consent, the method of 
electronic consent used will be based on each individual institution’s choice, as approved by the site’s IRB. In the event 
that IRBs of participating centers determine the trial meets criteria for exception from informed consent (EFIC), sites will 
have the option to pursue local procedures to include community consultation, etc. Below, we provide explanations that 
justify the use of delayed or exception from informed consent in this particular population. 
 
The trial compares two anesthesia approaches for EVT delivered as usual care. We have demonstrated clinical equipoise 
in participating stroke centers of excellence. Therefore, the trial meets criteria for comparative effectiveness research. 
Participation in SEGA should never delay the time-sensitive nature of providing emergent reperfusion therapy in acute 
ischemic stroke. In addition, a significant proportion of these severe stroke patients are air-transported to the 
comprehensive stroke centers (CSC) and family members must drive from the outlying hospital to the CSC. Due to the 
expected stroke severity routinely encountered with proximal intracranial occlusions, the majority of patients will be 
suffering from either aphasia (language disturbance of either comprehension or expression) or severe neglect (inability to 
understand or acknowledge they are suffering a stroke). Hence, the majority of patients will be unable to provide 
informed consent due to lack of capacity. Unfortunately, the majority of legal next of kin fail to arrive before the 
commencement of EVT procedures; including the transfer from the emergency department to the angio suite for EVT. 
 
As a result, traditional written approach to informed consent in this patient population is rarely feasible and will impact 
study recruitment, results and generalizability. First, the trial would recruit at a very slow pace and enrollments will be 
predominantly a less-severe subpopulation of strokes. Second, it is well established across clinical research that the 
patients who benefit the most from effective interventions are usually those most severely affected. Thus, our estimations 
of treatment differences would result in decreased probability of observing a difference between the study arms. 
Critically, traditional written emergent consent will inherently delay EVT procedures and possibly result in worse clinical 
outcomes. Pooled analyses from EVT RCTs have demonstrated that minor delays to arterial reperfusion of 20 minutes are 
associated with worse clinical outcomes. Third, participation in a clinical trial could directly benefit the patient and 
ultimately society if a new treatment is discovered.  The inability to participate in promising research for the most 
severely affected patients is sometimes interpreted as a breach of the ethical principle of justice. The basic concept of 
distributive justice, as it relates to clinical research, should not categorically exclude certain subgroups with clinically 
relevant characteristics such as disease severity, sex, age, etc. This discrimination is unjust and results in skewed 
generalizable knowledge that guides health care practices. 
We recognize that emergency research such as this trial or any research that requires study-related research outcomes will 
require subsequent written consent from the patient of legal next of kin. Therefore, each site must make a reasonable 
attempt to reach family members that are available in the hospital or will be arriving within 15 minutes. For patients 
enrolled via EFIC, explicit written consent must be obtained during the study period of 90-days. Usually, this should 
occur within 5 days of enrollment during the hospitalization. Ultimately, each participating center must follow their local 
IRB’s decision regarding consent in this trial 


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Table 2. Schedule of events. 
 
ASSESSMENTS 
VISITS 
Baseline 
<16 hours from stroke 
onset/LSN 
18-36 hours 
Day 7 or discharge, 
whichever occurs first 
90 ± 15 days 
Demographics 
Y 
Y 
Medical History 
Y 
Stroke History 
Y 
Y 
mRS 
Y 
Y* 
Y 
EQ-5D 
Y* 
NIHSS 
Y 
Y 
Y 
EVT Procedure Variables 
Y 
Imaging assessment 
Parenchymal - CT or 
MRI 
Arterial – CTA or MRA 
Y 
Y 
Y 
Assess for adverse events 
Y 
Y 
Y 
Note: Except those notated by *, all procedures and assessments are collected a usual care for acute ischemic stroke patients. 
 
6.2 Treatment Period 
 
6.2.1 Endovascular Procedure and Time Metrics 
 
As recommended by the AHA/ASA, the first line therapeutic embolectomy device should be a stent retriever. The use of 
a proximal balloon guide catheter or a large-bore distal-access catheter, rather than a cervical guide catheter alone, in 
conjunction with stent retrievers may be beneficial. Future studies should examine which systems provide the highest 
recanalization rates with the lowest risk for nontarget embolization 
 
Additional EVT therapies including, but not limited to, intra- or extracranial angioplasty ± stenting; antithrombotics (oral, 
IV or IA antiplatelets or anticoagulants) intra-arterial thrombolytics; are left to the decision of the local treatment team. 
Conversely, in general, off-label use or therapies not supported by scientific evidence are discouraged. Importantly, the 
use of these therapies will not be considered a protocol deviation. 
 
Time to reperfusion in EVT trials is correlated with improved outcomes and societies have published position statements 
on timing metrics. The current protocol provides guidance for centers derived from these recommendations (see table 3). 
26 
Table 3. SEGA recommended guidelines for timing metrics 
 
Acute Stroke Time Metric 
Maximal Target 
Time 
Door to Imaging (parenchymal imaging – non-contrast CT, MRI) 
15 minutes 
Door to IV-tPA bolus 
60 minutes 
Door to Groin Puncture 
90 minutes 
Angiosuite arrival to Groin Puncture 
20 minutes 
Door to Reperfusion 
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The following intra-procedure (thrombectomy) variables will be collected (see CRFs for further details): 
• Door to puncture time 
• Decision of intervention to puncture time 
• Time from puncture to first recanalization attempt 
• Time to Revascularization: defined as arterial puncture to TICI ≥ 2b revascularization or end of procedure. 
• Revascularization assessment at the end of the procedure (using Thrombolysis in Cerebral) Infarction (TICI) 
score. 
• Number of recanalization attempts (i.e. thrombectomy attempts or stent-retriever passes) 
• Name of the mechanical retrieval device used 
• Utilization of aspiration technique 
• Failure to reach clot 
 
6.2.2 Angiographic measures of arterial perfusion and collaterals 
 
Using angiography, the modified TICI (mTICI) score is defined according to the level of blood flow through an occlusion 
site and consists of 5 discrete categories (table 4a). 
 
 
Table 4a. Angiographic scoring of large vessel occlusions and reperfusion. 
 
mTICI 
score 
Definition 
0 
No Perfusion - No antegrade flow beyond the point of occlusion 
1 
Penetration with Minimal Perfusion - The contrast material passes beyond the area of obstruction but fails to opacify 
the entire cerebral bed distal to the obstruction for the duration of the angiographic run. 
2 
Partial Perfusion - Contrast material passes beyond the obstruction and opacifies the arterial bed distal to the 
obstruction; However, the rate of entry of contrast into the vessel distal to the obstruction and/or its rate of clearance 
from the distal bed are perceptibly slower than its entry into and/or clearance from comparable areas not perfused by 
the previously occluded vessel, e.g., the opposite cerebral artery or the arterial bed proximal to the obstruction. 
• 2a Only partial filling (< 50%) of the entire vascular territory is visualized. 
• 2b Filling of > 50% all of the expected vascular territory is visualized, but the filling is slower than normal. 
3 
Complete Perfusion - Antegrade flow into the bed distal to the obstruction occurs as promptly as into the obstruction 
and clearance of contrast material from the involved bed is as rapid as from an uninvolved other bed of the same vessel 
or the opposite cerebral artery. 
 
 
Cerebral collaterals play a key role in determining outcome in endovascular treatments for acute ischemic stroke. In 
addition, given the hypothesized effect of general anesthesia on blood pressure and cerebral perfusion, collateral grade 
may be a particularly relevant determinant of outcome in this cohort. Collaterals will be graded from the angiograms by 
society guidelines, as shown in Table 4b 25 


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Table 4b. Angiographic scoring of cerebral collaterals 
 
 
Collateral 
score 
Definition 
0 
No collaterals visible to the ischemic site. 
1 
Slow collaterals to the periphery of the ischemic site with persistence of some of the defect. 
2 
Rapid collaterals to the periphery of the ischemic site with persistence of some of the defect and to only a 
portion of the ischemic territory. 
3 
Collaterals with slow but complete angiographic blood flow to the ischemic bed by the late venous phase. 
4 
Complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde 
perfusion. 
 
6.3 90-day (± 15 days) Follow-up 
 
The study participation will be considered completed after the 90 day follow up visit has been completed. If for any 
reason the patient cannot visit the clinic/hospital for the follow up, the Investigator or research staff should ask permission 
from the patient and family if an in-person visit could take place at the current dwelling facility to assess patient’s 
neurological condition. In the event that in-person assessment is not possible, research team-members should conduct a 
phone interview. In the event that the patient cannot be reached or is unable to answer assessment questions, their 
caregiver or family member can be questioned. 
 
The patient’s quality of life will be assessed using the EQ-5D provide a numerical measure of the patient’s health utility. 
In the event the patient is unable to communicate or understand the questions, his/her next of kin (proxy) who knows the 
most about their current health state will be asked to fill out these questionnaires on behalf of the patient. Importantly, the 
proxy will be instructed to fill answer the quality of life questionnaires from the patient’s perspective – knowing 
everything they know about the patient, how would they answer if they capable. 


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7.0 ANESTHESIA GUIDANCE 
 
 
7.1 Sedation 
 
Sedation will be provided under the supervision of an anesthesiologist using a combination of fentanyl, midazolam, 
dexmedetomidine infusion (with or without loading dose), remifentanil infusion, and/or low-dose propofol by intermittent 
bolus or infusion, with a target Richmond Agitation Sedation Scale (RASS) score of -1 to -3 (light to moderate sedation – 
responds to verbal stimulation; see Appendix II). 
 
Sedation patients who do not tolerate sedation (e.g., patient agitation, airway difficulty, loss of consciousness, aspiration, 
cardiovascular instability) should be converted to Inhalational GA and the corresponding protocol followed. 
 
7.2 General Anesthesia 
 
Induction of anesthesia will be achieved with propofol and/or etomidate; muscle paralysis with succinylcholine or non- 
depolarizing paralytic (rocuronium or vecuronium); and adjuvant lidocaine and fentanyl as deemed appropriate by the 
anesthesiologist. Hyperventilation should be avoided during induction. 
 
Intravenous: Maintenance of anesthesia will be achieved by propofol infusion at 50 to 150 mcg/kg/min with redosing of 
non-depolarizing paralytic and fentanyl (and/or remifentanil infusion) as needed. 
 
Inhalational: Maintenance of anesthesia will be achieved with sevoflurane 1% to 2% or desflurane 3% to 6% end-tidal 
concentration with redosing of non-depolarizing paralytic and fentanyl (and/or remifentanil infusion) as needed. 
 
 
 
7.3 Blood Pressure Management 
 
Systolic blood pressure (SBP) should be maintained at 140 to 180 mmHg with pressors (e.g., phenylephrine, 
norepinephrine) or antihypertensives (e.g., nicardipine, labetalol) as needed. Diastolic blood pressure should be 
maintained <105 mmHg. 
 
In patients who are reperfused after EVT (defined as achieving TICI 2b or TICI 3), SBP should be maintained at 140 
mmHg in the first 24 hours to minimize the risk of reperfusion-related brain hemorrhage. Blood pressure of patients who 
fail to achieve recanalization will be left to the discretion of the individual stroke centers’ usual care. 
 
 
 
7.4 Anesthesia Monitoring 
 
Invasive hemodynamic monitoring should be attempted prior to induction of GA to allow for tight hemodynamic control. 
To limit any delay in time to revascularization, attempts to establish peripheral invasive arterial access should be limited 
to 5 minutes; after that time, continuously-cycled non-invasive blood pressure measurements should be performed until 
invasive hemodynamic monitoring can be achieved through the femoral sheath. SBP should be maintained at 140 to 180 
mmHg throughout with phenylephrine and/or norepinephrine as needed. Patients who are converted from sedation who 
already have invasive hemodynamic monitoring through the femoral sheath do not need additional arterial access. 


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End-tidal CO2 concentration (PETCO2) in patients receiving GA should be maintained at 35 to 40 mmHg (corresponding 
to a PaCO2 ~40-45 mmHg). 
 
All patients who are deemed medically appropriate for extubation should be awakened and extubation attempted at the 
conclusion of the procedure. Muscle paralysis should be reversed at the conclusion of the procedure using neostigmine or 
sugammadex; those patients with deep neuromuscular blockade that precludes reversal with neostigmine should be 
reversed with an adequate dose of sugammadex to avoid unnecessary prolonged intubation. 
 
 
7.5 Anesthetic Data Collection 
 
The following intra-procedural anesthesia variables will be collected: 
• 
Anesthetic agents used for GA or sedation 
• 
PETCO2 q5 min in GA group. 
• 
RASS score q15 min in sedation group. 
• 
Oxygen saturation q15 min 
• 
Continuous BP measurements from an electronic anesthetic record for determination of time spent with SBP <140 
mmHg. 
• 
Utilization of norepinephrine, phenylephrine, or other vasopressors as well as total dose administered. 
• 
Documentation of post-procedure extubation or the reason for remaining intubated. 
• 
Reason of crossover of anesthesia modality (sedation to GA) – patient agitation, airway difficulty, loss of 
consciousness, aspiration, cardiovascular instability 
 
 
8.0 SAFETY 
 
8.1 Adverse Events 
 
An adverse event could include any of the following events, which develop or increase in severity during the course of the 
study: 
• 
Any signs or symptoms whether thought to be related or unrelated to the condition under study; 
• 
Any clinically significant laboratory abnormality; 
• 
Any abnormality detected during physical examination. 
 
These data will be recorded on the appropriate CRFs, regardless of whether they are thought to be associated with the 
study arm treatment. Signs or symptoms will be graded by the Investigator as mild, moderate or severe according to the 
following definitions: 
Grade: 
Definition 
Mild: 
Causing no limitation of usual activities 
Moderate: 
Causing some limitations of usual activities 
Severe: 
Causing inability to carry out usual activities. 


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8.2 Serious Adverse Events (SAEs) 
 
A serious adverse event is defined as any event that suggests a significant hazard, contraindication, side effect or 
precaution. A serious adverse event includes any event that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Important or significant medical events that require medical or surgical intervention, based upon appropriate 
clinical judgment. 
 
The Investigator must assess the relationship of the adverse event to the study device using the following criteria 
categories and definitions: 
• 
Unrelated - The adverse event is determined to be due to a concurrent illness or effect of another device/drug and 
is not related to the type of anesthesia utilized. 
• 
Possible - The adverse event is determined to be potentially related to the treatments received for anesthesia and 
an alternative etiology is equally or less likely compared to the potential relationship to the type of anesthesia 
provided. 
• 
Probable - There is a strong relationship to the type of anesthesia, or recurs on re-challenge, and another etiology 
is unlikely. 
• 
Highly Probable - There is no other reasonable medical explanation for the event. 
 
 
8.2.1 Reporting of Serious Adverse Events 
 
Each clinical site will follow their internal policies for reporting SAEs to their IRB. In addition, sites will alert the UT- 
Houston data-core within 24-hours of becoming aware of the SAE. This alert will be relayed to the study PIs for review. 
If an SAE is confirmed, the coordinating site will be responsible for reporting to the DSMB as outlined in the DSMB 
charter. DSMB reports will be forwarded to all participating clinical sites for local IRB submission. 
 
The study sponsor is responsible for the coding and reporting any adverse event required by regulatory authorities. The 
study sponsor will code AEs using MedDRA (Medical Dictionary for Regulatory Affairs). Unanticipated serious adverse 
events that meet criteria for FDA submission per 21 CFR part 803 will be submitted by the study sponsor. 
 
 
8.3 Follow-Up of Adverse Events 
 
All adverse events will be collected from the time of randomization and monitored until day 7 or hospital discharge, 
whichever occurs first. AEs that do not meet criteria for resolution will be categorized as on-going after day 7 or 
discharge. 


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9.0 STATISTICAL METHODS 
The study will be conducted under a common umbrella protocol developed by UTHealth with the itention of combining 
data from all satellite centers for analysis. Each participating site will give utmost importance to follow the study protocol 
to maintain consistency in study execution at all centers. Detailed analysis plan for all pre-specified outcome measures 
are located in separate statistical analysis plan. 
 
9.1 Sample Size Justification 
 
A maximum of 260 patients, 130 per arm will be randomized. Assuming a neutral prior probability (centered at OR of 1.0, 
95% prior interval: 0.3–3.0) for the intervention effect, the sample size provides 80% power that General Anesthesia 
improves outcome (lower ordinal mRS) compared to Sedation if the true OR is >1.50. Monte Carlo simulations were 
performed using R to estimate the Bayesian power of the study for the primary outcome measure.  We assumed a 
threshold of 80% posterior probability of the OR >1.0 to declare effectiveness. See Appendix II for summary of 
simulation results. 
 
9.2 Statistical Analyses 
 
Intent-to-treat analyses will be performed. To summarize the data, descriptive statistics will be used. Demographics, vital 
signs, laboratory variables, stroke type and duration from onset of symptoms will be summarized for each treatment arm. 
Vital signs taken during the treatment period will be displayed graphically. In addition to ICH, other medical events will 
be tabulated by body system and severity. 
 
Primary analyses will focus on comparing GA (combining inhalational and IV anesthesia) to sedation. All analyses will 
be conducted under a Bayesian paradigm to obtain estimates of odds ratio (OR) for primary outcome (ordinal mRS), 
relative risk (RR) for binary outcomes, and probability of treatment benefit or harm (quantities that cannot be obtained 
from frequentist analyses). For the treatment effect, we will use a neutral prior centered at OR of 1.0 with 95% prior 
interval of 0.3-3.0. This prior assumes a priori equipoise and excludes large treatment effects. Weakly informative priors 
will be used for all other parameters to exclude large treatment effects.24 
 
Generalized linear mixed models will be used to analyze all outcomes and will include treatment group, terminal ICA 
occlusion and time from onset of symptoms (stratification variables) as covariates and center (stratification variable) as a 
random effect to account for center variability. For the primary outcome of ordinal mRS at 3 months (scores 5 and 6 
combined), we will use an ordinal logistic model. For binary outcomes we will use log binomial (or logistic in case of 
non-convergence) models to directly estimate relative risks (or odds ratios) and 95% CIs. The prior for the treatment 
effect will be a Normal (0, sd=0.57) in the log OR/RR scale. The prior for the intercept will be Normal (0, sd=10) and 
Normal (0,1) for other covariates in the model. A half-Normal(0,1) prior will be used for the standard deviation of the 
center random effect. For non-binary outcomes, we will select the best fitting models and use neutral, weakly informative 
priors that exclude large treatment effects. We will examine residuals from each model to ensure reasonable adherence to 
the assumptions of the models. 
 
If, despite randomization with stratification for center, tICA, and time from onset of symptoms, any important differences 
between intervention groups occur in baseline variables related to outcome, secondary analyses will be performed 
controlling for these factors. 
 
For the primary outcome of ordinal mRS at 3 months, a secondary analysis will be conducted comparing CS to 
inhalational anesthesia and to IV anesthesia adjusting for the stratifying variables. Models and priors will be the same as 
for the primary analysis. 


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9.3 Missing Data 
 
If patients are lost to follow-up at the 90-day end of study evaluation, the worst-case scenario will be entered into the 
database (i.e., mRS = 6). In the event that the percent of patients lost to follow-up exceeds 5%, we will use multiple 
imputation methods. This technique quantifies the uncertainty due to the missing data. 
 
 
9.4 Safety Monitoring 
 
Formal interim analyses of safety will occur when 100 and 200 patients are enrolled. Safety endpoints will consist of 
intracerebral hemorrhage within 18-36 hours and death. Bayesian interim monitoring will be used to assess whether 
systematic differences are evident among the treatment groups for the occurrence of the interim safety analysis endpoint. 
The posterior probability that either treatment group has a higher incidence of the interim safety analysis endpoint will be 
determined. These posterior probabilities for safety will be assessed using the log-binomial regression model with 
covariates, described more completely in section 9.2. Either treatment will be considered harmful (i.e., the DSMB may 
consider termination of the trial) if the posterior probability of treatment harm in one treatment arm compared to the other 
exceeds 97.5%. In addition to reporting the above posterior probability, the 95% credible interval for the RR, and the 
entire posterior distribution of RR will be presented graphically to the DSMB in order to assure a full appreciation of the 
range of possible values of each RR. 
 
9.5 Interim Efficacy Analysis 
 
One interim analysis is planned after the first n=132 patients (50% of data accrual) have been randomized and have 
completed the 3-month primary outcome assessment. Ordinal mRS outcome will be compared between GA and CS 
groups using a Bayesian logistic model detailed in section 9.2. The same neutral priors will be used to calculate posterior 
probabilities of benefit for either treatment group. Posterior median OR and 95% intervals will also be calculated. 
 
During the interim analyses of efficacy, the DSMB may consider termination if the posterior probability of benefit 
(improving independent clinical outcome) of either treatment arm compared to the other is greater than 95%. 
Given that this is a comparative effectiveness trial, no interim futility analyses will be conducted since they are not 
appropriate for evaluating therapies already in use.27 
 
10.0 DATA MANAGEMENT 
10.1 Data Collection 
 
Detailed clinical data collection will be performed using an established standard method approved by each site’s IRB. 
Data will be de-identified and recorded initially on paper CRFs and then transferred to the study’s secure web-based 
application. 
 
Every reasonable effort should be made to complete data entry within one week of data collection. Data discrepancies 
may be queried during ongoing review of data by the trial’s data coordinating center (DCC) or may be identified and 
queried during remote or in-person monitoring visits. Data monitoring will be performed to verify data accuracy and 
ensure queries are resolved. The Principal Investigator or Sub-investigator must ensure the accuracy and completeness of 
the recorded data and then provide his/her electronic signature on the appropriate CRFs. 
 
Each participating center will provide appropriate source documentation for data monitoring. Data monitoring can take 
place either remotely (review of eCRFs compared with uploaded, deidentified s 
mIRenBtsN) UorMiBn-EpRe:rsHoSnCb-yMaS-17-0436 


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designee of the trial PI. Remote data monitoring will require the site to scan the appropriate source documents. After 
scanning, local sites will be required to redact all patient identifiers. Finally, the redacted file will be saved and uploaded 
to the trial website’s secure repository. The DCC will be responsible for comparing the eCRF data and the uploaded 
source documents. 
 
 
11.0 STUDY COMMITTEES AND CORE LABS 
 
11.1 Steering Committee 
 
The steering committee will be responsible for oversight of the overall conduct of the study. These duties include 
protocol development and amendments, study progress, and overall data quality and integrity. The Steering Committee 
will oversee dissemination of study results through appropriate scientific meetings and publications. The Steering 
Committee may select additional investigators, based on enrollment, to participate on a Publication Committee. The 
Publication Committee will participate in the review and approval of all requests for data analysis, abstract and 
manuscript preparation and journal submission. 
 
11.2 Data Safety Monitoring Committee 
 
The Data Safety Monitoring Committee (DSMB) will include specialists in stroke neurology, neuro-intervention and 
biostatistics, none of whom are participating in the trial or have affiliation with the trial sponsor, UTHealth. The DSMB is 
responsible for monitoring subject safety through pre-defined, periodic review of the clinical study safety data. Details 
regarding DSMB responsibilities, qualifications, membership, meeting frequencies, and procedures are outlined in the 
DSMB charter. 
 
The trial’s un-blinded biostatistician will assist the data-core in preparing blinded DSMB reports. Data will be supplied 
to, and reviewed by, the DSMB as tables and/or figures. The DSMB can request more data. At each review the DSMB 
will evaluate whether the study should continue unchanged, require modification/amendment or be closed to enrollment 
and will inform the trial Co-PIs. 
 
The principal investigator (study sponsor), DSMB or the Institutional Review Board (IRB) have the authority to 
terminate, suspend, or require trial modifications. 
 
11.3 Imaging Core Labs 
 
An independent imaging core lab will blindly review baseline parenchymal and vascular imaging that is performed as 
each site’s routine care of acute ischemic stroke patients who may be eligible for EVT. The image-core interpretations of 
all neuroimaging will serve as the data source for analyses such as ASPECTS score, hemorrhage and hemorrhage 
classification (see table 5) and angiographic measures of occlusion, reperfusion and collateral grade (see table 4). 
Baseline imaging will usually include a non-contrast CT of the head, CT-angiogram of the head +/- neck and to a lesser 
degree, a CT-perfusion of the head. According to local practice, baseline MRI and MRA are also accepted. 
 
Follow-up neuroimaging (CT or MRI) that is routinely collected between 18-36 hours post thrombolysis or EVT will be 
used to determine the presence of infarction and hemorrhage. Conventional cerebral angiograms will be assessed for pre- 
intervention (e.g., diagnostic [first intracranial run] angiogram) clot location and TICI score. Reperfusion, graded using 
the modified TICI reperfusion score, will be recorded by the imaging core lab post EVT. Additional angiographic scales 
will be assessed including but not limited to collateral flow grade. All neuroimaging will be de-identified at the local site 


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and submitted to the sponsor DCC either digitally in DICOM format via a secure FTP portal or saved to a CD-ROM disc 
and mailed directly to the DCC. 
 
Table 5. Definition and description of intracranial hemorrhage. 
 
Intracranial 
Hemorrhage 
Definition 
HT-1 
Hemorrhagic Transformation Type 1. Small, scattered petechiae within ischemic field without 
mass effect. 
HT-2 
Hemorrhagic Transformation Type 2. Confluent petechiae within ischemic field without mass 
effect 
PH-1 
Hematoma within ischemic field with some mild space-occupying effect but involving ≤ 30% of 
the infarcted area 
PH-2 
Hematoma within ischemic field with space-occupying effect involving > 30% of the infarcted area 
RIH 
Any intraparenchymal hemorrhage remote from the ischemic field 
rPH-2 
PH-2 remote from the ischemic field 
IVH 
Intraventricular hemorrhage 
SDH 
Subdural Hematoma. Blood between the dura mater and the arachnoid mater 
EDH 
Epidural Hematoma - Blood between the dura mater and the skull 
SAH 
Subarachnoid hemorrhage 


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12.0 REFERENCES 
 
1. 
Roger, V.L., et al., Heart Disease and Stroke Statistics—2012 Update A Report From the American Heart 
Association. Circulation, 2012. 125(1): p. e2-e220 
2. 
Smith, W.S., et al., Prognostic significance of angiographically confirmed large vessel intracranial occlusion in 
patients presenting with acute brain ischemia. Neurocrit Care, 2006. 4(1): p. 14-7 
3. 
Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. 
N Engl J Med. Jan 1 2015;372(1):11-20. 
4. 
Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging 
selection. N Engl J Med. Mar 12 2015;372(11):1009-1018. 
5. 
Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic 
stroke. N Engl J Med. Mar 12 2015;372(11):1019-1030. 
6. 
Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N 
Engl J Med. Jun 11 2015;372(24):2285-2295. 
7. 
Avitsian R, Somal J. Anesthetic management for intra-arterial therapy in stroke. Current opinion in anaesthesiology. 
Oct 2012;25(5):523-532. 
8. 
Gupta R. Local is better than general anesthesia during endovascular acute stroke interventions. Stroke; a journal of 
cerebral circulation 2010; 41: 2718–2719. 
9. 
Brekenfeld C, Mattle HP, Schroth G. General is better than local anesthesia during endovascular procedures. Stroke; 
a journal of cerebral circulation 2010; 41: 2716–2717. 
10. John N, Mitchell P, Dowling R, Yan B. Is general anaesthesia preferable to conscious sedation in the treatment of 
acute ischaemic stroke with intra-arterial mechanical thrombectomy? A review of the literature. Neuroradiology 
2013; 55: 93–100. 
11. Powers WJ, Derdeyn CP, Biller J, et al. American Heart Association Stroke Council. 2015 American Heart 
Association/American Stroke Association focused update of the 2013 guidelines for the early management of 
patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from 
the American Heart Association/American Stroke Association. Stroke 2015;46:3020–3035. 
12. McDonald JS, Brinjikji W, Rabinstein AA, Cloft HJ, Lanzino G, Kallmes DF. Conscious sedation versus general 
anaesthesia during mechanical thrombectomy for stroke: a propensity score analysis. Journal of neurointerventional 
surgery. 2015;7(11):789-794. 
13. Abou-Chebl A, Yeatts SD, Yan B, . Impact of General Anesthesia on Safety and Outcomes in the Endovascular Arm 
of Interventional Management of Stroke (IMS) III Trial. Stroke; a journal of cerebral circulation 2015; 46: 2142– 
2148. 
14. Jumaa MA, Zhang F, Ruiz-Ares G, . Comparison of safety and clinical and radiographic outcomes in endovascular 
acute stroke therapy for proximal middle cerebral artery occlusion with intubation and general anesthesia versus the 
nonintubated state. Stroke; a journal of cerebral circulation 2010; 41: 1180–1184. 
15. Li F, Deshaies EM, Singla A, et al. Impact of anesthesia on mortality during endovascular clot removal for acute 
ischemic stroke. J Neurosurg Anesthesiol 2014; 26: 286–290. 
16. van den Berg LA, Koelman DL, Berkhemer OA, et al. Type of anesthesia and differences in clinical outcome after 
intra-arterial treatment for ischemic stroke. Stroke; a journal of cerebral circulation. May 2015;46(5):1257-1262. 
17. Berkhemer OA, van den Berg LA, Puck S.S. Fransen, et. al. The effect of anesthetic management during intra- 
arterial therapy for acute stroke in MR CLEAN. Neurology 2016;87: 656-664. 


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18. Bösel, J. (2015), Sedation vs. Intubation for Endovascular Stroke TreAtment (SIESTA) – a randomized monocentric 
trial. Int J Stroke, 10: 969–978. doi:10.1111/ijs.12488 
19. Sivasankar C, Stiefel M, Miano TA, et al. Anesthetic variation and potential impact of anesthetics used during 
endovascular management of acute ischemic stroke. J Neurointervention Surg 2015. Epub, doi:10.1136/neurintsurg- 
2015-011998. 
20. Mundiyanapurath S, Stehr A, Wolf M, et al. Pulmonary and circulatory parameter guided anesthesia in patients with 
ischemic stroke undergoing endovascular recanalization. Journal of neurointerventional surgery. Mar 16 2015. 
21. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute 
ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an 
observational study. Lancet 2007; 369: 275–282. 
22. Pedroza C, Han W, Truong VT, Green C, Tyson JE. Performance of informative priors skeptical of large treatment 
effects in clinical trials: A simulation study. Stat Methods Med Res. 2015 Dec 13. pii: 0962280215620828. 
[Epub ahead ofprint] PubMed PMID: 26668090. 
25.  Higashida, R. T. et al. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic 
stroke. Stroke; a journal of cerebral circulation 34, e109–37 (2003). 
26. McTaggart RA, Ansari SA, Goyal M, et al. Initial hospital management of patients with emergent large vessel 
occlusion (ELVO): report of the standards and guidelines committee of the Society of NeuroInterventional Surgery. J 
NeuroIntervent Surg 2017;9:316–323. 
27. Wittes J. Discussion of paper by Korn and Freidlin. Am J Bioeth. 2011 Mar;11(3):13-4. doi: 
10.1080/15265161.2010.546480. 
28.  William J. Powers, Alejandro A. Rabinstein, Teri Ackerson, Opeolu M. Adeoye, Nicholas C. Bambakidis, Kyra 
Becker, José Biller, Michael Brown, Bart M. Demaerschalk, Brian Hoh, Edward C. Jauch, Chelsea S. 
Kidwell, Thabele M. Leslie-Mazwi, Bruce Ovbiagele, Phillip A. Scott, Kevin N. Sheth, Andrew M. 
Southerland, Deborah V. Summers and David L. Tirschwell on behalf of the American Heart Association Stroke 
Council Stroke. 2018;49:e46-e110, 
29. G.W. Albers, M.P. Marks, S. Kemp, S. Christensen, J.P. Tsai, S. Ortega‑Gutierrez, R.A. McTaggart, M.T. Torbey, 
M. Kim‑Tenser, T. Leslie‑Mazwi, A. Sarraj, S.E. Kasner, S.A. Ansari, S.D. Yeatts, S. Hamilton, M. Mlynash, J.J. 
Heit, G. Zaharchuk, S. Kim, J. Carrozzella, Y.Y. Palesch, A.M. Demchuk, R. Bammer, P.W. Lavori, J.P. Broderick, 
and M.G. Lansberg, for the DEFUSE 3 Investigators* Thrombectomy for Stroke at 6 to 16 Hours with Selection by 
Perfusion Imaging N Engl J Med 2018;378:708-18. DOI: 10.1056/NEJMoa1713973 
30.  Nogueira RG, Jadhav AP, Haussen DC,et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between 
deficit and infarct. N Engl J Med 2018; 378: 11-21. 
31. Powers WJ, Derdeyn CP, Biller J, et al. American Heart Association Stroke Council. 2015 American Heart 
Association/American Stroke Association focused update of the 2013 guidelines for the early management of 
patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from 
the American Heart Association/American Stroke Association. Stroke 2015;46:3020–3035. 
32. American Society of Anesthesiologists Practice Guidelines for Preoperative Fasting and the Use of Pharmacologic 
Agents to Reduce the Risk of Pulmonary Aspiration. Anesthesiology. 2017;126:376–393. 
33. American Society of Anesthesiologists. Practice guidelines for sedation and analgesia by non-anesthesiologists. 
Anesthesiology. 2002;96:1004-1017. 
34. Green SM, Roback MG, Miner JR, Burton JH, Krauss. Fasting and emergency department procedural sedation and 
analgesia: a consensus-based clinical practice advisory. Ann Emerg Med. 2007 Apr;49(4):454-61. 


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13.0 APPENDICES 
Page 
Appendix I. Richmond Agitation Sedation Scale… ............................................................................... 27 
Appendix II.  SEGA simulation results of Bayesian power 
28 
analysis……………………………………………….... 
Appendix III. Prudent limits of targeted depth and length of ED procedural sedation and analgesia 
according to presedation assessment of aspiration risk ………………………………………… 
30 


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Appendix I. Richmond Agitation Sedation Scale (RASS) 
 
 
 


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Appendix II. Monte Carlo simulation results of Bayesian power 
 
1. Primary outcome of ordinal mRS at 90 days 
 
Based on data from 3 previous trials, we assumed rates of 10%, 14%, 11%, 19%, 18%, and 28% for mRS outcome 
categories of (0, 1, 2, 3, 4, 5+6) for Conscious Sedation group. Data from ANSTROKE trial was downweighted 50%. We 
assumed a treatment effect size corresponding to an OR=1.53 (GA group having better outcomes). We simulated 10,000 
trials for two total sample sizes, N=265 and N=250 and assuming rates of follow-up of 100%, 98%, 97%, 95%, and 90%. 
We calculated power (Table 1) to declare benefit based on range of thresholds to declare effectiveness (i.e., 
Pr(OR>1)>threshold). For analyses, we used a neutral prior centered at OR of 1.0 (95% CI: 0.3–3.0) for the treatment 
effect and ordinal logistic analysis detailed in Section 9.2. Assumed cross-over rate of CS group to GA group is 10%. 
Type I error rates are given in Table 2. 
 
Table 1: Power under a neutral prior and cross-over rate of 10%. 
Pr(OR>1)> N=265 N=260 N=257 N=250 N=245 N=242 N=238 N=225 
0.95 
0.50 
0.49 
0.49 
0.48 
0.47 
0.47 
0.46 
0.44 
0.90 
0.66 
0.64 
0.64 
0.64 
0.63 
0.62 
0.62 
0.60 
0.85 
0.74 
0.73 
0.73 
0.73 
0.72 
0.72 
0.71 
0.70 
0.80 
0.81 
0.80 
0.80 
0.80 
0.79 
0.79 
0.78 
0.77 
0.75 
0.85 
0.85 
0.84 
0.85 
0.84 
0.83 
0.83 
0.82 
 
 
 
Table 2: Type I error rates under a neutral prior and cross-over rate of 10%. 
Pr(OR>1)> N=265 N=260 N=257 N=250 N=245 N=242 N=238 N=225 
0.95 
0.04 
0.04 
0.04 
0.03 
0.04 
0.04 
0.04 
0.04 
0.90 
0.08 
0.08 
0.08 
0.08 
0.08 
0.08 
0.09 
0.08 
0.85 
0.13 
0.13 
0.13 
0.13 
0.13 
0.13 
0.14 
0.13 
0.80 
0.18 
0.18 
0.18 
0.18 
0.18 
0.18 
0.18 
0.18 
0.75 
0.23 
0.23 
0.23 
0.23 
0.23 
0.23 
0.23 
0.24 
 
2. Secondary outcome of dichotomized mRS at 90 days 
 
We assumed good outcome (mRS of 0-2) rates of 45% for General Anesthesia group and 35% for Conscious Sedation 
group. We simulated 10,000 trials for each of the sample sizes in Table 3 and calculated power to declare benefit based on 
range of thresholds to declare benefit (i.e., Pr(RR>1)>threshold). For analyses, we used a neutral prior centered at RR of 
1.0 (95% CI: 0.3–3.0) for the treatment effect and a log binomial model detailed in section 9.2. 
 
Table 3: Power under a neutral prior and cross-over rate of 10%. 
Pr(RR>1)> 
N=265 
N=260 
N=250 
N=242 
N=225 
0.95 
0.42 
0.43 
0.42 
0.37 
0.41 
0.90 
0.58 
0.57 
0.56 
0.54 
0.56 
0.85 
0.67 
0.67 
0.66 
0.62 
0.64 
0.80 
0.73 
0.74 
0.73 
0.71 
0.72 
0.75 
0.79 
0.79 
0.77 
0.76 
0.77 


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To compute type I error, we assumed equal rates of good outcomes of 35% for both groups. We used the same neutral 
prior (RR of 1.0, 95% CI, 0.3–3.0) and log binomial model for analysis. Type I error rates are given in Table 4. 
 
Table 4: Type I error rates under a neutral prior and cross-over rate of 10%. 
Pr(RR>1)> 
N=265 
N=260 
N=250 
N=242 
N=225 
0.95 
0.05 
0.04 
0.04 
0.05 
0.04 
0.90 
0.09 
0.09 
0.08 
0.09 
0.08 
0.85 
0.14 
0.14 
0.14 
0.15 
0.12 
0.80 
0.19 
0.21 
0.19 
0.19 
0.17 
0.75 
0.24 
0.25 
0.23 
0.24 
0.24 
 
We also computed the power under a skeptical prior expressing prior belief that Conscious Sedation will have higher rates 
of good outcome. Using a skeptical prior centered at RR of 0.82 (95% CI: 0.27–2.5) for the analyses gives power shown 
in Table 5. Here, there will be >50% power to convince a skeptic of benefit of General Anesthesia (RR>1) using a 
posterior probability threshold of 90% or lower. 
 
Table 5: Power under a skeptical prior and cross-over rate of 10%. 
Pr(RR>1)> 
N=265 
N=260 
N=250 
N=242 
N=225 
0.95 
0.37 
0.40 
0.37 
0.40 
0.34 
0.90 
0.52 
0.56 
0.53 
0.53 
0.50 
0.85 
0.62 
0.65 
0.61 
0.63 
0.58 
0.80 
0.70 
0.73 
0.70 
0.71 
0.65 
0.75 
0.76 
0.78 
0.75 
0.77 
0.71 


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Appendix III. 
Prudent limits of targeted depth and length of ED procedural sedation and analgesia 
according to presedation assessment of aspiration risk