Intraoperative Monitoring and Management Protocol to Reduce Strokes (IMMPRES): Pilot Study
Phase: NA
Conditions: Cardiac Surgery
Sponsor: Parthasarathy Thirumala

Official Title: Intraoperative Monitoring and Management Protocol to Reduce Strokes 
(IMMPRES): Pilot Study 
 
NCT04543838 
 
Document Date: 6/23/2022 
 

 
Study Protocol 
If the patient is eligible, interested, and provides consent, they will complete initial 
preoperative baseline surveys and assessments. These assessments include: Medical 
History, Medications, Neurological Exam, NIH stroke Scale, Questionnaire for Verifying 
Stroke-Free Status (QVSFS), Delirium Screen, Modified Rankin Scale, Barthel Index, 
Digit Symbol Substitution Test (Cognitive Assessment), Trail Making Test part B (TMT-B) 
(Cognitive Assessment), and Montreal Cognitive Assessment (MoCA) (Cognitive 
Assessment), Depression Scale, and Quality of Life scale. General history, risk factor 
profile and physical examination (H&P) will be performed prior to entering the study. 
Neurological examinations, NIHSS, Modified Rankin Scale and Barthel Index will be 
performed by study neurologist. A Questionnaire for Verifying Stroke-Free Status 
(revised Questionnaire for Verifying Stroke-Free Status (QVSFS)), QOL assessment, 
Delirium and Cognitive assessment will be administered to each potentially eligible 
patient by a research coordinator. Subjects of child bearing age will complete a 
pregnancy test. 
 
Baseline surveys and assessment will collected during a pre-operative session, either in 
conjunction with a pre-op clinic visit in-person prior to surgery during their surgical 
admission. This will allow maximum flexibility in timing, without interfering with clinical 
care. 
 
 
Clinically collected data will be abstracted from the electronic medical record (EMR) for 
research purposes. We will review the patients preoperative medical records to screen 
patients for the use of intraoperative monitoring. This is currently a standard clinical 
practice. After enrollment, the subject will be randomized into the control or intervention 
group. Subjects will be computer randomized to condition 1:1. It will take approximately 
a half an hour to complete surveys and study procedures. On the day of surgery, EEG 
and somatosensory evoked potentials assessments will be performed preoperatively. 
The study team will code data to distinguish remote from in person assessment on the 
individual instruments. 
 
Procedure: The cardiac surgeons who will be performing surgery will be informed by the 
principal investigator. The medical management of patients before, during, and after the 
procedure will be continued as routine medical care in standard medical therapy group. 
In the intervention group, standard medical therapy with intraoperative monitoring and 
management protocol will be done. Our IMMP will be a) intraoperative monitoring with 
SSEP and EEG during surgery and continued for 4 hours after; b) management protocol 
will be treating patients based on a SSEP and/or EEG changes. In patients with bilateral 
SSEP and/or EEG changes, we will aim for a MAP target of the greater of 20% above 
the patient’s preoperative baseline or an absolute threshold of 80 mmHg. In patients 
with persistent unilateral SSEP and/or EEG changes, the higher MAP target will be 
maintained followed by immediate post-operative evaluation for stroke. 
In the control group, the patient will receive standard of care. 
 

Post-Procedure/Pre-Discharge: Brief history and physical examination daily while 
patient is in hospital. Neurological examination performed by study Neurologist. Delirium 
screen will be performed. NIH Stroke Scale (NIHSS) performed by study neurologist 18 
to 54 hours post procedure. MRI will be performed before discharge. The MRI will be 
completed at the MRI Research Center. This trial will include 1.5 T MRI scanners. 
All subjects will have continuous monitoring with a pulse-oximeter. MR technologists will 
monitor pulse-oximeter. They will terminate the scan, and call an investigator to 
evaluate the subject, if pulse-oximeter data goes below/above some defined threshold 
(sustained heart rate over 100 bpm, oxygen saturation below 90%). The responsible 
investigator for each study scan when scheduled and who will available to respond if 
necessary will be selected on a case-by-case basis in REDCap "MRI Completion" 
instruments. The Digit Symbol Substitution Test (Cognitive Assessment), Trail Making 
Test part B (TMT-B) (Cognitive Assessment), and and Montreal Cognitive Assessment 
(MoCA) (Cognitive Assessment) will be performed. 
 
Follow-up: At 30 days post-op: Modified Rankin Scale, Barthel Index, Questionnaire for 
Verifying Stroke-Free Status (QVSFS), Quality of Life Assessment, Digit Symbol 
Substitution Test (Cognitive Assessment), Trail Making Test part B (TMT-B) (Cognitive 
Assessment), and Montreal Cognitive Assessment (MoCA) (Cognitive Assessment) will 
be performed. The Cognitive Assessments (DSST, TMT-B, & MoCA) & Neurological 
Assessments (MRS & The Barthel Index) through mail and telemedicine/Microsoft 
Teams. 
 
Follow-up: At 3 months: Neurological exam, Modified Rankin Scale, Barthel Index, 
TIA/Stroke Questionnaire, Quality of Life Assessment, Digit Symbol Substitution Test 
(Cognitive Assessment), Trail Making Test part B (TMT-B) (Cognitive Assessment), and 
Montreal Cognitive Assessment (MoCA) (Cognitive Assessment) will be performed. The 
Cognitive Assessments (DSST, TMT-B, & MoCA) & Neurological Assessments (MRS & 
The Barthel Index) through mail and telemedicine/Microsoft Teams. 
 
Follow-up: At 1 year: Neurological exam, Modified Rankin Scale, Barthel Index, 
TIA/Stroke Questionnaire, Quality of Life Assessment, Digit Symbol Substitution Test 
(Cognitive Assessment), Trail Making Test part B (TMT-B) (Cognitive Assessment), and 
Montreal Cognitive Assessment (MoCA) (Cognitive Assessment) will be performed. The 
Cognitive Assessments (DSST, TMT-B, & MoCA) & Neurological Assessments (MRS & 
The Barthel Index) through mail and telemedicine/Microsoft Teams. 
 
Assessments and Questionnaires: 
1. NIH Stroke Scale (NIHSS): The NIHSS was specifically designed for assessment of 
interventions in clinical trials. Rather than measuring function specifically, the NIHSS 
operates a 15-item ordinal, non-linear, neurological impairment scale covering 
consciousness, ocular movement, vision, coordination, speech and language, sensory 
function, upper and lower limb strength, facial muscle function, and hemi-neglect61. 
NIHSS became the gold standard for stroke severity rating after the first successful trial 
in acute stroke therapy62. 
2. Stroke/TIA Questionnaire: The Questionnaire for Verifying Stroke-Free Status 

(QVSFS) 50is an 8-item structured interview designed to identify stroke-free individuals. 
The QVSFS has negative predictive value of the QVSFS was 0.96, with positive 
predictive value of 0.71. The QVSFS can effectively identify stroke-free individuals with 
a high degree of accuracy, even in a population with a large proportion of patients with 
prior stroke or TIA. 
3. Cognitive Assessment: The Montreal Cognitive Assessment (MoCA), a widely used 
test will be used measure to assess cognitive decline. It has shown to be superior to the 
Mini-Mental State Exam (MMSE) in evaluation of executive, visuo-spatial and language 
skills after stroke63,64. The MoCA instrument assesses multiple cognitive domains65: 
visuospatial abilities, executive functions, short-term memory recall, attention, 
concentration, working memory, language, and orientation to time and space and we 
feel this will provide a thorough assessment of the impact of acute perioperative covert 
stroke. MoCA scores range from 0 to 30 with higher a higher score indicating superior 
cognitive function. A decrease of 2 points or more in MoCA score is perceived to be 
important to patients, and has been used as a cut-off for important cognitive 
decline.21,66 The Digit Symbol Substitution Test (DSST) is a widely used sensitive test 
to evaluate cognitive decline across a wide range of clinical populations. DSST 
evaluates cognitive speed, attention, and executive functions by requiring participants to 
match symbols to numbers within a 120 second time limit using a key.67 Scores range 
from 0 to a maximum of 133 with a higher score indicating superior cognitive ability. We 
will utilize a decrease of 5 or more points on the DSST is considered clinically 
meaningful cognitive decline on the basis of differences in score observed between 
patients aged 70 and 75 years old in the Cardiovascular Health Study68,69 The Trail 
Making Test part B (TMT-B) is the widely used test for cognitive decline after cardiac 
procedures.56 The TMT-B measures cognitive domains of processing speed, 
sequencing and mental flexibility by measuring the time (in seconds) to connect 
numbers and letters 
randomly placed on a page in an alphanumerical order, alternating between numbers 
and letters. Completion times between 78 and 128 seconds are considered average for 
adults aged 75 to 98 years of age. We will use a threshold of an increase of 10% or 
more in TMT-B completion time has been considered meaningful cognitive decline in a 
recent sub study of the HOPE-3 trail. 
4. Modified Ranking Scale(mRS). The Modified Rankin Scale (MRS) is a brief physical 
function assessment, which covers the entire range of functional outcomes from no 
symptoms to death, has demonstrated validity with measures of stroke pathology (eg, 
infarct volumes) and agreement with other stroke scales. It is widely used in clinical 
trials72 and has demarcated effective and ineffective acute stroke therapies in trials with 
appropriately powered sample sizes73. 
5. Barthel’s index: The BI operates according to a 10-item scale in which patients are 
judged upon degree of assistance required when carrying out a range of basic activities 
of daily living (ADL). The assessment is a validated questionnaire comprising a total 
score of 100 for the 10 items of the scale. The patient’s answers on each item are 
scored based upon actual ability (preferably observed by the assessor). The usual 
scoring for each item is 0 points for “no ability” to do the item independently, 5 points for 
“moderate help” with the item, and 10 points for being able to manage the item 
independently. The BI has emerged as the second most popular tool for assessment of 

post-stroke outcome in clinical stroke trials74. 
6. Delirium Assessment: We will utilize modified Confusion Assessment Method 
(CAM)52, 3D CAM59 for hospitalized patients and ICU CAM75 for patients in the ICU to 
evaluate for delirium. 3D CAM, a 3-minute structured assessment has a sensitivity of 
95% [84%, 99%] and specificity of 94% [90%, 97%] to identify delirium in the hospital76. 
In a large systematic review, ICU CAM to diagnose delirium had a pooled sensitivity of 
the CAM-ICU was 80.0% (95% confidence interval (CI): 77.1 to 82.6%), and pooled 
specificity of 95.9% (95% CI: 94.8 to 96.8%). Delirium after cardiac surgery can be high 
(41%) and an Independent Predictor of Functional Decline. 
7. Quality of Life assessments: We will utilize EuroQol 5-dimension (EQ-5D) 
questionnaire to assess the patients’ health-related quality of life. EQ-5D is a self 
reported questionnaire designed to measure the health status and can be collection by 
phone or video interview. The EQ-5D questionnaire consists of two parts. The first part 
contains the EQ-5D descriptive system, comprising of 5 questions regarding mobility, 
selfcare, usual activities, pain, and depression (scores range from 0 to 1). The second 
part is a vertical, visual analogue scale with the end-points of “best imaginable health 
state” and “worst imaginable health state” (scores range from 0 to 100). EQ-5D has 
been used as a measure of health-related quality of life in patients who have suffered 
an clinical stroke7879, covert stroke21, and in those undergoing cardiac surgery. 
8. Assessment of Depression: Depression after stroke affects approximately one third of 
stroke survivors in the first year after stroke, with a cumulative incidence of 55%.81,82 
We will use the 9 – item Patient Health Questionnaire to measure the incidence of 
depression. The 9-item Patient Health Questionnaire (PHQ-9) (sensitivity: 0.86; 95% CI, 
0.70–0.94; specificity: 0.79; 95% CI, 0.60– 0.90) appeared to be the optimal measures 
for screening and was suggested to be more pragmatic 83. 
 
Intraoperative Neurophysiological Monitoring: Blood 
pressure management will be institutional standard of care as determined by the 
Anesthesiologist per standard of care. Electroencephalography (EEG): EEG recording 
and analysis during carotid surgery has as previously described by the group18. 
Electrode placement on the scalp is based on the international 10-20 EEG system. EEG 
recording will start after anesthesia had been successfully induced and continue 
throughout the procedure. We will record 16 channel EEG system The EEG recording 
parameters are as follows: notch filter 60 Hz, the band pass filter for 1-70 Hz; sensitivity 
will vary between 5-7 microvolts/div and a time base of 30 mm/sec. Significant EEG 
changes, will be defined as a loss of in the amplitude of fast frequency and /or increase 
of delta activity by more than two fold15. A raw digital and quantitative EEG will be 
processed using software provided by the Natus Medical ® Pleasanton, CA. 
Somatosensory evoked potentials (SSEP): SSEP recording and analysis during cardiac 
surgery will be performed as previously described by the group18. We will 
independently stimulate the bilateral median nerve at the wrist using adhesive sticky 
pad electrodes. Scalp electrodes will be placed at P4/Fz and P3/Fz will be placed per 
the international 10–20 system. A cervical electrode is localized at the CV2, and 
peripheral electrodes are placed at the erb’s point bilaterally (EPs and EPd). Three 
channels of data will be collected for each median nerve SSEP: FZ-P4/P3 to record the 
cortical potential, FZ-CV2 to record the cervical potential, and EPs-EPd to record the 

erb’s point potential. Stimulation frequency will be set to 2.33-2.41 Hz with duration of 
0.2-0.3 milliseconds. Band pass filters are set at 10-300 Hz for the cortical channel, 30-
1,000 Hz for the cervical channel, and 100Hz- 1 kHz for the erb’s point channel. The 
analysis time is 100 milliseconds. Significant SSEP changes, a variable of interest will 
be defined as greater than 50% decrease in the amplitude N20-P30 in SSEP in the Fz-
P4/P3 channel 14any time during.