Perioperative Multimodal General AnesTHesia Focusing on Specific CNS Targets in Patients Undergoing carDiac surgERies - the PATHFINDER II Study
Phase: NA
Conditions: Postoperative Delirium, Hemodynamic Instability, Pain, Neurocognitive Dysfunction
Sponsor: Beth Israel Deaconess Medical Center

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
PART B
STUDY DESCRIPTION
B1.
PURPOSE OF PROTOCOL
B2.
SIGNIFICANCE AND BACKGROUND FOR THE STUDY
Title of Protocol
Perioperative multimodal general AnesTHesia FocussINg on specific
CNS targets in patients undergoing carDiac surgERies - The
PATHFINDER II study
Principal Investigator
Dr. Balachundhar Subramaniam MD, MPH, FASA
In the PATHFINDER 2 trial, we will test our intraoperative EEG-guided multimodal general anesthesia
(MMGA) management strategy in combination with a postoperative protocolized analgesic approach to:
1.) reduce the incidence of perioperative neurocognitive dysfunction in cardiac surgical patients
2.) ensure hemodynamic stability and decrease use of vasopressors in the operating rooms
3.) reduce pain and opioid consumption postoperatively
Specific Aims:
In this randomized (1:1) study on 70 patients (age ≥60 years) undergoing cardiac surgery, we aim to:
1.) Demonstrate that the perioperative EEG-guided MMGA bundle reduces the postoperative
increase in plasma levels of Interleukin -6 and Neurofilament light
2.) Demonstrate that the perioperative EEG-guided MMGA bundle reduces concurrent EEG burst
suppression and cerebral desaturation events by 20% from the baseline/ standard of care group.
3.) Develop an EEG-guided MMGA curriculum for cardiac anesthesiology with preexisting online
modules from Dr. Brown’s lab supplemented with common clinical scenarios during a cardiac
surgical case and establishing education and training for anesthesiologists and postoperative
ICU nurses
Multimodal General Anesthesia (MMGA) and inflammation
General anesthesia is a drug-induced reversible state consisting of unconsciousness, amnesia, antinociception,
and immobility while maintaining physiological stability1. The primary objective of general anesthesia is to
eliminate pain during surgery and invasive diagnostic procedures. The state of general anesthesia eliminates
pain by preventing both nociception (the transmission of noxious neural sensory signals) and conscious
perception of nociception. The current practice of balanced anesthesia typically uses opioids for antinociception,
intravenous propofol to induce and inhaled ethers to sustain unconsciousness and produce amnesia, and muscle
relaxers for immobility1, 2. However, recent advances in understanding specific neural circuits involved in
antinociceptive and arousal pathways allows for the synergistic use of medications to create the state of general
anesthesia while reducing total anesthetic agent exposure3. As described in Brown et al., multimodal general
anesthesia (MMGA) uses a combination of medications to control nociception, each targeting a different
component of the nociceptive system. These medications also decrease arousal. Hence, less hypnotic agent is
required to achieve unconsciousness. MMGA will utilize two or more drugs providing anesthesia from multiple
brain circuits (e.g. Propofol, Dexmedetomidine, and Ketamine) and for analgesia (Dexmedetomidine, Ketamine,
Remifentanil, Hydromorphone, and local anesthetic block) and muscle relaxants. By simultaneously targeting
different neural circuits in low doses guided by EEG, clinicians can thereby maximize the therapeutic benefit
while minimizing drug exposure and concomitant side effects. Rationally designed MMGA regimens have the
potential to drastically benefit anesthesiology practice, particularly for surgeries where anesthetic dosing may
interfere with surgical outcomes.

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Study Description – Part B
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PI Revision Date:
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Common occurrence of cognitive disturbances after surgery and anesthesia has initiated studies trying to
understand the mechanism underlying the disturbances. Factors such as hypoxemia, hypotension,
Cardiopulmonary Bypass management, hypothermia, anticoagulation, cerebral blood flow have been studied4.
Inflammation triggered by the perioperative stress also has been proposed to be a factor involved in perioperative
cognitive decline5,6. The mechanism behind this is that the stress can cause a systemic inflammatory response
leading to release of inflammatory cytokines like Interleukin (IL-6) and lipocalin-2, which in turn leads to
neuroinflammation. In response to this, neuronal injury happens leading to release of neuronal proteins into the
plasma. Measuring the rise of the inflammatory cytokines and neuronal components can indicate the magnitude
of neuroinflammation. Neurofilament light is a neuronal cytoplasmic protein highly expressed in large caliber
myelinated axons and has been seen to proportionally increase to the extent of neuronal damage7.
Apart from reducing the amount of drugs administered during anesthesia, MMGA titrated by EEG also can
potentially reduce the incidence of perturbations to perioperative brain health. This eventually can reduce the
neuroinflammation and thereby the perioperative cognitive disturbances.
Nociception is the propagation of noxious stimuli through the sensory system, whereas pain is the conscious
perception of nociceptive information.8 Nociception due to the injury and inflammation of tissue with surgery is the
main reason for providing general anesthesia. Opioids are the commonly used antinociceptive agents during the
perioperative period. Despite all the advantages, they can cause respiratory depression, nausea, vomiting, urinary
retention, constipation, ileus, and pruritus.9 Moreover, increased dependence on opioids have resulted in an opioid
epidemic in the United States.10
Considering the disadvantages associated with opioids, the current strategy for balanced anesthesia uses multiple
agents in addition or without opioids to achieve the anesthetic state. This approach defined as multimodal general
anesthesia includes agents that have specific central nervous system targets. Moreover using more drugs at
minimal doses could maximize the advantages and minimize the adverse effects.11
Nociceptive pathways
Understanding nociceptive pathways becomes vital in formulating a successful strategy. The nociceptive system
consists of nociceptors, ascending pathways, and descending pathways. Nociceptors are free nerve endings seen
in peripheral tissue and viscera that initiates nociception or pain. Ascending pathways transmit nociceptive stimuli
from the periphery to the spinal cord, brainstem (medulla and midbrain), amygdala, thalamus, relaying with the
sensory cortex. Descending pathways begin in the sensory cortex and project to the hypothalamus and amygdala.
These projections then synapse with periaqueductal gray in the midbrain and the nucleus of the tracts solitarius and
projects to the spinal cord primarily through the rostral ventral medulla. These pathways are activated immediately
by the ascending pathways and modulate nociception. Moreover, descending pathways are strongly connected
with the arousal pathways, which explains the decrease in arousal effect caused by antinociceptive agents.
Simultaneously focus on multiple targets in the nociceptive system is the key concept underlying the design of
multimodal general anesthesia.
Opioids and nociception
Opioids act on receptors located on periaqueductal gray, spinal cord, amygdala, rostral ventral medulla, and cortex.
These agents, a) block afferent nociceptive inputs into the spinal cord, b) enhance descending inhibition of
nociceptive inputs, c) decrease nociceptive perception and the emotional effect of pain stimulation, d) decrease
arousal through their inhibitory actions on brainstem cholinergic circuits, e) enhance cholinergic action on sinoatrial
node (bradycardia) and reduces sympathetic responses with nociception
Ketamine and nociception
Ketamine targets N-methyl-d-aspartate (NMDA) glutamate receptors on peripheral afferent nociceptive neurons
synapsing with the dorsal horn of the spinal cord. Its action on cortex and arousal system results in antinociceptive
and decreased arousal. Glutamatergic projections from the parabrachial nucleus and medial pontine reticular
formation are the target region for altering arousal. At higher ketamine doses, inactivation of these arousal
pathways leads to unconsciousness with distinct electroencephalogram patterns (alternating slow-delta with
gamma).
Dexmedetomidine

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Study Description – Part B
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Dexmedetomidine causes inhibition of descending nociceptive transmission by activating inhibitory interneurons
synapsing at the dorsal horn of the spinal cord. It also exerts an antinociceptive effect by decreasing arousal. It acts
on presynaptic receptors and decreases the release of norepinephrine from locus ceruleus neurons projecting to
the basal forebrain, intralaminar nucleus of the thalamus, preoptic area of the hypothalamus, and diffusely to the
cortex. Consequently, this results in decreased arousal and the EEG shows spindle and slow-delta oscillations at
low-to-moderate doses, and only slow-delta oscillations at a higher dose.
Propofol & Sevoflurane
These agents have no direct action on nociceptive pathways but decrease the perception by rendering the patient
unconscious. They act on GABAA receptor synapses of inhibitory neurons to pyramidal neurons in the cortex,
thalamus, brainstem, striatum, and spinal cord. Moreover, inhaled agents also block potassium channels, cyclic
nucleotide-gated channels, and NMDA receptors. EEG shows characteristic slow-delta and alpha oscillations.
Above 1 MAC (minimal alveolar concentration), inhaled anesthetics show a decrease in the alpha power and an
increase in the delta that gives the appearance of a theta oscillation.
Monitoring for unconsciousness and antinociception
There is evidence that intraoperative EEG monitoring reduces anesthetic dose and recovery time.12 Few studies
suggest there may be a lower incidence of postoperative delirium (POD), as well as postoperative cognitive
dysfunction (POCD) with processed electroencephalogram-monitored care. United Kingdom’s National Institute
for Health and Care Excellence published 2012 guidelines recommending the use of processed EEG monitoring,
especially in “high-risk” patients to improve cognitive outcomes.13
In a recent study, EEG-guided anesthetic administration was not found to decrease the incidence of postoperative
delirium as compared to the standard care.14 However, the authors found a significant decrease in mortality up to 30
days after surgery in patients who received EEG guided anesthetic. They computed EEG suppression ratio and
Bispectral Index (BSI) as exposure measures and multimodal anesthesia was not used.
Components of Multimodal General Anesthesia
Elderly patients undergoing cardiac surgery are at a high risk for adverse consequences in the
perioperative period including comparatively higher rates of morbidity, mortality, complication rates,
repeat hospital admissions, and healthcare utilization15,16,17. Cardiac anesthesiology is challenging due to
the high-risk nature of bypass and valve procedures, distinct mean arterial pressure (MAP) goals at
different phases of surgery, and repeated nociceptive stimuli. Interference of the surgical procedure with
the typical signs used to titrate anesthetic agents further complicate cardiac anesthesiology, as blood
pressure and heart rate no longer provide insight into nociception during cardiac bypass. Intraoperative
hemodynamic instability and postoperative cognitive dysfunction are also more common in elderly
cardiac surgical patients due to factors such as limited cardiac and autonomic reserve, decreased
cognitive reserve, and increased susceptibility to deeper anesthetic states18,19,20. While EEG-guided
anesthesia has not previously shown clear improvement in perioperative outcomes21,22, the lack of
traditional nociceptive signaling during cardiac bypass necessitates a role for direct brain monitoring via
EEG in cardiac surgery to enable personalized anesthesia care and reduce incidence of hypotension,
morbidity, mortality, and complications in the postoperative period.
There is a compelling association between increased postoperative myocardial and renal dysfunction
with increasing duration of intraoperative hypotension23 (hypotension threshold defined as MAP < 65 mm
of Hg) in non-cardiac surgical patients. However, targeting higher MAP during cardiopulmonary bypass
can likewise increase adverse events24. Reduction of anesthetic dosing could potentially reduce
COMPONENT
DRUGS
Antinociception
Ketamine, Remifentanil, Dexmedetomidine, Acetaminophen
Unconsciousness (amnesia)
Propofol, Sevoflurane
Immobility
Atracurium, Rocuronium, Succinylcholine

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
anesthetic-induced myocardial depression and vasodilation, therefore providing better hemodynamic
stability with less vasopressor support.
Pilot Studies:
We have performed prior studies to test the relationship between vasopressor use, hemodynamic
stability, and postoperative complications23,25,26. We have also performed pilot studies to determine the
effects of multimodal pain management strategies on postoperative cognitive dysfunction23, 24. Finally, we
have performed a feasibility study to determine the safety and efficacy of rationally designed EEG-
guided MMGA in a small cohort of patients undergoing cardiac surgery.
In a retrospective analysis of 6000 cardiac surgical patients, increased use of vasopressors was
associated with increased postoperative complications23 (manuscript under review). In an ongoing
retrospective study, we have found that an increased duration of hypotension was associated with
increased mortality, renal failure, and stroke. Our multivariate logistic regression model showed that
there is a significant association of a composite outcome of stroke, renal failure, and death with the
fourth quartile of duration of hypotension with MAP < 65 mmHg and total vasopressor dose in mg16 [2.09
with 95% CI = 1.35 - 2.38 and 1.65 with 95% CI 1.08 - 2.56, respectively]. At a different institution, in a
randomized clinical trial of 239 patients undergoing elective cardiac surgery the use of processed EEG
using a visible Narcotrend (NT) monitor significantly reduced the intraoperative vasopressor
(noepinephrine) dose29. After adjusting for type of surgery, intraoperative norepinephrine application was
reduced in visible-NT (n=120, mean of cumulative dose 4.71 μg/kg bodyweight) compared to blinded-NT
patients (n=119, 6.14 μg/kg bodyweight) with an adjusted robust mean difference of 1.71, with 95% CI
0.33 – 3.10 μg/kg bodyweight.
In the PATHFINDER pilot study30 (NCT04016740), we used an EEG-guided MMGA strategy for elderly
patients (age ≥60 years) undergoing cardiac surgery with cardiopulmonary bypass. We successfully
implemented our non-randomized prospective observational feasibility trial in the operating rooms and
intensive care unit at the Beth-Israel Deaconess Medical Center (Boston, MA) from July 2019 to January
2020 and did not find any adverse effects associated with MMGA. Thus, we are prepared to compare
MMGA in cardiac surgery with standard of care. We found similar intraoperative hemodynamic stability
(intraoperative hypotension, coefficient of variation), reduced intraoperative midazolam use, and a trend
towards reduced postoperative delirium (17%, 3/17 PATHFINDER MMGA subjects with one excluded for
an unrelated postoperative complication) when comparing our EEG-guided MMGA to historic controls
from our postoperative acetaminophen DEXACET trial28 (29%, 17/59 DEXACET subjects).
Though our postoperative acetaminophen trial showed a small reduction in postoperative pain intensity
and analgesic use, when intraoperative MMGA and postoperative acetaminophen are used as a bundle
to manage nociception they could have additive or synergistic analgesic effects.
We propose to randomize (1:1) 70 patients undergoing cardiac surgery to our perioperative EEG-guided
MMGA bundle (described in full below) or standard-of-care management based primarily on the use of
sevoflurane for unconsciousness and intermittent doses of fentanyl and hydromorphone for
antinociception.
We will test our intraoperative EEG-guided MMGA management strategy in combination with a
postoperative protocolized analgesic approach to ensure hemodynamic stability and decreased use of
vasopressors in the operating rooms and reduce pain and opioid consumption postoperatively. We will
also investigate whether EEG-guided MMGA strategy reduces the incidence of perioperative
neurocognitive dysfunction in cardiac surgical patients. This approach will further individualize care and
minimize the use of intraoperative vasopressor-inotropic dose, dose of anesthetic medications, and
postoperative opioids given to each patient potentially preventing hemodynamic complications and post-
operative cognitive dysfunction after surgery.

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
B3.
DESCRIPTION OF RESEARCH PROTOCOL
A.
Study Design – Overview, Methods, Procedures
Study Design:
This is a randomized control trial. Study enrollment will consist of 70 patients (1:1 allocation, 35 controls, 35
experimental) (age ≥60 years) undergoing coronary artery bypass grafting (CABG) and/or valve or aortic
cardiac surgery procedures with cardiopulmonary bypass (CPB) who are eligible for fast tracking (early
extubation within 6 hours achieved with time directed protocols and low dose opioid anesthesia) in the
intensive care unit at Beth Israel Deaconess Medical Center. Patients meeting inclusion criteria with no
exclusions will be approached by a research team member and PI to obtain written informed consent.
Enrollment:
Study subjects will be identified from the perioperative information management system (PIMS), surgical
consult lists, cardiac surgical clinic visit schedules and pre-admission testing (PAT) clinic visit schedules.
We have requested a waiver of authorization for pre-screening purposes. After confirming eligibility, the
patient will be approached by an IRB approved research team member to discuss the study in detail.
Written informed consent will be obtained research team member and PI before initiation of any study
procedure.
Allocation of patients:
70 patients will be enrolled in this study and randomized by 1:1 allocation. 35 patients will be randomized to
the perioperative EEG-guided MMGA bundle and 35 patients will receive standard-of-care management
based primarily on the use of sevoflurane for unconsciousness and intermittent doses of fentanyl and
hydromorphone for antinociception.
Study Procedures:
Preoperative
Assessment by an anesthesiologist, including detailed patient education about:
i.
Multimodal general anesthesia and
ii.
Postoperative pain management
iii.
Standardized education training to train clinical anesthesiologists involved in the
intervention
1.
Short YouTube modules published by Prof. Emery Brown’s lab
2.
IARS (International Anesthesia Research Society) tutorials and certification
(paperwork will be stored in our REDCap database)
3.
Instruction in Management Strategy: Creation of standard scenarios
requiring drug administration changes in the intraoperative period
Intraoperative
The anesthesiologists involved in this study will be taught using a combination of online resources and in-
person training to infer differences in anti-nociception, unconsciousness, movement, and changes during
other perioperative events by monitoring the EEG. They will also be trained in titrating hypnotic medications
and antinociceptive medications based on changes in heart rate, blood pressure, specific surgical time-
points, and the EEG waveforms.
i.
Routine anesthetic induction
Standard practice of induction using 250mcg (3-5 mcg/kg) of IV fentanyl, 50-200mg of Propofol or 10-20mg
of Etomidate and endotracheal intubation will be facilitated by 50-100mg of IV rocuronium.
ii.
Bilateral Pecto-intercostal fascial block (PIFB) block

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Study Description – Part B
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PI Revision Date:
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Intervention patients will receive a bilateral PIFB block will be administered by trained anesthesiologists
after induction and before incision using 20 ml of 0.2% Ropivacaine on both sides (total of 40 ml). Trained
anesthesiologists will use ultrasound guidance to administer the PIFB in the plane between the external
intercostal and the pectoralis major muscles.
iii.
Medications
iv.
EEG monitoring (level of unconsciousness and titration of drugs) : EEG stickers
attached and connected to the Sedline monitor (described below in perioperative
EEG and Cerebral Oximetry (CO) monitoring) at least 5 minutes prior to start of
induction.
v.
CO monitoring : CO stickers attached, connected to the Sedline monitor and data
collected passively (no titration of drugs).
Postoperative
i.
Standard pain management protocol (both control and intervention groups)

IV Acetaminophen 1gm x 4 doses at 6 hourly intervals starting from 1 hour
after ICU arrival

IV Hydromorphone/fentanyl boluses as needed per current practice for
rescue analgesia

Other oral pain medications as per standard of care (Oxycodone etc.)
ii.
Dexmedetomidine infusion 0.4-1.4 mcg/kg/hr (EEG guided for intervention group)
iii.
Dexmedetomidine infusion will be continued till extubation and dose will be titrated
based on patient response, hemodynamic stability and EEG monitoring.
iv.
Propofol infusion may be added/used for sedation based on the treating physician’s
discretion
v.
Parasternal block (PIFB or Transversus Thoracic Plane Block) on Postoperative day 0
– currently incorporated into standard pain management after surgery based on
physician discretion (for control groups)
vi.
PIFB on postoperative day 1 (provided they are extubated or getting ready to be
extubated) to help with mobilization (for intervention group)
vii.
Passive collection of CO data will be continued postoperatively
Data will be collected in order to determine whether there is a difference in opioid consumption or pain
scores following surgery. Subjects will be followed postoperatively to assess their pain and cognitive
function daily until discharge. Subjects will also undergo repeat neurocognitive assessments at one month
and six months with T-MOCA postoperatively, via telephone.
Two 30 minute training sessions will also be conducted by the study PI, educating nurses on what to look for
in an EEG, and how to read and interpret the monitor. These sessions will utilize online training videos for
guiding the sedation in patients of the intervention group in the ICU/during postoperative care.
The anesthesia research team will also be available to assist during the postoperative period.
Drug
Dose
Dose changes based on
Ketamine
0.1 to 0.2 mg/kg/hr
EEG monitoring
Patient
responses/nociception
Hemodynamic stability
Remifentanil
0.05 to 0.4 mcg/kg/min
Dexmedetomidine
0.2 to 0.5 mcg/kg/hr
Propofol
15 to 200 mcg/kg/min
Sevoflurane
Inhaled as needed
Rocuronium
Boluses
Train
of
Four
(TOF)
monitoring and clinical status

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Study Description – Part B
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PI Revision Date:
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Perioperative EEG and CO monitoring
All patients will undergo EEG and CO monitoring during intraoperative and postoperative period (up
through 24 hours/till extubation whichever occurs earlier). Electroencephalograms and CO will be recorded
using the SedLine monitor (Masimo Corporation, Irvine California).￼SedLine is a FDA approved, patient-
connected, 4-channel processed electroencephalograph EEG and Cerebral oximetry monitor designed
specifically for intraoperative or intensive care use. It displays electrode status, EEG waveformsDensity
Spectral Array (DSA) and bilateral regional cerebral oxygen saturation.
The Sedline EEG electrode (Images A-E) array records approximately at positions Fp1, Fp2, F7, and F8,
with reference approximately 1 cm above Fpz and ground at Fpz. The spectrograms will be computed
using the Multitaper method from the unprocessed EEG signals recorded at a sampling frequency of 250
Hz. Individual spectra will be computed in 3-sec windows with 0.5 sec overlap between adjacent
windows.￼Multitaper spectral estimates have near optimal statistical properties that substantially improve
the clarity of spectral features.
The CO sensors (Images F and G) are applied on the forehead as shown in images F and G.

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PI Revision Date:
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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
EEG Display
The EEG waveforms reflect electrical activity mostly from the front of the brain. The display is configured to
contain 4 data input sources, acquired from the 4 sensor electrodes: L1, R1, L2, and R2.
Patient State Index (PSi)31,32
The PSi is a processed EEG parameter that is related to the effect of anesthetic agents, and takes into
consideration, among other factors:
(1) changes in power in various EEG frequency bands
(2) changes in symmetry and synchronization between critical brain regions
(3) the inhibition of regions of the frontal cortex.
May need 3-5 uV/mm for elderly

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PI Revision Date:
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Density Spectral Array (DSA)31,32
The DSA contains left and right spectrograms representing the power of the EEG on both sides of the brain.
Multitaper DSA32
When using a Multitaper DSA, EEG data are transformed into the frequency domain, which may provide a
better display of EEG features.
Postoperative pain assessment
Postoperative pain will be assessed with a standard 11-point scale and by pain medication intake. Pain
scores will be obtained by asking the subject and also collected from the medical record when documented
clinically. Pain medication intake will be extracted from the medical record.
Delirium and cognition assessment

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Once consent is obtained, a trained research team member will proceed with baseline preoperative and
postoperative cognitive, delirium, and depression assessments.
Baseline assessment
This will include the assessment of cognitive function using the:
1) Montreal Cognitive Assessment (MoCA), supplemented with
2) Days of the week (DOW) & Months of the year (MOY) for additional attention testing
3) Delirium Symptom Interview (DSI) to capture symptoms of delirium
4) Confusion Assessment Method (CAM): Using data from the cognitive testing and DSI, the
researcher will complete the long CAM which includes the diagnosis of delirium using the CAM
diagnostic algorithm.
These detailed assessments will take no more than 45 minutes.
If this baseline assessment shows a MoCA score <10, the subject will be excluded from the study.
Postoperative assessment
On each postoperative day during the hospital stay a research team member will administer a
1) Standard cognitive assessment, including DOW, MOY, CAM, and DSI. These daily assessments
will take approximately 10-15 minutes.
2) If a subject is intubated postoperatively, a CAM-ICU will be performed instead of a CAM
assessment.
3) If a participant declines to complete a daily standard cognitive assessment, trial staff will offer the
3D-CAM as a shorter alternative. If the participant refuses both the daily standard cognitive
assessments and the 3D-CAM, trial staff will use the CAM Only, a conversation based method to
score the CAM.
4) If daily assessments have plateaued for 3 consecutive days (CAM negative each day), they will
then only need to be completed every other day, as long as the subject remains CAM negative, until
the date of discharge.
5) In addition, medical charts will be reviewed every day until discharge or day 30 (whichever occurs
first) to identify delirium. Any events related to delirium during the hospital stay and at the follow-
up time points (1 month and 6 months ) will be recorded on REDCap eCRF. Events such as trying
to get out of bed, verbal abuse, falls, pulling tubes, inappropriate behavior during the hospital stay
as noted in the medical charts will be recorded. At phone follow-up : prolonged rehabilitation,
cognitive decline will be recorded.
Remote assessments
After the patient consents to participate in the study and opts in for phone call assessments, the study
team may use the t-MoCA as a substitute to the MoCA for remote assessment of baseline cognition. The
standard cognitive assessment forms used for daily, in-hospital assessment in the postoperative period
may be administered remotely as well. For the discharge assessment, we may use the a-MoCA or the t-
MoCA as a substitute to the MoCA if inability to in-person visits arise. The study team may conduct
substitution assessments via phone or HIPAA approved telemedicine video conferencing platform.  The
a-MoCA and the t-MoCA are identical assessments but differ in naming, where the term “a-MoCA” is
used for in-person assessments, and the term “t-MoCA” is used for assessments conducted via phone.
Both assessments exclude the visuoconstructional tests of alternating trails, drawing of cube and clock,
and animal naming.  
Discharge assessment
On the day of discharge, the MoCA, with DOW and MOY, the CAM, and the DSI will be completed. (If the
discharge assessment was performed in anticipation of discharge on a specific day but the discharge was
delayed (i.e. logistical reasons, clinical reasons), this will not be considered a protocol deviation.)

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Follow-up assessment
Follow-up assessments will be administered at 1 month (+14 days /- 7 days) and 6 months (+/- 30 days)
after the date of surgery. These will be completed by a research team member via telephone and will
include a telephone version of the MoCA (t-MoCA), with DOW and MOY, the CAM, and the DSI. These
assessments will be done at the patient’s convenience and ability to finish the evaluations.
Standard Therapy (Usual Care)
All study participants (n = 70) will receive standard pain management during postoperative period that
comprises of nurse-administered boluses of IV opioids (intravenous morphine/ hydromorphone/ fentanyl)
or oral opioids such as oxycodone or IV Acetaminophen titrated to pain relief. However, the study
participants receiving MMGA (n = 35) will receive EEG guided Dexmedetomidine and Propofol infusion in
addition to the above mentioned pain management postoperatively. They will also receive bilateral PIFB
(similar to what they received in the intra-operative period) with 20 ml of 0.2 % Ropivacaine on both sides (
total of 40 ml) on postoperative day 1. The block will be administered by trained anesthesiologists using
ultrasound guidance for placement of the local anesthetic in the plane between the external intercostal and
the pectoralis major muscles.
Delirium treatment
The delirium research assessments will not be provided to the treating clinicians. Treating clinicians will
assess and treat delirium per the standard of care.
Data Collection, Outcomes and their Measurement
Patient related information such as baseline characteristics including, comorbid conditions, medications,
surgical and anesthetic data will be obtained from Society of Thoracic Surgery database, Anesthesia
Information Management Systems and patient’s medical record. EEG changes, waveforms and other
related data will be recorded from the monitor. Additionally, to track other important factors related to
outcome and protocol adherence, we may extract clinical data from the medical record including, but not
limited to:
1) Anthropometric data (e.g. age, height, weight, race/ethnicity)
2) Admission type
3) Medications
4) Pain scores
Assessments
Baseline Daily Discharge 1 month 6 months
Montreal Cognitive Assessment (MoCA)
X
X
Days of the Week (DOW)
X
X
X
X
X
Months of the Year (MOY)
X
X
X
X
X
Delirium Symptom Interview (DSI)
X
X
X
X
X
Confusion Assessment Method (CAM or CAM-
ICU) (3D CAM/CAM Only if participant not
compliant)
X
X
X
X
X
Standard Cognitive Assessment (Registration
and Memory Recall, Digit Span, and Orientation)
X
Charted Delirium
X
X
Pain Score / Pain Medication Intake
X
X
Telephone Montreal Cognitive Assessment (t-
MoCA)
X
X

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5) Respiratory physiological data
6) Hemodynamic data (e.g. heart rate, blood pressure)
7) Laboratory data
8) Complications data
9) Hospitalization-related time data (e.g. admitting diagnosis, hospital and ICU length of stay)
10) Vital status
These data will be merged with subject cognitive assessment data. All data will be stored on password-
protected computers, in locked file cabinets and/or offices, or REDCap. We are working with a collaborator
on the study, Emery Brown MD PhD, at Massachusetts General Hospital (MGH). Dr. Brown’s group will
assist in the analysis of the EEG and hemodynamic data collected during the study. There is at present no
plan to exchange intellectual property. Dr. Subramanian and his research group will be responsible for
conducting and collecting data from this study.
BIDMC will provide MGH EEG data and data on the intraoperative anesthetic management to analyze. No
PHI will be shared between institutions as all data will be fully de-identified before secure transfer to MGH.
Biospecimens
Collection: To better understand how the perioperative bundle impacts nociception35, whole blood
specimens will be collected at five time points: Baseline (time of the pre-operative study assessments or on
day of surgery),end of bypass ( in the OR) , end of surgery (in the OR) , POD 1 (in the ICU), and on POD 2
(in the ICU). One purple top EDTA tube (10 cc) will be collected at each time point, for a total of 50 cc’s of
blood collected per patient. Blood samples will be collected by nursing staff or by a study team member
trained in phlebotomy. All efforts will be made to use existing catheters (e.g. arterial lines) or harmonize with
clinical blood collection to reduce patient discomfort.
Processing & Storage: All samples will be centrifuged within 30 min of collection at 25 °C at 2300 × g for 10
minutes and plasma and buffy will be aliquoted into smaller vials and stored at –80 °C in the locked
Anesthesia research lab space of DANA 7. All samples are logged into a centralized sample tracking system
to provide efficient storage, retrieval and chain of custody information. The specimens will be analyzed in
batches at the end of the trial using commercially available ELISA assays. These results will be integrated
with the other data collected within the study and used to test a number of post-hoc hypotheses.
Data related to specimen collection, including documentation of signed consent for collection will be stored
in REDCap or on password-protected computers on BIDMC secure servers only, which will ensure privacy
of subjects and protection of confidentiality. Specimens will be labeled with subject ID and timepoint of
collection and no other identifiable information. Both data and specimen will only be accessible by CCI
approved study team members listed on the study protocol and RSF.
Study Outcomes:
Primary Outcomes
Surgical and delirium markers: Increase in plasma levels of IL-6 and neurofilament light from baseline to
postoperative days 1 and 2 will be compared between the groups. Blood samples will be collected, stored,
and analyzed at five time points through the perioperative course. Plasma levels of these markers will be
quantified at baseline, postoperative day 1, and postoperative day 2.
Secondary Outcomes
1.) Concurrent EEG burst suppression and cerebral desaturation: Incidence and cumulative duration of
episodes of concurrent burst suppression and cerebral desaturation will be extracted and quantified
from the monitors.
2.) Opioid consumption and postoperative pain control: Total postoperative opioid dose, opioid
consumption and pain scores will be quantified and compared between the two groups.

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
Total dose of opioids consumed by all the study patients in the 48 hours post-operative period will be
obtained from the medical records. This will be converted to morphine equivalents for
standardization of the outcome and for ease of analysis. Pain will be assessed postoperatively by
nursing staff every 4-8 hours and data will be collected form patient’s electronic medical records
3.) Duration of Burst suppression will be extracted and quantified from the EEG record and compared
between both the groups.
4.) Incidence of Postoperative Delirium (POD): POD will be diagnosed by our trained research
members based on the Confusion Assessment Method (CAM) algorithm postoperatively until
discharge.
5.) Cognitive function: Postoperative cognitive dysfunction at 1- and 6- months will be assessed with
telephone version of the Montreal Cognitive Assessment (t-MoCA)
6.) Hemodynamic stability: metrics of total vasopressor dose in norepinephrine equivalents, time above/
below 90-130 mmHg systolic blood pressure, area under the 65 mmHg mean arterial blood pressure
curve, and coefficient of variation of mean arterial blood pressure will be collected from the
intraoperative record and medical records to be quantified and compared.
7.) Other Surgical and delirium markers: Plasma cortisol will be quantified at baseline, end of bypass,
and end of surgery. Lipocalin will be quantified at baseline, postoperative day 1 and postoperative
day 2.
Pain is routinely assessed in the postoperative period by nurses on an 11-point scale (i.e. patients
are asked to rate their pain on a scale of 0 to 10). This is typically assessed every 4-8 hours by
nursing staff and is readily available on the patient’s electronic medical records. The total dose of
opioids consumed in the 48 hours post-operative period will be obtained from the patient’s medical
records. This will be converted to morphine equivalents for standardization of the outcome and for
ease of analysis. Data will be collected and stored REDCap or on password-protected computers.
Any data collected on paper will be stored in locked study offices or file cabinets.
Cohort Retention
To maximize retention of the trial cohort throughout the 6-month follow-up period, trial staff will send
reminder letters to participants one month before the 6 month phone call. Staff will collect up to three contact
methods from each participant, as well as contact information for a designated secondary contact.
Additionally if the participant opts in, trial staff may align the 1 month follow-up survey with the participant’s 1
month post-surgery follow-up appointment to conduct the assessment in-person.
Multiple phone calls may be required to reach patients; If participants cannot be reached by phone for the
follow-up surveys after three attempts, trial staff may 1) mail them the survey materials with a self-
addressed, stamped envelope to return at their convenience or 2) email the survey questions via email
through a secure REDCap link. The mailed and online version of the survey will not include the t-MOCA
questionnaire as this needs to be administered verbally rather than self-administered.If we do not receive
any response, a request letter will be mailed to the patient’s address. Furthermore, for participants who are
out of window, trial staff will cross-check with participant’s provider to verify whether participant’s contact
information is up to date.
Adverse Event Reporting
We will follow the current CCI reporting policy with regard to adverse event reporting. Subjects will be
monitored daily during their hospital stay, for up to four post-operative days. This time window is selected
based on the half-life of the medications used for MMGA. All serious or related events will be reported to the
CCI within the required time frame.

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
B.
Statistical Considerations
In addition, we will collect data on clinical events unrelated to the study intervention such as arrhythmias,
hypertension, respiratory depression, infection, hypotension, hematoma, and local anesthetic systemic
toxicity
Sample Size Justification:
In this study, we are looking to test our intraoperative EEG-guided management strategy in combination
with a postoperative protocolized analgesic approach to compare to the standard of care approach
among cardiac surgical patients. For this randomized control trial, we plan to enroll and analyze 70
patients (1:1 allocation 35 in intervention group, 35 in control group).
We performed sample size estimation power analysis for the ANOVA repeated measure within factors
using the data on IL-6 collected as part of a published randomized clinical trial we conducted36. The IL-6
data which is yet to be published showed a mean increase of 226 pg/mL from baseline to postoperative
day 2. We hypothesized that patients in the intervention group will have a 30% lesser change i.e. mean
increase of 158.2 pg/mL. Using the information above, we require a sample size of 58 for analysis using
the following scenario; effect size Cohen’s f = 0.17, 0.05 level of significance, 80% power, and three
measurements per patient to show the statistically significant difference between the two groups. We
require total participants of 62 (31 per group) considering a 5% attrition rate. 
From a previous study on the changes in plasma neurofilament light levels with anesthesia and surgery,
a mean increase of 12.8 pg/mL from baseline to 48 hours was observed37. Using a 0.05 level of
significance and a power of 80%, expecting a 30% reduction in the increase, we would need a sample of
33 patients per group based on power analysis for the ANOVA repeated measure within factors.
Considering 5% attrition (2 per group), we would require total of 70 patients (35 per group).
Concurrent EEG burst suppression and cerebral desaturation: Data from our ongoing multisite RCT
(NCT04093219) shows mean bypass period of 88 minutes and mean of 8.0 minutes of both burst
suppression and cerebral desaturation. We assume there would be a 25% reduction in the intervention
group. Based on power analysis for the Poisson regression, a sample size of 35 per group will have 80%
power to detect this difference accounting for 5% attrition.
EEG Burst Suppression. In our pathfinder 1 trial, we observed burst suppression duration 9[6] mins in
MMGA patients. If we take this as a 33% reduction, we assume that in control group this would be 15
minutes (our two control patients showed an average of 20[10] minutes). A sample size of 20 patients
per group will have more than 90% power to detect this difference.
Exploratory Aims. Our exploratory aims are considered as such either due to low statistical power for
capturing effects or lack of data enabling estimation of effect. Detecting the expected change in
postoperative delirium (17% vs. 33%, alpha=0.05, 80% power using Fisher’s exact test) would require
125 patients per group. Detecting a 25% reduction in mean vasopressor dose would likewise require
>100 patients per group. We have yet to develop a metric for anesthetist effort aside from total
vasopressor dose or bolus count. Likewise, we do not have baseline expectations for cortisol at each
timepoint. Thus, we seek to explore these outcomes in this intermediate-size trial. We plan, upon
successful completion of this trial, to expand to a multicenter clinical trial where we can study these
metrics with the appropriate statistical power.

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
Data Analysis:
Analyses will be conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC) or later. The Shapiro-
Wilk test will be used to assess normality. Descriptive statistics of the data will be performed.
Continuous data (age, pain scores, and opioid consumption) will be represented using median
(interquartile range), and frequencies and percentages will be used to summarize categorical variables.
Descriptive statistics will be reported for time to extubation, as well as secondary outcomes. Electronic
data will be stored on password-protected computers behind the BIDMC firewall or in REDCap directly.
All data from the study will be stored on password protected computers or locked cabinets. Data will be
analyzed by a statistician at BIDMC. Data sharing will be allowed between studies to facilitate use of
patient-level data.
Primary Outcome: The primary outcome of the proposed study is total increase in Interleukin-6 and
neurofilament light levels from baseline to day 1 and day 2, which will be quantified and compared
between the two study groups. The differences in increase will be compared using Repeated measure
two way ANOVA.The primary analysis will be conducted on a modified intention-to-treat (ITT) basis,
which includes all patients who received at least one dose of the study drug. Given the randomized trial
design, results of the unadjusted analysis will be reported.
Secondary Outcomes: Concurrent burst suppression and cerebral desaturation events will be
quantified as cumulative duration and compared between the groups using Poisson Regression
. Total postoperative opioid dose, opioid consumption and pain scores will be quantified and compared
between the two study groups. This value will be reported as overall morphine equivalents and
assessed between treatment groups. Differences morphine equivalents, will be compared using
parametric or non-parametric t-tests, as appropriate. Duration of delirium, defined as the total number
of in-hospital postoperative days in which delirium is present, and severity of delirium, evaluated both
as the peak (highest) and sum CAM-S score over all hospital days, will be assessed between groups
using a t-test or non-parametric equivalent. Interrater reliability testing will be performed, with percent
agreement, kappa, and weighted kappa reported for all CAM variables. Further, a hierarchical linear
regression model will be used to characterize the trajectory of t-MoCA, scores over time. This
framework was chosen because of its flexibility with the timing of patient interviews and the repeated
observations in each patient over time. This will include data from patients at discharge, one and six
months postoperatively. Differences in burst suppression duration during surgery, overall hospital and
ICU length of stay will be compared using parametric or non-parametric t-tests, as appropriate.
Adjusted Analyses: Given the randomized nature of this trial, we do not anticipate differences between
treatment groups at baseline. However, if baseline differences exist, we will fit a multivariable model
adjusting for any potential confounders identified. We anticipate adherence to the randomization
assignment to be high; however, it is possible that patients may not complete their course of the study
drug. We will therefore perform a sensitivity analysis on a per-protocol basis, including only patients who
were randomized and completed the appropriate treatment regime.
Effect Modification by Key Biological Variables: We will evaluate whether the effect of EEG-guided
MMGA bundle differs across subsets of patients defined by few targeted factors, specifically sex, age
groups, treating institution, sedation regimens, surgery type, preoperative cognitive dysfunction (MoCA <
23), history of alcohol abuse, and history of chronic opioid use. We will conduct a Cochran-Mantel-
Haenzel analysis and test for effect modification using the Breslow-Day test.
Missing Data: The frequency and percentage of missing values for each variable will be collected,
analyzed, and reported. For the proposed trial, we anticipate that the proportion of participants with
missing primary endpoint values will be small (<1%). Further, in our previous study, from which much of
the preliminary data was obtained, less than 6% of all data was missing. We therefore do not plan to

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
impute missing data. Anyone who received even a single dose of the study medication will be included in
this modified ITT analysis

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
C.
Subject Selection
Inclusion Criteria
1) Age ≥60 years
2) Undergoing any of the following types of surgery with cardiopulmonary bypass:

CABG with or without valve surgery (aortic and/or mitral)

Isolated valve surgery
Exclusion Criteria
1) Preoperative LVEF <30% (justification: hemodynamic compromise will be detrimental in these
patients)
2) Emergent surgery (justification: insufficient time to initiate intervention)
3) Aortic surgeries
4) Non-English speaking (Justification: cognitive assessment instruments are not validated in a
sufficient range of languages, and the research team lacks polylingual capabilities or the
financial resources to hire interpreters for the duration of all proposed assessments.)
5) Cognitive impairment as defined by total MoCA score < 10 (justification: baseline cognitive
dysfunction will confound primary outcome measure)
6) Currently enrolled in another interventional study that could impact the primary outcome, as
determined by the PI (justification: confounding of primary outcome)
7) Significant visual impairment (justification: will be difficult for patients to draw individual
components in MOCA score)
8) Chronic opioid use for chronic pain conditions with tolerance (total dose of an opioid at or more
than 30 mg morphine equivalent for more than one month within the past year) (justification:
these patients have different post-operative analgesic requirements, which will confound
interpretation of secondary endpoints)
9) Hypersensitivity to any of the study medications (justification: safety concerns)
10) Active (in the past year) history of alcohol abuse (≥5 drinks/day for men or ≥4 drinks/day for
women) as determined by reviewing medical record and history given by the patient
(justification: altered drug metabolism could result in unpredictable effects)
11) Liver dysfunction (liver enzymes > 4 times the baseline, all patients will have a baseline liver
function test evaluation), history and examination suggestive of jaundice. (justification: altered
drug metabolism could result in unpredictable effects)
Drop-out Criteria
Prior to the continuation of any study medications in the postoperative period in ICU, the following
criteria will be assessed. If the patient meets any of the following, the infusions will be discontinued.
1) Unable to meet the standard Fast Track Criteria postoperatively, as determined by the surgical
and ICU Physician Assistants (justification: unstable/ patients with complications are not
suitable for providing study medications)
2) Hemodynamically unstable (defined as HR > 120, SBP < 80, MAP < 50 within 30 minutes prior
to drug administration) (justification: administering study medications will be detrimental to these
patients)
3) Abnormal chest tube output (1000cc in 2 hours) (justification: administering study medications
will be detrimental to these patients)
4) Oxygenation outside of normal limits (defined as PaO2 < 60mmHg on an FiO2 of 1.0 or SpO2 <
85% within 30 minutes prior to drug administration deemed significant per clinical judgment –
e.g. transient desaturation with repositioning will not disqualify the patient) (justification:
administering study medications will be detrimental to these patients)
5) Received an infusion or bolus ≥0.05 mcg/kg/min of epinephrine (justification: administering
study medications will be detrimental to these patients)

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
B4.
POSSIBLE BENEFITS
B5.
POSSIBLE RISKS AND ANALYSIS OF RISK/BENEFIT RATIO
6) Received an infusion or bolus ≥0.50 mcg/kg/min of milrinone (justification: administering study
medications will be detrimental to these patients)
7) Received an infusion or bolus ≥0.20 mcg/kg/min of norepinephrine (justification: administering
study medications will be detrimental to these patients)
8) Significant clinician or nursing concern (justification: administering study medications and
monitoring without treating clinician’s or nursing cooperation will be impossible)
Subjects will not be recruited on the basis of race, ethnicity, or gender. However, it is not clear whether
the final study sample will contain a representative spread of the BIDMC racial and gender makeup, as
a result of the exclusion of non-English speaking patients. There is no reason to exclude pregnant
women from this protocol. However, based on the study plan to recruit patients 60 years of age or older,
presenting for cardiac surgery, we will be recruiting from a subject pool generally exclusive of pregnant
women.
There are no guaranteed health benefits to the patient being included in this study. This study will be
more likely to be beneficial to future patients if these protocols get implemented among cardiac
surgery patients with future trials. An improved understanding, and potentially information as to
whether or not this MMGA strategy could improve outcomes after cardiac surgery for other patients in
the future.
Risk of the study drugs
Dexmedetomidine and Remifentanil
The drugs Dexmedetomidine and remifentanil are FDA approved for sedation and analgesic
purposes. Bradycardia, hypotension and respiratory depression are less common side effects. In an
intensively monitored setting of operating room and cardiac vascular intensive care unit, the risks of
bradycardia, hypotension and respiratory depression if any can be managed effectively.
Ketamine
Ketamine is an FDA approved drug for perioperative analgesic and anesthetic purposes.
Psychomimetic events (hallucinations, dreams, and diplopia), sedation, cardiac dysrhythmias and
liver toxicity were some of the side effects reported. However, these side effects are almost never
been reported with low dose infusions (IV infusion rate of less than 1.2 mg/kg/h and bolus dose less
than 1 mg/kg).26 Moreover, in an intensively monitored setting of operating room and cardiac vascular
intensive care unit, these risks can be identified early and managed effectively.
Ropivacaine
Ropivacaine is an FDA approved medication for nerve blockade. Cardiotoxicity, which includes
arrhythmias, hypotension, bradycardia and cardiac arrest, is less common when the doses used do

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
not exceed toxic limits. Although incidence of cardiotoxicity is extremely low, ropivicaine is intensively
monitored in the setting of cardiac ICU, and any signs of impending cardiotoxicity can be identified
early and managed effectively. Ropivacaine systemic toxicity can also manifest as seizures, which is
less common in the doses used in the study. Further, other central nervous system reactions include
restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors. Despite this, ropivacaine is
effectively used in regional anesthetic techniques and the advantages of effective analgesia in terms
of better patient recovery seem to outweigh the risks.
Risks Associated with Block Administration
PIFB is a relatively superficial block and is devoid of complications like pneumothorax, especially
when performed under ultrasound guidance. Infection secondary to the invasive procedure is rare
because of the sterile aseptic precautions used to administer the block. There is a minor risk of
hematoma associated with any regional block but the pecto-intercostal fascial plane is a relatively
avascular plane and the use of ultrasound guided visualization further reduces the risk of hematoma.
More Common [>5% occurrence]

Propofol: Low blood pressure, decreased function of the muscles of the body,
burning, stinging or pain at the injection site

Dexmedetomidine: Low blood pressure, slow or increased heart rate, high blood
pressure, slowed breathing, nausea, anxiety

Ketamine:
The
following,
collectively
known
as
an
‘emergence
reaction’:
hallucinations (which may include flashbacks or floating sensation), vivid dreams, and
nightmares, feeling ill at ease, confused, anxious and irrational behavior. Unusual eye
movements, increased muscle tone and muscle twitches (which may resemble ‘fits’ or
convulsions), double vision, increased blood pressure and pulse rate, breathing more
quickly, nausea, vomiting.

Remifentanil: Muscle stiffness, low blood pressure, feeling sick or being sick

Ropivacaine: Constipation, nausea, vomiting
Less Common [>1% but <5% occurrence]

Propofol: Nausea, vomiting, high blood pressure, slow or abnormal heart rate,
decreased production of blood by heart, decreased respiratory function, mild itching
or skin rash

Dexmedetomidine: Decreased respiratory function, swelling in the legs, swelling,
increased thirst or dry mouth, decreased urine output, decreased kidney function,
shortness of breath, accumulation of fluid in chest or lung, respiratory failure

Ketamine: Loss of appetite, feeling anxious, slowing of heart rate, changes in heart
rhythm, lowering of blood pressure, breathing more slowly, narrowing of the voice-box
leading to difficulty in breathing, pain, inflammation of the skin or rash at the injection
site.

Remifentanil: Breathing problems, constipation

Ropivacaine: Abnormal nervous system function including excitation, depression,
numbness, tingling sensation, seizures, drowsiness, unconsciousness, abnormal
heart functions including abnormal rhythm, decreased heart rate, decreased blood
pressure, or heart block.
Rare [<1% occurrence]

Propofol: Decreased kidney, liver or lung function, heart failure

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Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023

Dexmedetomidine: Reduced heart function, swelling of the stomach, thirst, a
condition where there is too much acid in the body, low albumin level in blood,
shortness of breath, hallucinations

Ketamine: Allergic symptoms (‘anaphylaxis’) such as breathing problems, swelling
and rash, drifting in and out of consciousness (with feeling of confusion and
hallucinations), flashbacks, feeling ill at ease, sleeplessness, feeling disorientated,
effect on the reflexes which keep your airways clear, resulting in temporary inability to
breathe, increase in salivation, inflammation of the bladder and/or pain when urinating
(‘cystitis’).

Remifentanil: Allergic reactions, heart function disorders

Ropivacaine: Allergic reactions including hives, itching, redness, swelling, coughing,
sneezing and breathing difficulty. Persistent numbness, tingling and weakness at the
site of administration
Awareness
There is a slight risk of awareness as with any anesthesia technique where you might be
aware of conversation, movement, pressure or discomfort during surgery which is rare.
However, as we are monitoring the brain with EEG and giving the anesthetics, there is no
increased risk of awareness in this study.
Ultrasound
Ultrasound is a very safe technology, and has no additional risks associated with it. There
is also a minor risk of hematoma associated with the administration of any block; however
use of ultrasound to guide administration of the block lessens the possibility of this risk.
EEG and CO
EEG and CO monitoring are FDA approved and are considered safe procedures. It has no
discomfort and produces no sensation. In addition, there is no electric shock. The
monitoring will be performed by trained doctors and nurses.
Risk associated with blood draw
There is a small risk of phlebotomy to obtain serum for the serum biomarker assays at 5 time points
during the study. Wherever possible (and this will be for the majority of cases), the serum collection will
be obtained at the same time as phlebotomy and other labs for routine clinical laboratory work, thereby
eliminating an additional risk imposed by a separate phlebotomy for study purposes. However, in rare
cases such (e.g. no arterial access, or pre-discharge sample collection) patients may require a separate
lab draw. The risks of the phlebotomy procedure itself are minimal and are primarily related to pain or
bruising at the needle puncture site. Due to the small volume requested for research (50 cc within a four-
week span), the risks from anemia or blood loss are negligible.
Risk of Questionnaires
Patients will not be given the scores of their MoCA or CAM assessments, but if they were to become
aware of a decline in their performance this could be stressful or disconcerting to the patient. Additional
counseling regarding any psychological or emotional distress stemming from this will be provided by the
principal investigator at the request of the patient or family.
Risk of a Confidentiality Breach
Any patient participating in a research study runs a small risk of breach of confidentiality. All study
staff for this trial are well trained in HIPAA regulations and BIDMC confidentiality standards. Patient

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Study Description – Part B
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PI Revision Date:
07/05/2023
B6.
RECRUITMENT AND CONSENT PROCEDURES
data will be stored in locked cabinets and will be password-protected computers on BIDMC network
secure servers or in REDCap directly. Data will be fully de-identified and transferred in a secure
manner to MGH.
Risk/Benefit Ratio
The drugs used in this study are FDA approved for perioperative sedation, analgesia and anesthesia.
When administered at recommended safe dosages and when monitored in the operating room and
intensive care setting, the risks of complications associated with these drugs are far too small
compared to the benefits of decreased pain and enhanced recovery following cardiac surgery.
Recruitment
Prescreening will be accomplished by reviewing the operating room schedule and surgical consult lists.
Patient medical records will be reviewed for inclusion and exclusion criteria. All patients who meet
inclusion criteria with no exclusions will be approached in the cardiac catheterization holding area, PAT
clinic, cardiac surgery clinic, or in the preoperative holding area for full written informed consent.
Besides the regular signature of the paper consent form, we will also offer the option of electronic
consent signature (eConsent) through a secure platform. After confirming the eligibility from the medical
records, we will send letters of recruitment (snail mails) to the eligible patients and if they respond
expressing their interest, we will approach them via telephone for eConsent.
Consent
Written informed consent will be obtained from every subject prior to any study procedures. Well-trained
study team members will introduce the study to gauge patient interest. For patients who express interest
in learning more/joining the study, the study staff will contact appropriate study physician to join the
conversation. At the time of consent, all study procedures will be explained in detail, including the
associated risks and benefits. The subjects will have the opportunity to ask any and all questions and
will be reminded that participation is voluntary. All subjects will be consented with in-person curtains
drawn or the door closed, assuring patient privacy. They will also be consented at a time and location of
their convenience via telephone call by the study staff after they express their interest to the letter of
recruitment. Written informed consent will then be obtained prior to surgery and initiation of any
research procedures. In all instances, the study physician will be sure to review the full consent with
prospective participants. The subjects will have the opportunity to ask any and all questions, and are
free to decline participation at any time. Written informed consent will be obtained and copies provided
to the patient and filed in the medical record.
The research staff undergoes a rigorous consent training process. Within the Sadhguru Center for
Conscious Planet (SCCP) at BIDMC, this training includes: didactic sessions, mandated attendance at
CCI/HSPO seminars related to the informed consent process, shadowing of informed consent in a
variety of contexts, trainee-led informed consent conversations with the aid of consenting checklists and
accompanied by senior staff member and/or PI, robust feedback sessions, and clear communication
when the team member is skilled enough to engage in informed consent discussions without direct
supervision. All SCCP members, including non-physicians, undergo this training.
The consent process can now also be performed by delivering the Informed Consent Form to
prospective study subjects remotely through a secure electronic-consent platform called “REDCap”.
Subjects will receive an email with a link that will bring them to the electronic informed consent
document. Utilizing a secure software platform, they will go through the electronic consent form with a
study team member, in person. If they elect to consent to the trial, they will confirm with a study
physician and sign and date the consent form electronically. The document will then also be signed by

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Study Description – Part B
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PI Revision Date:
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B7.
STUDY LOCATION
the study physician who is conducting the e-consent process and the prospective patient’s electronic
consent and signature will be collected via photo, or email, and stored in their medical record.
Withdrawal: The patient has the authority to consent or decline all level of study activities. Should this
occur during the active treatment phase of the study, investigators should request permission to
contact the patient for follow-up and also to access the patient record for safety and outcomes data.
Use of specimens collected to date should also be discussed.
Patients who experience unexpected surgical events may be withdrawn at the discretion of the local
investigator. Enrolled patients who have open chest and / or circulatory assist device will be
withdrawn. These subjects will not receive study drug, will not undergo research cognitive
assessments, and will not have research labs drawn. These patients will be included in any intention
to treat (ITT) analyses, but not in the primary modified intention to treat (mITT) analysis. Patients who
withdraw before pharmacy confirmation on the day of surgery will not be included in the ITT analysis.
Subject Protection
Vulnerable subjects (employees, minors, pregnant women) or subjects potentially under undue
influence are not anticipated to be study candidates. While the study does not specifically target
patients with cognitive impairment, it is possible that some patients presenting for eligible surgical
procedures may have mild preexisting cognitive decline. The study protocol does not exclude these
patients, as this population is particularly in need of treatments for postoperative delirium. Instead,
study staff will perform a careful capacity screen and ensure use of LARs as necessary. Patients will
be informed that their decision to participate or not to participate will in no way affect their relationship
with their health care provider. Patients have the ability to discontinue their participation at any time.
Privacy
All efforts will be taken to ensure patient privacy. Patient interactions including consent will take place
either in private clinical settings with curtains/doors closed so as to provide privacy and comfort. If the
patients express their interest to the letter of recruitment, we will approach them via telephone at a
time and setting that the patient is comfortable with. Throughout the study, only the minimum required
information will be collected, assuring patient privacy during the study protocol as with usual patient
care. Data collection from chart extraction will occur only on password-protected computers secured
by the BIDMC firewall or in REDCap directly. Data collected will be limited to only the minimum
necessary to accomplish the stated research purposes.
Physical Setting
All patients will be enrolled at BIDMC, or via telephone at a time that is convenient for the patient.
Consent will be obtained from eligible participants in the cardiac catheterization lab holding area,
PAT clinic, cardiac surgery clinic, or in the preoperative holding area or via telephone and e-
consent. Study procedures, including administration of the PIFB will be performed in the operating
room, the subject’s inpatient room in the intensive care units, or in the ward at BIDMC. Data will be
abstracted from the patients’ chart and will be stored on password-protected computers behind the
BIDMC firewall or in REDCap directly. All data collected on paper will be maintained in locked study
offices accessible to only the study team. De-identified data analysis will take place at MGH only in
a secure setting.

(CCI) Committee on Clinical Investigations
Page 24 of 26
Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
B8.
DATA SECURITY
B9
Multi-Site Studies
B10
Dissemination of Research Results
B11
References
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2010;363(27):2638-2650. doi:10.1056/NEJMra0808281
2.
Berger M, Terrando N, Smith SK, Browndyke JN, Newman MF, Mathew JP. Neurocognitive Function after
Cardiac Surgery: From Phenotypes to Mechanisms. Anesthesiology. 2018;129(4):829-851.
doi:10.1097/ALN.0000000000002194
3.
Brown EN, Pavone KJ, Naranjo M. Multimodal General Anesthesia: Theory and Practice. Anesthesia &
Analgesia. 2018;127(5):1246-1258. doi:10.1213/ANE.0000000000003668
4.
Hogue, Charles W. Jr MD; Palin, Christopher A. FRCA; Arrowsmith, Joseph E. FRCP, FRCA. Cardiopulmonary
Bypass Management and Neurologic Outcomes: An Evidence-Based Appraisal of Current Practices. Anesthesia &
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Data will be stored on password-protected computers behind the BIDMC firewall and entered into a
computer database (REDCap). Computers and data collected on paper will be stored in locked
rooms. For all analyses subjects will be identified only by their unique coded study ID number
assigned for the sole purpose of this project. Limited information will be retained on patients who are
prescreened and do not qualify, or who is approached and declined, for the purposes of generating a
CONSORT diagram for the trial.
N/A – Single Center Study
Is the BIDMC the coordinating site?
Yes
No
Is the BIDMC PI the lead investigator of the multi-site study?
Yes
No
Patients will be thanked for their time throughout the study. Because study results are likely to be
published a few years after a given subject’s participation, study investigators are concerned that
mailing the published manuscript and an additional thank-you note years after participation risks
violating subject privacy, as mailing addresses are increasingly likely to change with passing time. It
is out of the scope of this study to continue tracking mailing addresses after study completion.

(CCI) Committee on Clinical Investigations
Page 25 of 26
Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
12. MacKenzie KK, Britt-Spells AM, Sands LP, Leung JM. Processed Electroencephalogram Monitoring and Postoperative
Delirium: A Systematic Review and Meta-analysis. Anesthesiology 2018;129(3):417–27.
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14. Wildes TS, Mickle AM, Ben Abdallah A, et al. Effect of Electroencephalography-Guided Anesthetic
Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES
Randomized Clinical Trial. JAMA 2019;321(5):473–83.
15. Nicolini F, Agostinelli A, Vezzani A, et al. The Evolution of Cardiovascular Surgery in Elderly Patients: A
Review of Current Options and Outcomes. Biomed Res Int. 2014;2014:1-10. doi:10.1155/2014/736298
16. Mahanna-Gabrielli E, Schenning KJ, Eriksson LI, et al. State of the Clinical Science of Perioperative Brain
Health: Report from the American Society of Anesthesiologists Brain Health Initiative Summit 2018. Br. J.
Anaesth. 2019;123(4):464-478. doi:10.1016/j.bja.2019.07.004
17. Maheshwari K, Ahuja S, Khanna AK, et al. Association Between Perioperative Hypotension and Delirium in
Postoperative Critically Ill Patients: A Retrospective Cohort Analysis. Anesth Analg. November 2019:1.
doi:10.1213/ANE.0000000000004517
18. Ni K, Cooter M, Gupta DK, et al. Paradox of Age: Older Patients Receive Higher Age-Adjusted Minimum
Alveolar Concentration Fractions of Volatile Anaesthetics Yet Display Higher Bispectral Index Values. Br. J.
Anaesth. 2019;123(3):288-297. doi:10.1016/j.bja.2019.05.040
19. Hesse S, Kreuzer M, Hight D, et al. Association of Electroencephalogram Trajectories During Emergence From
Anaesthesia With Delirium in the Postanaesthesia Care Unit: An Early Sign of Postoperative Complications. Br. J.
Anaesth. 2019;122(5):622-634. doi:10.1016/j.bja.2018.09.016
20. Purdon PL, Pavone KJ, Akeju O, et al. The Ageing Brain: Age-dependent changes in the Electroencephalogram
During Propofol and Sevoflurane General Anaesthesia. Br. J. Anaesth. 2015;115:i46-i57. doi:10.1093/bja/aev213
21. Sun Y, Ye F, Wang J, et al. Electroencephalography-Guided Anesthetic Delivery for Preventing Postoperative
Delirium in Adults: An Updated Meta-analysis. Anesthesia & Analgesia. 2020;Publish Ahead of Print.
doi:10.1213/ANE.0000000000004746
22. Pedemonte JC, Plummer GS, Chamadia S, et al. Electroencephalogram Burst-suppression during
Cardiopulmonary Bypass in Elderly Patients Mediates Postoperative Delirium. Anesthesiology. Published online
April 22, 2020. doi:10.1097/ALN.0000000000003328
23. Armengol M, Rangasamy M, Bastos AB, et al. Association of Intraoperative Hypotension with Postoperative
Stroke, Acute Kidney Injury, and Death in Patients Having Cardiac Surgery with Cardiopulmonary Bypass. 2020.
Manuscript under review (Anesthesiology)
24. Walsh M, Kurz A, Thabane L. Relationship between Intraoperative Mean Arterial Pressure and Clinical Outcomes
after Noncardiac Surgery. Anesthesiology. 2013: 119: 507-515. doi:10.1097/ALN.0b013e3182a10e26
25. Gibson LE, Henriques TS, Costa MD, et al. Comparison of Invasive and Noninvasive Blood Pressure
Measurements for Assessing Signal Complexity and Surgical Risk in Cardiac Surgical Patients: Anesthesia &
Analgesia. 2020;130(6):1653-1660. doi:10.1213/ANE.0000000000003894
26. Packiasabapathy S, Prasad V, Rangasamy V, et al. Cardiac surgical outcome prediction by blood pressure
variability indices Poincaré plot and coefficient of variation: a retrospective study. BMC Anesthesiol.
2020;20(1):56. doi:10.1186/s12871-020-00972-5
27. Tanvi Khera, Kadhiresan R. Murugappan, Akiva Leibowitz, Noa Bareli, Puja Shankar, Scott Gilleland, Katerina
Wilson, Achikam Oren-Grinberg, Victor Novack, Senthilnathan Venkatachalam, Valluvan Rangasamy,
Balachundhar Subramaniam. Ultrasound Guided Pecto-Intercostal Fascial Block for Postoperative Pain
Management in Cardiac Surgery: A Prospective Randomized Placebo-Controlled Trial. Journal of Cardiothoracic
and Vascular Anesthesia, 2020. doi: 10.1053/j.jvca.2020.07.058
28. Subramaniam B, Shankar P, Shaefi S, et al. Effect of Intravenous Acetaminophen vs Placebo Combined With
Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The
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Clin Monit Comput. 2020;34(1):71-80. doi:10.1007/s10877-019-00284-1
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31. www.masimo.com/siteassets/us/documents/pdf/plm-10355c_quick_reference_guide_sedline_english.pdf.

(CCI) Committee on Clinical Investigations
Page 26 of 26
Study Description – Part B
CCI Form: 9-2015
PI Revision Date:
07/05/2023
32. Purdon PL, Sampson A, Pavone KJ, Brown EN. Clinical electroencephalography for anesthesiologists: part I:
background and basic signatures. Anesthesiology 2015;123(4):937–60.
33. Lurati Buse GAL, Schumacher P, Seeberger E, et al. Randomized comparison of sevoflurane versus propofol to reduce
perioperative myocardial ischemia in patients undergoing noncardiac surgery. Circulation 2012;126(23):2696–704.
34. Jouguelet-Lacoste J, La Colla L, Schilling D, Chelly JE. The use of intravenous infusion or single dose of low-
dose ketamine for postoperative analgesia: a review of the current literature. Pain Med 2015;16(2):383–403.
35. Subramaniam K, Sciortino C, Ruppert K, Monroe A, Esper S, Boisen M, Marquez J, Hayanga H, Badhwar V.
Remifentanil and perioperative glycaemic response in cardiac surgery: an open-label randomised trial. Br J
Anaesth. 2020 Jun;124(6):684-692. 
36. Subramaniam B, Shankar P, Shaefi S, et al. Effect of Intravenous Acetaminophen vs Placebo Combined With
Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The
DEXACET Randomized Clinical Trial. JAMA. 2019;321(7):686–696. doi:10.1001/jama.2019.0234
37. Evered L, Silbert B, Scott DA, Zetterberg H, Blennow K. Association of Changes in Plasma Neurofilament Light
and Tau Levels With Anesthesia and Surgery. JAMA Neurol. 2018;75(5):542-547.
doi:10.1001/jamaneurol.2017.4913