Continuous Cerebral Autoregulation Monitoring to Reduce Brain Injury From Cardiac Surgery
Phase: NA
Conditions: Thoracic Surgery, Cardiopulmonary Bypass
Sponsor: Northwestern University

PROTOCOL TITLE:  Continuous Cerebral Autoregulation Monitoring to Reduce Brain 
Injury from Cardiac Surgery 
PRINCIPAL INVESTIGATOR:  
Name  
Charles Hogue, MD 
Department  
Anesthesiology  
Telephone Number 
312-926-2280 
Email Address  
Charles.Hogue@nm.org 
VERSION NUMBER: 3.0 
VERSION DATE: 08/15/2019 
  
Abstract Summary  
Brain injury during cardiac surgery results primarily from cerebral embolism and/or 
reduced cerebral blood flow (CBF). The latter is of particular concern for the growing 
number of surgical patients who are aged and/or who have cerebral vascular disease. 
Normally, CBF is physiologically autoregulated (or kept constant) within a range of blood 
pressures allowing for stable cerebral O2 supply commensurate with metabolic demands. 
Cerebral autoregulation is impaired in patients undergoing cardiac surgery who have 
cerebral vascular disease and in many others due to other conditions. This could lead to 
brain injury since current practices of targeting low mean arterial blood pressure 
empirically (usually 50-70 mmHg) during cardiopulmonary bypass may expose patients 
with impaired cerebral autoregulation to cerebral hypoperfusion. The hypothesis of this 
proposal is that targeting mean arterial pressure during cardiopulmonary bypass to a level 
above an individual’s lower autoregulatory threshold reduces the risk for brain injury in 
patients undergoing cardiac surgery compared with the current standard of care of 
empiric blood pressure management. Monitoring of cerebral autoregulation will be 
performed in real time using software that continuously compares the relation between 
arterial blood pressure and CBF velocity of the middle cerebral artery measured with 
transcranial Doppler and with cerebral oximetry measured with near infrared 
spectroscopy. The primary end-point of the study will be a comprehensive composite 
outcome of clinical stroke, cognitive decline, and/or new ischemic brain lesions detected 
with diffusion weighted magnetic resonance (MR) imaging. Autoregulation is mediated by 
reactivity of cerebral resistance vessels. A secondary aim of this proposal is to evaluate 
whether near infrared reflectance spectroscopy can be used to trend changes in cerebral 
blood volume and provide a reliable monitor of vascular reactivity (the hemoglobin volume 
index). Assessments for extra-cranial and intra-cranial arterial stenosis will be performed 
using MR angiography to control for this potential confounding variable in the analysis. 
An additional aim of the study will be to assess whether perioperative transcranial Doppler 
examination of major cerebral arteries can identify patients who are prone to the 
composite neurological end-point. Near infrared oximetry is non-invasive, continuous, 
requires little care-giver intervention and, thus, could be widely used to individualize 
patient blood pressure management during surgery. The role of p16 in PBTLs will be 

evaluated as a predictor of outcomes after cardiac surgical procedures. Finally, pilot data 
will be obtained on whether two novel risk factors (frailty and depth of anesthesia) might 
be associated with postoperative delirium. Brain injury from cardiac surgery is an 
important source of operative mortality, prolonged hospitalization, increased health care 
expenditure, and impaired quality of life. Developing strategies to reduce the burden of 
this complication has wide public health implications and is within the mission of the 
NHLBI. 
 
OBJECTIVES: 
The specific aims of this proposal are: 
Aim 1: To determine whether targeting blood pressure to a level above an individual’s 
lower CBF autoregulatory threshold during CPB (cardiopulmonary bypass) reduces the 
frequency of the composite end-point of clinical stroke, or a diffusion-weighted MRI brain 
lesion, or postoperative cognitive decline 4 to 6 weeks after surgery, compared with 
patients who receive standard empiric blood pressure management. Hypothesis: 
Targeting mean arterial pressure during CPB to a level above an individual’s lower 
autoregulatory threshold reduces the risk for brain injury in patients undergoing cardiac 
surgery. 
Aim 1a: To assess whether extracranial and/or intracranial arterial stenosis (detected by 
MR angiography), or other patient characteristics such as age, gender, hypertension, 
diabetes, or prior stroke, modify the effect of maintaining blood pressure above an 
individual’s lower CBF autoregulatory threshold on the risk for the above composite 
neurological outcome. Hypothesis: Targeting blood pressure during CPB to a level 
above an individual’s lower autoregulatory threshold reduces the risk for brain injury in 
patients undergoing cardiac surgery who have extra- and/or intra-cranial arterial stenosis. 
Aim 1b: To assess whether targeting MAP to a level above an individual’s lower CBF 
autoregulatory threshold during CPB reduces the frequency of cognitive decline 1 year 
after surgery compared with the use of standard blood pressure management. 
Aim 2: To compare three methods of continuous monitoring of CBF autoregulation 
derived from the linear regression correlation between cerebral oximetry O2 saturation 
and blood pressure (oximetry index), near infrared-derived relative total hemoglobin and 
blood pressure (hemoglobin volume index), and transcranial Doppler measured CBF 
velocity and blood pressure (mean velocity index). Hypothesis: Mean velocity index, 
cerebral oximetry index, and hemoglobin volume index provide complimentary data on 
detecting the lower limit of CBF autoregulation. 
 
Aim 2 has been satisfactorily addressed and will no longer be an aim of this project. 
Aim 3: To evaluate whether perioperative transcranial Doppler measurements of major 
cerebral artery blood flow velocity can identify patients prone to the composite 
neurological end-point. Hypothesis: Perioperative transcranial Doppler examination can 

identify patients with cerebral arterial stenosis who are at risk for the composite 
neurological outcome. 
At this point we feel we have enough data to answer this question when the analysis is to 
be performed. Therefore, we will not be doing the formal TCD study on subjects going 
forward. 
Aim 4: To assess whether targeting MAP during CPB to a level above an individual’s 
lower CBF autoregulatory threshold during CPB reduces the frequency of postoperative 
delirium, as assessed with a structured examination, compared with the use of standard 
blood pressure management. 
Aim 5: To determine whether baseline frailty is independently associated with delirium or 
functional decline after cardiac surgery. Hypothesis: Baseline frailty assessments will 
identify patients at high risk for delirium or functional decline. 
 
BACKGROUND: 
A pervasive contemporary view is that cerebral embolism is the dominant cause of brain 
injury during CPB and that cerebral hypoperfusion is a minor precipitant.5,7-12 This view 
has shaped current CPB management practices that include tolerating conditions that 
would be unacceptable in other medical settings. Such conditions include: a) reduced 
brain O2 delivery (hematocrit often <21%); b) low mean arterial blood pressure, typically 
between 50 and 60 mmHg; and c) CBF that is reduced by 40%–50% from 
baseline.9,10,50,51 Understanding the mechanisms of brain injury is important because 
strategies to increase CBF during CPB (e.g., by raising blood pressure and/or PaCO2) 
might paradoxically worsen injury by increasing cerebral embolic load.5,52 Moreover, 
embolism and hypoperfusion might interact synergistically to exacerbate injury from 
impaired embolic clearance (“washout”).5,11,21,53 Cerebral hypoperfusion likely has a 
larger role in current practices than it has in the past due to a growing prevalence of 
patients with cerebrovascular disease. Multiple series using brain MRI have revealed 
cerebral infarction in 40%–50% of patients before surgery.14-20,23 These lesions are 
usually clinically asymptomatic, are associated with cerebral arterial stenosis, and 
increase the risk for new perioperative brain injury. Using SPECT imaging, Moraca et al.22 
found that 75% of 82 patients had abnormal regional cerebral perfusion (defined as >2 
SD below age-matched controls) before CABG surgery, even though patients with prior 
stroke or transient ischemic attack had been excluded from the study.  
Postoperative stroke occurred in 5% of patients and only in those with a preoperative 
regional perfusion defect. Our group has further reported on the high proportion of 
watershed strokes after cardiac surgery (see Effect of Mean Arterial Pressure on CPB 
and Watershed Stroke) and the relationship of this hypoperfusion-associated injury with 
decreases in mean arterial pressure >10 mmHg from baseline on CPB.54 Importantly, 
preoperative brain imaging is not routine; therefore, patients with cerebral vascular 
disease receive the same empiric management during CPB as do patients without this 
disease. Reports showing jugular O2 desaturation in 17%–23% of patients during CPB 

document that, for some patients, CBF resulting from current practices is inadequate to 
meet cerebral O2 demands during at least portions of surgery.14,55,56 
Cerebral Blood Flow Autoregulation 
During CPB, systemic blood flow is calculated based on body surface area and body 
temperature and is then adjusted, depending on indicators of adequate global tissue 
perfusion (SvO2, pH, etc.). Currently, there are no widely accepted clinical monitoring 
procedures to ensure adequate cerebral perfusion. Thus, CBF is assumed to be sufficient 
based mostly on older data showing that CBF–arterial pressure autoregulation remains 
intact with CPB flows between 1.6 and 2.4 L/min/m2 (using α-stat pH management).9,10 
Supported by these data, a mean arterial pressure of 50 mmHg is widely considered to 
be the minimal acceptable blood pressure during CPB. This practice fails to consider that 
CBF–blood pressure autoregulation has wide individual variation, is altered in many 
common conditions (e.g., hypertension, diabetes, stroke), and is derived using statistical 
methods that have been questioned.24,25,57-62 Moreover, rewarming from hypothermia 
could potentially lead to disruption of cerebrovascular reactivity, leading to CBF 
dysregulation.30 Data supporting a mean arterial pressure of 50 mmHg (or lower) during 
CPB are inconsistent and are mostly from older studies that have included few patients 
at high risk for brain injury.10,11,63 Indeed, Gold et al.64 found that combined myocardial 
and neurologic adverse events were less frequent when mean arterial pressure during 
CPB was maintained at between 80 and 100 mmHg, rather than between 50 and 70 
mmHg. These data are corroborated by retrospective analysis showing beneficial effects 
of higher mean arterial pressure for patients at risk for neurologic injury.65,66 
 
Individualizing blood pressure targets to be above a patient’s lower autoregulatory 
threshold might provide a means to avoid cerebral hypoperfusion during and after CPB. 
Monitoring of cerebral autoregulation with a moving linear regression correlation 
coefficient between cerebral perfusion pressure and middle cerebral artery TCD 
measured blood flow velocity (mean velocity index) has been validated in volunteers and 
in patients with head trauma, carotid artery stenosis, acute ischemic stroke, and 
subarachnoid hemorrhage.31-37, 39, 67 When autoregulation is lost, flow velocity has a 
correlation of 1 with cerebral perfusion pressure at low frequencies. This method provides 
a way to monitor autoregulation continuously at the bedside in contrast to the intermittent 
(“snap shot”) measurements provided by other methods (e.g., PET, inert gas washout). 
This feature allows for assessment of CBF autoregulation in individual patients rather 
than estimating a patient’s autoregulatory threshold based on summary data obtained 
from a group of patients. This ability is important in surgical patients, as CBF 
autoregulation is dynamic and potentially influenced by many perioperative perturbations, 
including rewarming from hypothermia, volatile anesthetics (dose dependently), and 
anemia.30, 68, 69 These methods have been applied in several clinical situations, and 
measurement of mean velocity index correlated with the degree of carotid artery stenosis 
and improvement of cerebral dysautoregulation after carotid recanalization.34, 35 

No gold standard exists for measuring CBF to determine autoregulation.68 TCD 
monitoring of CBF velocity is a commonly used surrogate of CBF that assumes that small 
changes in middle cerebral artery diameter have minimal influence on CBF 
measurement.70 In most instances, these assumptions have minimal clinical impact. 
Monitors of brain oxygenation, such as direct tissue O2 tension measurement, jugular 
bulb O2 saturation measurement, and transcranial near-infrared spectroscopy have been 
used as surrogates of CBF for measuring autoregulation.68,71 Clinical monitoring of near-
infrared spectroscopy can be performed with two FDA-approved devices.72,73 The INVOS 
device (Somenetics Corp, Troy, MI) uses light-emitting diodes in two channels to provide 
a continuous-wave spectrometer that measures relative changes in regional O2 saturation 
of the frontal lobe. The Fore-Sight device (CAS Medical Systems, Branford, CT) uses 
fiberoptic light in four channels to monitor phase shifts at 754 nm, 785 nm, and 816 nm 
in reference to 780 nm to accurately measure brain tissue oxygenation. The spacing of 
the light source and receivers determines the depth of sampling. A shallow receiver 
subtracts O2 saturation derived from extracranial tissue. Near-infrared spectroscopy 
provides an estimate of oxyhemoglobin saturation in the underlying frontal lobe that is 
weighted toward venous blood, thus indicating the adequacy of regional cerebral O2 
supply versus demand. Our group has demonstrated that cerebral oximetry provides a 
clinically acceptable surrogate of CBF for experimental and clinical autoregulation 
monitoring (see Cerebral Autoregulation Monitoring).38 Using nearinfrared spectroscopy 
a variable, cerebral oximetry index was generated to describe the moving linear 
correlation between cerebral O2 saturation and cerebral perfusion pressure. Monitoring 
CBF autoregulation with the cerebral oximetry index has many clinically attractive 
features: it is noninvasive, its output is continuous and updated every 60 sec, monitoring 
requires little caregiver intervention, and it has sufficient resolution to discriminate the 
lower autoregulatory threshold. Unlike TCD, the use of cerebral oximetry as a proxy for 
CBF does not require a trained technician and, thus, can be widely applied in a broad 
range of clinical settings and locations. 
 
Autoregulation is mediated by reactivity of cerebral resistance vessels (vascular 
reactivity), which consists of dynamic, low-frequency vessel diameter changes in 
response to changes in arterial blood pressure. In most physiologic instances, limits of 
pressure reactivity are wider than limits of autoregulation.74 Assessing vascular reactivity 
involves measuring the relationship between blood pressure change and a measure of 
cerebral blood volume.39,40 Low-frequency oscillations in cerebral blood volume are 
attributed to changes in the dynamic collective vascular radius. In health, vascular 
diameter changes to oppose changes in arterial blood pressure (decreased diameter for 
increased blood pressure). Vascular reactivity is measured clinically using the pressure 
reactive index, which is the moving linear correlation between slow waves of intracranial 
pressure and blood pressure.39 A positive-pressure reactive index, indicating pressure 
passivity, is associated with death in adults with traumatic brain injury.75 A negative-
pressure reactive index, indicating pressure reactivity, is associated with survival in adults 
with traumatic brain injury. The pressure reactive index can delineate a range of perfusion 
pressure with maximal vascular reactivity in most patients with traumatic brain injury, and 
deviation from this optimal perfusion pressure is associated with death and persistent 

vegetative state.33 The strength of these data led to a citation in the guidelines for the 
management of severe traumatic brain injury from The Brain Trauma Foundation, with a 
new option for autoregulation monitoring to optimize cerebral perfusion pressure goals.76 
Invasive intracranial pressure monitoring is a prerequisite for pressure reactive index 
monitoring. Cardiac surgery patients cannot have invasive intracranial pressure 
monitoring but may benefit from precise blood pressure management using this index. 
Our preliminary data (see Cerebrovascular Reactivity Measured by Near-infrared 
Spectroscopy) suggest that near-infrared reflectance spectroscopy can be used to trend 
changes in cerebral blood volume (relative total hemoglobin in the reflectance arc) and 
provide a reliable monitor of vascular reactivity (the hemoglobin volume index). 
 
Regional brain areas in a vascular territory of a flow-limiting arterial stenosis would likely 
have impaired autoregulation.28,34,77-79 Blood flow to these brain areas would, thus, be 
pressure dependent. Intra- and extra-cranial vascular stenosis could influence the 
effectiveness of targeting blood pressure during CPB, based on a global measurement of 
CBF autoregulation. However, maintaining blood pressure above the lower CBF 
autoregulatory threshold, even if estimated from vascular territories with functional 
autoregulation, would likely ensure an adequate cerebral perfusion to pressure 
dependent brain regions. On the other hand, compensatory vasodilation in response to 
lowered blood pressure during CPB to these same brain areas with intact autoregulation 
could potentially lead to a “steal phenomenon,” whereby CBF is directed away from the 
pressure-dependent vascular territories.77-79 Interpretation of the effectiveness of a 
strategy of basing blood pressure management during CPB on CBF autoregulation 
measurement requires knowledge on the extent of cerebral vascular disease. 
Detection of Brain Injury 
Brain injury after cardiac surgery has a range of clinical manifestations, including clinical 
stroke (detected in ~2%–5% of patients) and cognitive decline (reported in 18%–40% of 
patients, depending on statistical criteria and timing of testing).5 Cognitive testing has 
methodologic limitations that lower its sensitivity and specificity for detecting neurologic 
injury (as opposed to its use for studying the effects of surgery on cognition), including 
difficulty with distinguishing the confounding effects of preexisting cerebral vascular 
disease.41-43 Moreover, preexisting brain infarction is associated with cognitive 
impairment, regardless of surgery, thus lowering the likelihood of being able to diagnose 
further cognitive decrement from new injury or “basement effect.” 41-44 Nonetheless, our 
data indicate that cardiac surgery results in changes in cognition indicative of brain injury. 
Cognitive decline, though, appears to be a transient phenomenon, with most individuals 
returning to near baseline by 3–6 months after surgery.41,80 More controversial is the 
relationship between perioperative cognitive decline and long-term cognitive decline. 
Data from our colleagues suggest that the rate of long-term cognitive decline is not 
different for patients undergoing CABG surgery than it is for patients with documented 
coronary artery disease undergoing medical management.41 These findings suggest that 
the natural progression of cerebral vascular disease, as opposed to the use of CPB per 
se, is a major determinant of longitudinal decline in cognition after cardiac surgery. 

Understanding the impact of interventions aimed at reducing brain injury from cardiac 
surgery on long-term cognition may help assess their overall benefit for patient outcome. 
Advanced MRI techniques such as diffusion-weighted imaging allow for the detection of 
early ischemic changes in the brain.45-49 Diffusion-weighted imaging is an MRI sequence 
capable of demonstrating changes within minutes of experimental ischemia.47-49 It is 
believed that ischemia-induced energy depletion increases the influx of water from the 
extracellular to the intracellular space, restricting water motion and resulting in a bright 
signal and low calculated apparent diffusion coefficient.81,82 Although there is wide 
individual variability, the apparent diffusion coefficient signal remains low for 4 days, 
pseudonormalizes at 5–10 days, and increases thereafter. This temporal evolution of the 
diffusion-weighted imaging signal allows one to determine the age of a stroke and 
differentiate acute from chronic ischemia. Investigations combining conventional MRI with 
diffusion-weighted imaging have revealed new small lesions after cardiac surgery in 
26%–50% of patients.19,20,23,83-85 In our own series, we found DWI lesions after surgery in 
56% of patients. The lesions are broadly distributed in the brain and often have a 
watershed distribution with/without an embolic signature. Watershed strokes (i.e., lesions 
in end-vascular territories) in the general population are usually secondary to focal 
hypoperfusion, although the mechanism in cardiac surgical patients is not as certain.86 
Most diffusion-weighted imaging lesions that are seen after cardiac surgery are not 
associated with clinically detected stroke, and preliminary analysis suggests that they 
may occur without detectable short-term cognitive decline. However, in these studies, 
patient follow-up might have been too short to detect a relationship between “silent” MRI 
cerebral infarctions and cognitive decline, 87 or the cognitive battery might not have been 
sensitive to the functions of the actual injured brain regions. Regardless, new diffusion-
weighted imaging lesions do represent ischemic brain injury, as they can become brain 
infarction when re-examined with conventional MRI 1–2 weeks later.88 Furthermore, in 
the general population, clinically “silent” infarction detected with brain imaging is 
increasingly recognized to be associated with cognitive decline, depression, and reduced 
functional capacity.89 Combined diffusion-weighted imaging and perfusion-weighted 
imaging (PWI) will enable us to determine whether lesions detected by the former method 
occur in relatively hypoperfused brain areas. Although diffusion-weighted imaging is 
sensitive for detecting ischemic brain injury, post-cardiac surgery lesions may occur in 
brain areas not involved with higher cognitive function. Thus, combining detection of 
lesions by diffusion-weighted imaging with clinical neurologic end points (including 
cognitive deficits) will provide a highly sensitive evaluation of perioperative brain injury. 
The findings will be especially important for examining mechanisms and/or prevention of 
brain injury related to cardiac surgery. 
Frailty 
Frailty is commonly used to characterize the most vulnerable subset of older adults, with 
decreased physiologic reserve across multiple organ systems.181 Using data from the 
Cardiovascular Health Study, a frailty phenotype was derived by Fried et al.188 and 
includes: unintentional weight loss, low grip strength, self-reported exhaustion, gait 

speed, and low physical activity. In community-based cohort studies, frailty has been 
associated with new falls, decreased mobility, disability, hospitalization, and death.190 
However, the impact of frailty on outcomes after surgery has not been well studied. In 
non-cardiac surgery, measures of frailty have been independently associated with 
postoperative complications and length of stay,180 institutionalization,191 and mortality.192 
In cardiac surgery, frailty has similarly been associated with mortality and 
institutionalization,182 and the addition of frailty to existing risk models can slightly improve 
prediction of mortality.183 However, the measurement of frailty in the surgical literature 
has been inconsistent,180,183,191 and there have been no studies which have examined 
important patient-centered outcomes, including delirium and functional status. Delirium 
and functional status-decline are important patient-centered outcomes that are 
hypothesized to occur more in frail vs. non-frail patients after cardiac surgery, given the 
reduced physiologic reserve of frail patients to recover from stressors. The incidence of 
delirium after cardiac surgery has been estimated to occur in up to 52% of patients 
(consistent with our data), 193 and the consequences of postoperative delirium in older 
adults can be profound. Delirium after cardiac surgery is independently associated with 
reduced functional capacity, 194 and mortality.153 Although a small study in non-cardiac 
surgery demonstrated an increased risk of delirium among frail patients, 195 the 
association between frailty and delirium in cardiac surgery patients has not been studied, 
nor has the ability of frailty to improve current prediction models of delirium been 
examined. Similarly, change in functional status after cardiac surgery has not been well 
studied among frail older adults, with evidence suggesting that physical function might 
improve196 or decline194 after cardiac surgery, depending on the measure of functional 
status and the baseline function of the population assessed. Thus, the impact of baseline 
frailty on change in functional status after cardiac surgery is not known. 
Depth of Anesthesia 
Depth of anesthesia may represent a modifiable target to improve outcomes after surgery 
in frail adults. In both cardiac and non-cardiac surgery, greater depth of anesthesia (as 
measured by the Bispectral Index [BIS], a processed encephalogram) has been 
associated with mortality.184, 185 In current practice, depth of anesthesia as reflected by 
BIS values has been shown to vary widely,197 and importantly, older adults may 
experience greater depth of anesthesia at the same drug dose because of increased 
susceptibility to anesthetic agents,198 potentially resulting in relative anesthetic overdose. 
In order to determine whether actively reducing depth of anesthesia could reduce 
postoperative delirium, a collaborator at Johns Hopkins Bayview (Dr. Frederick Sieber) 
randomized 114 patients undergoing hip fracture repair under spinal anesthesia to light 
vs. deep intraoperative sedation and found a 50% reduction in delirium in the light 
sedation group.186 In a separate trial of non-cardiac surgery patients undergoing general 
anesthesia, a BIS-guided protocol for depth of anesthesia was reported to reduce 
postoperative delirium from 24.1% to 15.6% (P=0.001).187 However, these results in 
spinal anesthesia or non-cardiac general anesthesia may not be generalizable to patients 
undergoing cardiac surgery, because of different patient populations and perioperative 
insults (e.g. cardiopulmonary bypass).  

In addition, the range of BIS values during cardiac surgery is unknown. These data 
motivate our current proposal to examine the range of depth of anesthesia (BIS values) 
during cardiac surgery for both frail and non-frail patients. We anticipate that frail patients 
will spend a significant amount of time with BIS values less than cutoffs for general 
anesthesia (BIS 45-60), and time of BIS<45 will be greater in frail vs. non-frail patients. 
These results would support the future development of a protocol to maintain BIS values 
at higher ranges (45-60) while reducing total anesthetic dose, particularly in frail patients. 
Preliminary Studies 
The team comprises highly experienced researchers who have performed seminal 
investigations into the frequency, causes, and consequences of neurologic complications 
after cardiac surgery. The group is a multidisciplinary team that encompasses the 
specialties 
of 
anesthesiology, 
neurology, 
neuroradiology, 
cardiac 
surgery, 
neuropsychology, and biostatistics organized to study perioperative neurologic injury with 
the intent of developing strategies to reduce its frequency. The experiences of the team 
members provide evidence of a track record in conducting neurologic outcomes research 
in cardiac surgical patients. The researchers are experienced with all of the proposed 
measurements. 
Neurologic Outcomes after Cardiac Surgery 
Our neurologic team has been studying the cognitive and neurologic outcomes after both 
conventional and off-pump CABG surgery.41, 90-92 Our current cohort, which is being 
followed up to 6 years after surgery, was recruited to determine if CABG is associated 
with late or delayed cognitive impairment. To control for the effect of coexisting 
cerebrovascular disease in an aging population, we included a control group with similar 
risk factors for cerebrovascular disease as the surgical group and a group of healthy 
subjects. Our studies and those of others have shown that a significant proportion of 
candidates for CABG surgery have abnormal cognitive performance even before surgery. 
Our data do not support disproportionate decline among CABG patients compared to 
nonsurgical controls, although both groups performed lower than healthy controls lacking 
risk factors for cerebrovascular disease. In addition to highlighting the importance of 
including control groups, our studies also illustrate the importance of the choice of 
statistical criteria for defining postoperative cognitive decline. Some commonly used 
criteria, such as 20% decline on 20% of tests, will result in significantly inflated estimates 
of postoperative cognitive decline. We have proposed more powerful and appropriate 
analyses using random effects regression models, which can account for practice effects 
and for heterogeneity among subjects in the levels and trends of their test scores. 
Additionally, we have assembled a multi-disciplinary team to assess delirium in the 
postoperative period using rigorous assessment with the Confusion Assessment Method. 
We have successfully assessed delirium in over 70 patients undergoing cardiac surgery 
at Johns Hopkins, thus demonstrating the feasibility of our aims. 

Effect of Mean Arterial Pressure on CPB and Watershed Stroke 
In a study of 98 patients with clinically detected stroke after cardiac surgery (between  
1998 and 2003), we found, based on diffusion-weighted imaging, 
that 68% had at least unilateral watershed strokes and 48% had 
bilateral watershed strokes (Fig. 1).54 This prevalence of 
watershed stroke suggests that the frequency of infarction due to 
cerebral hypoperfusion is higher than in the general stroke 
population. We sought to determine the role of change in mean 
arterial pressure from baseline during CPB in the development of 
watershed strokes. Patients with a drop from baseline in mean 
arterial pressure of ≥10 mmHg during CPB were 3.25 times more 
likely to have a watershed infarct than those who had a smaller drop 
in mean arterial pressure. The odds ratio for a watershed infarct 
after adjustment for preoperative mean arterial pressure, history of 
hypertension, CPB time, and circulatory arrest was 4.1 (95% CI, 
1.03–15.90). 
  
Patients with a drop in mean arterial pressure ≥10 mmHg also were 3.2 times more likely 
to have a larger infarct volume (95% CI, 1.1–10.7). Operative mortality was higher for 
patients with bilateral watershed strokes than for those with other types of cerebral 
infarctions (17% vs. 4%, p=0.04).  
These preliminary data suggest that an important factor in the development of watershed 
strokes is change from baseline in mean arterial pressure during CPB, not the absolute 
intraoperative mean arterial pressure. As the studied patients represented only those with 
symptomatic stroke, it is likely that the frequency of watershed injury might be even 
higher. Regardless, these data support the hypothesis that reduced CBF during CPB is 
an important contributor to neurologic complications. The data further suggest that low 
CBF-associated brain injury is related to an individual’s baseline blood pressure. 
Therefore, it is plausible that affected patients might have their autoregulatory threshold 
shifted to the right, thus exposing them to cerebral hypoperfusion by current blood 
pressure management practices. 
Cerebral Autoregulation Monitoring 
We have performed preliminary laboratory and clinical investigations of CBF blood 
pressure autoregulation reactivity. In these studies, analog signals from arterial pressure 
and surrogates of CBF measurements are digitally converted, stored in a laptop 
computer, and then processed by ICM+ software (Cambridge University; Cambridge, 
UK).31-37 CBF autoregulation can be monitored with a moving linear regression 
correlation coefficient between cerebral perfusion pressure and TCDmeasured middle 
cerebral artery (MCA) blood flow velocity (mean velocity index or Mx).25-33When 
autoregulation is functional, there is no correlation between CBF velocity and MAP, but 
when MAP is outside the autoregulation limits, Mx approaches 1, meaning that flow is 
Fig 
1. 
MR 
diffusionweighted 
imaging of a patient 
with 
bilateral 
watershed stroke after 
cardiac surgery. 

pressure-dependent. No gold standard exists for measuring CBF to determine 
autoregulation.35 Near infrared spectroscopy-measured regional cerebral oxygen 
saturation (rScO2) is weighted toward venous blood, thus indicating the adequacy of O2 
supply versus demand. Our group has demonstrated that rScO2 provides a clinically 
acceptable surrogate of CBF for clinical autoregulation monitoring.38,134,135 The variable 
COx is generated as the correlation coefficient between cerebral perfusion pressure and 
rScO2.Similar to Mx, when CBF is outside the limits of autoregulation COx approaches 1, 
but it approaches zero or is negative when autoregulation is functional (no correlation 
between CBF and MAP). Monitoring CBF autoregulation with COx has many clinically 
attractive features: it is noninvasive, monitoring requires little caregiver intervention, and 
it has sufficient resolution to discriminate the lower autoregulatory threshold. In a 
laboratory study of 3- to 8-day-old piglets, we evaluated autoregulatory reactivity by 
comparing laser-Doppler–derived red cell flux in the frontoparietal cortex with perfusion 
pressure.38 These studies were used to evaluate whether near-infrared cerebral oximetry 
might serve as surrogate for CBF. If so, it would provide a clinically feasible means for 
measuring CBF autoregulation in real time across a wide array of clinical practices. 
Hypotension was induced by inflation of a balloon catheter in the inferior vena cava. The 
autoregulatory breakpoint was determined by plotting CBF (flux) as a function of perfusion 
pressure and intersecting the two best-fit lines with the lowest combined squared error. 
Cerebral oximetry was performed, and the waveform plotted as a function of perfusion 
pressure, but an autoregulatory plateau was not seen. Two time-domain indices of 
autoregulation were measured during these experiments: the laser-Doppler index 
(velocity index), which correlates laser-Doppler flux with blood pressure, and the oximetry 
index (Fig. 2). Note, when perfusion pressure is <LLA, CBF and perfusion pressure 
become correlated, indicated by increasing laser Doppler index (LDx) and COx (arrows). 
Data combined from multiple experiments in piglets show that a cerebral oximetry value 
of ≥0.3 has a sensitivity of 89%, specificity 64%, and likelihood ratio 2.5 for detecting the 
lower limit of autoregulation. 

 
Our group has experience with TCD monitoring in patients undergoing cardiac surgery.97 
In pilot studies, TCD monitoring of the right and left middle cerebral arteries was 
performed in patients; the data were combined with arterial signals, digitally converted at 
58 Hz, and stored in a laptop computer for processing by methodology similar to that 
described above. In these studies, CBF autoregulation was defined as the relationship 
between CBF velocity and mean arterial pressure (mean velocity index). Of note, mean 
arterial pressure—not cerebral perfusion pressure—is measured because we have found 
that central venous pressure measurements (needed for calculating cerebral perfusion 
pressure) are not reliable during CPB. The reason is that vacuumassisted venous 
drainage during CPB collapses the right atrium and vena cava, resulting in highly negative 
central venous pressure measurements. As described above, a correlation between CBF 
velocity and mean arterial pressure (rising velocity and oximetry indices) indicates that 
CBF is pressure dependent, or not autoregulated, and vice versa. 

We initially assessed CBF autoregulation in nearly 
150 patients undergoing cardiac surgery using the 
methods and equipment proposed for this study. 
Data from 60 patients with complete transcranial 
Doppler and NIRS data were analyzed. There was 
a significant correlation (r=0.55, p<0.0001) and 
good agreement (bias=0.082±0.18, 95% CI, -0.327 
to 0.43) between COx and Mx for the timeaveraged 
data during CPB. Coherence between slow waves 
(20 s to 2 min) from NIRS and TCD signals was high 
(0.74) suggesting that NIRS can be substituted for 
TCD for monitoring CBF autoregulation. The mean 
lower autoregulatory threshold determined by Mx 
(mean±SD) in our early data was 61±15 mmHg and 
by COx, 60±15 mmHg. The range of mean arterial 
blood pressures at the autoregulatory threshold was 
40–80 mmHg. We have subsequently validated COx 
versus Mx in adult patients undergoing CPB.135 In our 
studies that have included >450 patients thus far, rScO2 remained >50% in two-thirds 
of patients when MAP was below the LLA, indicating that COx might provide indication 
of low perfusion pressure earlier than rScO2. An example of Mx and COx monitoring in 
a patient during CPB is shown in Fig. 3. 
Cerebrovascular Reactivity Measured by Near-infrared Spectroscopy 
The prototype index of vascular reactivity is the pressure reactivity index. The 
pressurereactivity index describes cerebral vessel activity by correlation of slow waves of 
intracranial pressure and arterial blood pressure. The pressure reactivity index analysis 
assumes that slow waves (Lundberg B waves) of intracranial pressure are caused by 
vascular diameter changes. We reasoned that slow changes in the relative total 
hemoglobin (rTHb) measured by transcranial near-infrared reflectance spectroscopy 
would also reflect vascular diameter changes (i.e., increases in rTHb results from 
increased vessel diameter and vice versa). We hypothesized that the hemoglobin volume 
index correlates with the pressure reactivity index using the Fore-Sight device, as 
proposed in this submission. The latter monitor is a continuous-wave reflectance 
spectrophotometer that uses 4 laser-bandwidth wavelengths of light in the near-infrared 
spectrum to quantify the percentage of saturated hemoglobin in cortical tissue. 
Transcranial near-infrared light transmittance is inversely proportional to the 
concentration of absorbing chromophores in the tissue. Oxyhemoglobin and 
deoxyhemoglobin have different absorption spectra between wavelengths of 600 and 
1000 nm, but an isobestic wavelength for these two chromophores is near 800 nm. These 
relationships form the basis of oximetry, which reports the ratio of oxygenated-tototal 
hemoglobin concentration in the light path as a percentage of total hemoglobin 
concentration. The tissue concentration of hemoglobin determined in this way is a 
function of both the hematocrit and the blood volume in the tissue. Oximetric methods 
Fig 3. Arterial pressure, Mx, and COx values in  
5 mmHg bins, and the percent time at each  
MAP. Increasing Mx and COx with declining 
MAP indicates threshold of autoregulation 
(arrow). 

cancel the effect of changes in blood volume by reporting the percentage of oxygenated 
hemoglobin. The intensity of light detected at the point of the reflected arc by the sensing 
optode, (I), is inversely proportional to the concentration (c) of the chromophore being 
measured when the intensity of the light source (Is) is held constant. We were able to use 
1/I from a nearly isobestic wavelength (805 nm) of infrared light to derive an index of 
autoregulation. Because the relative change in total hemoglobin is a small fraction of the 
absolute hemoglobin during autoregulation, a logarithmic transformation may not be 
necessary. Moreover, the phase of the blood volume waveform is more important than 
the power when describing vascular reactivity. The hemoglobin volume index was 
continuously recorded as a moving linear correlation between slow waves (20–300 sec) 
of arterial blood pressure and rTHb. The pressure reactive index was similarly 
continuously recorded. Autoregulation curves were constructed by averaging values of 
the pressure reactivity index and hemoglobin volume index in 5 mmHg bins according to 
the cerebral perfusion pressure at which they were recorded. 
The lower limit of autoregulation as determined by laser-Doppler flow velocity was 
29.4±6.7 mmHg (±SD). Relative total hemoglobin displayed a high degree of 
lowfrequency coherence with ICP. Using all 2242 paired measurements, hemoglobin 
volume index was linearly correlated with pressure reactivity index (Spearman r=0.73). 
The pressure reactivity index and hemoglobin volume index were both accurate 
measures of vascular reactivity, showing higher values below the lower limit of 
autoregulation and lower values above this limit. Receiver operating characteristics 
(ROC) of the autoregulation curves derived by hemoglobin volume index and pressure 
reactivity index were delineated using the individually derived lower limits of 
autoregulation as standards. Areas under the ROC curves were 0.88 for the pressure 
reactivity index (95% CI, 0.82–0.96) and 0.85 for the hemoglobin volume index (95% CI, 
0.75–0.94). The demonstrated coherence between the relative total hemoglobin and 
intracranial pressure waveforms at the frequency of slow waves (Fig. 4) suggest that slow 
waves of intracranial pressure are the result of blood volume changes. The hemoglobin 
volume index has potential for further development as a noninvasive alternative to the 
pressure reactivity index for patients at risk of neurologic compromise. 

Fig 4. Intracranial pressure and 
relative total hemoglobin (rTHb) 
coherence 
averaged 
for 
8 
animals. 
Coherence 
scores 
between 
the 
intracranial 
pressure 
and 
relative 
total 
hemoglobin waveforms are high 
at frequencies corresponding to 
the observed slow waves of 
intracranial pressure, ≤0.02 Hz. 
An example of hemoglobin volume index compared with mean velocity and cerebral 
oximetry indices in a patient during nearly 90 min of CPB is shown in Fig 5.  
Together, our preliminary data support our ability to carry out the measurements 
necessary to address our specific aims and suggest the immense potential clinical utility 
of these noninvasive brain monitors. 
 
Fig 5. An example of CBF autoregulation monitoring in a 62 year old patient undergoing 
cardiac surgery. In this patient the autoregulatory threshold based on TCD-derived mean 
velocity index (>0.2) was 55 mmHg in both hemispheres. There was a 5 mmHg lag in 
detection of this threshold based on cerebral oximetry index (>0.3). In contrast, 
hemoglobin volume index demonstrated changes that correlated with lowering blood 
pressure 5 mmHg higher than mean velocity index in the left and right hemispheres. This 
example demonstrates the potential value of noninvasive monitoring of the CBF 
autoregulation with cerebral oximetry and hemoglobin volume index. 

COx and Clinical Outcomes 
We have found that there is a wide inter-individual range of MAPs at the LLA during CPB 
(40 to 90 mmHg) and that these limits are difficult to predict based on clinical 
information.137 These data indicate that monitoring autoregulation is a more precise 
means for determining individual MAP targets during CPB than empirically choosing 
targets, as is the current standard of care. Moreover, our results show that patients 
experience MAP below the LLA for varying durations of time when MAP targets are 
empirically determined. Acute kidney injury (AKI) increases the risk for mortality after 
cardiac surgery.6-8 To assess whether MAP below the LLA has any meaningful 
consequences for patient outcome, we monitored COx in 349 patients during CPB.41 
Based on the RIFLE criteria,8,10,42 AKI developed within 7 days of surgery in 121 (34.7%) 
patients. Excursions of MAP below the LLA (mmHg × min/h of CPB) (relative risk, 1.02; 
95% CI, 1.01 to 1.03; p<0.0001) were independently associated with AKI. Each 5 mmHg 
x min/h of MAP below the LLA increased the risk for AKI by 10%. In an analysis of 450 
patients, we found that the duration of MAP < LLA was higher in patients (n=83) with 
major organ morbidity or mortality (stroke, renal failure requiring dialysis or increase > 2 
mg/dL, mechanical lung ventilation > 48 h, operative mortality, inotrope use > 24 h or new 
requirement for IABP insertion) than in those without this complication (odds ratio, 2.21; 
95% CI, 1.32 to 3.71; p=0.003).43 These data support the premise that individualizing 
MAP during CPB based on physiologic endpoints such as COx monitoring, rather than 
empiric targets, may provide a means for modifying the risk for AKI and major organ 
morbidity and possibly mortality. 
COx and Neurologic Complications: Our group has been investigating CBF  
autoregulation for a number of years. Interim analysis has shown a relationship between 
MAP < LLA as detected with COx (i.e., independent of TCD metrics), and neurologic 
dysfunction (ND), defined as postoperative DWI lesions, or clinical stroke, or transient 
ischemic attack, or clinically detected delirium (Table 1). 
These data are from 176 patients of a planned enrollment of 254 patients. The limit of 
autoregulation was defined as that MAP at which COx increases to >0.3.136 Excursions 
were defined as mmHg × min/h of CPB of MAP below the LLA. MRI was available from 
82 patients. Obtaining MRI after cardiac surgery is not possible in all patients because of 
retained pacemaker wires (i.e., temporary pacing wires left in place rather than having 
them removed postoperatively as is the usual practice), unavailability of research MRI 
scanners, patient’s level of illness, or death. These factors are only known after surgery, 
not during screening. As a result, some enrolled patients later are found not to be eligible 
for MRI scanning. Thus, the primary impetus of this renewal, to continue enrollment until 
an adequate number of patients have been studied with MRI. Regardless, our preliminary 
results show that patients with ND had a larger magnitude and duration of time with MAP 
< LLA. Delirium was diagnosed based on clinical observations as previously described.23 
Clinical assessments underestimate the frequency of delirium compared with structured 
instruments, particularly hypoactive variants that may go unrecognized clinically.146 

The etiology of perioperative delirium is likely multifactorial. Contributing factors include 
pharmacologic and other perturbations in individuals with preexisting vulnerability. 
Whether perioperative hypotension contributes to the etiology of delirium has not been 
extensively examined. The small number of studies that have addressed this issue 
produced conflicting findings, did not use structured assessments for delirium, varied in 
the timing of blood pressure recordings (i.e., every 5 min in some studies), had small 
numbers of patients, and were associated with other limitations. Based on our findings of 
a wide inter-individual variability of MAP at the LLA, we believe that examining the 
relationship between hypotension and delirium using a priori blood pressure cutoffs, 
rather than individualized definitions based on autoregulation monitoring, is imprecise. 
We have performed a retrospective analysis of our data obtained from several trials of 
patients undergoing CPB. Of 496 patients monitored with COx, 10% developed delirium 
based on clinical criteria. In a multivariate logistic regression model, the 
magnitudeduration of MAP < LLA during CPB determined with COx was associated with 
postoperative clinical delirium (odds ratio, 1.10, 95% CI, 1.10-1.11, p=0.0203) after 
adjusting 
for 
age, 
history 
of 
hypertension, stroke, 
and duration of CPB. 
We have also obtained 
preliminary 
delirium 
data in our current 
randomized 
trial 
comparing 
MAP 
management 
with 
autoregulation monitoring to standard of care in patients during CPB. In this latter 
analysis, Drs. Brown and Neufeld carefully assessed for the presence of delirium using 
structured instruments as proposed in this submission (see Delirium Assessment). In that 
preliminary analysis, the frequency of delirium (19 of 37 [51%] patients) tended to be 
lower in patients who were randomized to have MAP managed during CPB based on 
real-time autoregulation monitoring than in patients who received standard of care (33% 
vs. 66%, p=0.134). Acknowledging the limitations of the preliminary analysis, our 
early results provide evidence of a relationship between MAP < LLA and ND 
including delirium. Our methods would challenge current standard practice of 
empirically determining MAP targets during CPB and support COx monitoring as a 
clinically feasible approach for improving patient outcomes from cardiac surgery. 
HOW PATIENTS WILL BE SCREENED FOR ELIGIBILTY: Authorized research 
personnel will screen for eligible participants during cardiac preoperative visits scheduled 
at the surgeons office. Potential participants will be introduced to the study by authorized 
research personnel at this time.   
INCLUSION AND EXCLUSION CRITERIA: 

Inclusion criteria will be male or female patients, ≥55 years old, undergoing primary or 
re-operative CABG, aortic root replacement and/or valvular surgery that requires CPB 
(but not undergoing circulatory arrest) who are at high risk for neurologic complications 
(stroke or encephalopathy) as determined by a Johns Hopkins Encephalopathy Risk 
score of >0.05, or Stroke Risk > 0.02.132 This prediction algorithm, devised from data 
analysis by the investigative team, identifies probability of an adverse neurologic outcome 
based on five patient-related factors: age, prior stroke, diabetes, hypertension, or the 
presence of a carotid bruit. Women of childbearing potential will have a urine pregnancy 
test done prior to surgery to insure that they are not pregnant. 
Patients will be ineligible for this study if they have any of the following exclusion criteria: 
1. Contraindication to MRI imaging (e.g., permanent pacemaker, cerebral arterial 
vascular clips); 
2. AST, ALT and Alkaline phosphatase obtained before surgery which is more than 
twice the upper limit of institutional normal value and which, in the opinion of the 
principal investigator, is believed to be related to hepatic dysfunction; 
3. Chronic renal failure requiring renal dialysis. (Subjects with an estimated glomerular 
filtration rate ≤60 mL/min who do not require dialysis may be included in the study. 
However, these subjects will not receive gadolinium during their MRI/MRA.); 
4. Emergency surgery; 
5. Inability to attend outpatient visits; 
6. Visual impairment or inability to speak and read English; or 
7. Female of child bearing capacity with a positive pregnancy test. 
8. Individual adults less than 54 years old 
9. Prisoners  
 
The patient will be excluded from further study if an adequate temporal window for TCD 
monitoring cannot be identified before surgery. 
STUDY-WIDE NUMBER OF PARTICIPANTS: Initially we are conducting a 5-year study 
that includes a 1-month interval for investigator training and start-up, 56 months for 
enrollment of 280 patients (~5 patients/month), and 3 months for final patient followup 
testing, data analysis, manuscript preparation, and dissemination of the results (see 
Rapid Dissemination of Clinical Research). The initial study time line is schematically 
summarized in Table 2. 
STUDY TIMELINES: 

 
Table 2. Summary of Study Timeline During the Initial Phase of the Project  
We will continue this study for an additional 5-years that will enroll 350 new patients (in 
addition to the 280 patients of the initial study) over a 45-month period (~8 patients/month) 
with the remaining duration of the proposed funding used for patient follow-up testing, 
data analysis, manuscript preparation, and dissemination of the results. As of June 2016, 
we have enrolled 280 patients in the first five years and 244 patients in the second five 
year study. We need approximately 150 patients to complete enrollment. 
Patient Randomization  
Patients will be prospectively randomized after anesthesia induction, but before CPB, 
using a computer generated randomization program into one of two single-blinded 
groups:  
1) 
Blood pressure intervention group (Intervention Group) in which mean arterial 
pressure during surgery is targeted to be kept above the patient’s lower CBF 
autoregulatory threshold based on continuous monitoring of mean velocity index or 
cerebral oximetry index (see CBF Autoregulation Measurements) or  
2) 
Control Group in which mean arterial pressure is maintained during surgery, 
including CPB, using institutional standard of care.  
Blinding: Clinicians caring for the patients will participate in managing blood pressure in 
the Intervention Group and, thus, cannot be blinded. Individuals making the neurologic 
assessments and performing data analysis will be blinded to the intraoperative 
management group, providing effective double blinding. 
Drugs/ Substances/ Devices 
a. 
The rationale for choosing the drug and dose or for choosing the device to be 
used.The algorithm for the management of mean arterial pressure during 
cardiopulmonary bypass as detailed in Appendix A which reflects the current standard of 
care for the institution. The difference between the two randomized groups is when that 
intervention will take place. For the Control group, the algorhythm will be followed as per 
routine standard of care. For the Blood Pressure Intervention Group, the algorhythm will 
be instituted when the blood pressure is below the lower autoregulatory limits as 
determined by mean velocity index or cerebral oximetry index. 

b. 
Justification and safety information if FDA approved drugs will be administered for 
non-FDA approved indications or if doses or routes of administration or participant 
populations are changed. N/A 
c. 
Justification and safety information if non-FDA approved drugs without an IND will 
be administered. N/A 
Perioperative Management 
Preoperative Variables: Preoperative demographics, medical history (including 
euroScore131 calculated based upon the medical history), and medications will be 
recorded. A history of prior stroke or transient ischemic attack will be made by review of 
medical records, the results of prior brain imaging studies, or by contacting the patient’s 
primary care physician. Preoperative left ventricular function as assessed by 
ventriculography or echocardiography will be recorded as normal, mildly depressed 
(ejection fraction ≥40% but <50%), moderately depressed (ejection fraction ≥35% but 
<40%), or severely depressed (ejection fraction <35%). The results of carotid artery 
ultrasound imaging studies obtained before surgery will be recorded. 
Anesthesia and Patient Monitoring: To avoid hypotension during surgery, patients will not 
be given angiotensin converting enzyme inhibitors on the day of surgery. The patients will 
be connected to the NIRS monitor (Invos, Covidien, Boulder, CO) with two self-adhesive 
probes attached to the forehead, according to manufacturer guidelines. Arterial blood 
pressure will be measured via a cannula inserted into the radial or femoral artery placed 
for clinical purposes. Anesthetic drugs will be standardized and will consist of midazolam, 
propofol, fentanyl, isoflurane, and skeletal muscle relaxants. During CPB, isoflurane will 
be administered via the membrane oxygenator. Sedation after surgery will be started 
when sternal wires are placed and will consist of propofol. Propofol will be titrated off 
when the patient meets institutional standards for tracheal extubation. Postoperative pain 
will be managed per hospital standard. 
A deficiency of current clinical practice is that urine output is measured crudely and 
intermittently, and it is not precisely recorded. For this study, the patient’s urine flow will 
be measured every 1 min with automatic gravimetric sensing device connected to the 
urinary catheter collection bag (RenAdapter: Urine Flowmeter and Multiparameter 
Monitor). The urine bag will hang on the Renalert device intraoperatively to monitor urine 
output during surgery. At the conclusion of the surgery the device will be removed before 
the patient is transferred to the intensive care unit. 
Assessment of Depth of Anesthesia through BIS monitoring 
We will measure depth of anesthesia during surgery using the Bispectral Index Monitor 
(BIS), which is an FDA-approved device to measure processed electroencephalogram 
signals. Two adhesive pads will be placed on the patient’s forehead during surgery for 
this monitoring. 

Cardiopulmonary Bypass: A 40-μm or smaller filter will be placed in the CPB circuit. Blood 
flow during CPB will be maintained between 2.0 and 2.4 L/min/m2 using nonpulsatile flow. 
Nasopharyngeal temperature will be measured during surgery and the temperature nadir 
recorded. In addition to continuous in-line monitoring, arterial blood gases will be recorded 
30 min after the start of CPB and every 60 min thereafter. The patients will be managed 
using α-stat pH management. Hemoglobin will kept >8.0 g/dL with transfusion of packed 
red blood cells. Blood glucose will be measured at the onset of CPB and at least every 
60 min thereafter. Blood glucose will be managed per routine standard of care. 
Rewarming will be at an arterial inflow temperature of ≤37oC. Nasopharyngeal 
temperature will not exceed 36oC. Surgical field CO2 insufflation will be performed. 
Cardiotomy suction will be returned to the CPB circuit after being processed with a cell 
saver device for patients undergoing CABG surgery or directly to the CPB circuit for open 
chamber procedures, as is our usual practice. 
Perioperative Blood Pressure Monitoring and Recording: A decrease in arterial blood 
pressure that occurs any time preoperatively could confound analysis of the data. Blood 
pressure will be monitored using standard operating room and ICU monitors. Transducers 
will be placed level with the right atrium and zeroed to atmospheric pressure before the 
start of anesthesia, before the start of CPB, and after separating from CPB. Blood 
pressure will be recorded continuously during surgery and recorded on a computer 
interfaced with the operating room hemodynamic monitor (using ICM+ software, see 
Cerebral 
Autoregulation 
Monitoring 
and 
CBF 
Autoregulation 
Measurements). 
Computerized medical record systems will record arterial pressure every 15 min in the 
ICU. Study personnel will review these medical records daily for the duration of the ICU 
admission. The number of hypotensive episodes (mean arterial pressure <70 mmHg) will 
be recorded to adjust for the effect of this potential confounding variable on the primary 
outcomes. The dose and duration of any vasoconstrictor or vasodilator drugs given during 
surgery and in the ICU will be recorded.  
The patients will be visited on the postoperative ward daily by members of the surgical 
team to evaluate for adverse events, cardiac arrhythmias, and other events necessitating 
medical intervention, including hypotension or other complications. 
Perioperative Variables: The patients will receive routine institutional perioperative care 
that includes continuous arrhythmia monitoring with telemetric ECG after surgery. 
Postoperative variables, including complications that affect organ systems, will be 
collected during the hospitalization. Patients will undergo 12-lead ECGs before surgery 
and on arrival to the ICU after surgery as well as for the first 3 postoperative days. The 
definition of myocardial infarction will be a new Q-wave >0.04 sec and/or >1/3 the height 
of the R-wave. Data sheets for each patient will be completed to denote no myocardial 
infarction or Q-wave myocardial infarction. The data will then be entered into the study 
database. 

Autoregulation Monitoring 
CBF autoregulation will be monitored continuously by members of the investigative team. 
The patient’s forehead will be cleansed with the supplied alcohol sponge and wiped dry. 
Then, two Foresight monitoring electrodes will be calibrated, as specified by the 
manufacturer, and placed on the patient’s forehead. The electrodes will be attached to a 
Fore-Sight cerebral oximeter (CasMed, Branford, CTI) specially equipped with an output 
signal for this project. We will perform TCD monitoring (DWL, Compumedics DWL, El 
Paso, TX) of the right and left middle cerebral arteries using two 2.5-MHz transducers 
fitted on a headband and positioned over 
the temporal bone windows to obtain 
bilateral 
continuous 
measurement 
of 
baseline velocity. Depth of insonation will 
be varied between 35 and 52 mm until 
representative spectral middle cerebral 
artery flow is identified.  
Arterial 
pressure 
from 
an 
indwelling 
cannula (started for clinical indication), 
along with TCD signals from the middle 
cerebral arteries and the near-infrared 
spectroscopy signals, will be sampled with 
an analog-to-digital converter using ICM+ 
software at 58 Hz.31-37 Digital rScO2 
signals from the NIRS monitor will be 
transferred directly to a laptop computer. Blood 
pressure, TCD, and rScO2 signals will then be 
time integrated as non-overlapping 10-sec 
mean values, equivalent to applying a moving 
average filter with a 10-sec time window and 
re-sampling 
at 
0.1 
Hz. 
This 
operation 
eliminates high-frequency noise from the 
respiratory and pulse frequencies, according to the Nyquist theorem, allowing detection 
of oscillations and transients that occur below 0.05 Hz. A continuous, moving Pearson 
correlation coefficient will be calculated between mean arterial pressure and TCD CBF 
velocity of the middle cerebral arteries, rendering the variable mean velocity index (Mx). 
Similar methods will be performed to calculate the Pearson correlation coefficient 
between mean arterial pressure and cerebral oximetry signals, rendering the variable 
cerebral oximetry index, and between mean arterial pressure and relative total 
hemoglobin signals, generating the hemoglobin volume index (see Cerebrovascular 
Reactivity Measured by Nearinfrared Spectroscopy). Consecutive, paired, 10-sec 
averaged values from 300-sec duration will be used for each calculation, incorporating 
30 data points for each index.35,37 Mx and COx values for each patient will be placed 
into 5 mmHg MAP bins and displayed on the laptop computer (Figs. 3 and 6). When MAP 
is within the limits of CBF autoregulation, Mx and COx approach zero, but when MAP is 
Fig 6. Dysregulated pattern when COx is >0.3 
at all MAPs. In this patient optimal MAP is 70-
75 mmHg. Note, the top panel is the MAP time 
series. The y-axis on the remaining graphs is 
left and right COx, respectively, on a scale of 
0 to 1.0. The xaxis is MAP in 5 mmHg bins. 

outside the limits of autoregulation, Mx and COx approach 1, indicating that CBF is blood 
pressure dependent. Based on our prior studies, we designate the LLA as the highest 
MAP associated with Mx ≥ 0.2 or Cox ≥ 0.3. These values are within the range found to 
be associated with poor outcome after traumatic brain injury and adverse outcomes after 
cardiac surgery.17,40,151,152 In about 20% of patients, impaired autoregulation is observed 
when Mx and COx are ≥0.3 at all MAPs during CPB (Fig. 6). An attenuated autoregulation 
plateau is usually observed. Thus, the “optimal” MAP, defined as the MAP with the lowest 
Mx, will be the blood pressure target during CPB, as this point is observed in patients with 
functional and impaired autoregulation. As blood pressure varies during the usual course 
of surgery, including during the initiation of CPB, no specific interventions are needed to 
establish autoregulation indices. Clinicians will have access to COx data only for patients 
randomized to the Intervention Group. 
The autoregulatory threshold will be defined as the mean arterial pressure at which 
the mean velocity index increases to ≥0.2 or cerebral oximetry index increases ≥0.3.  
Information regarding the mean arterial pressure at which the lower CBF autoregulatory 
threshold is detected will be made available to the anesthesiologist, perfusionist, and 
critical care doctors who are caring for the patients in the Intervention Group before and 
after surgery. Physicians and perfusionists will be told specifically that a patient has been 
randomized to the Intervention Group and that his/her mean arterial pressure should be 
kept higher than that value associated with a mean velocity index ≥0.2 or cerebral 
oximetry index ≥0.3. During surgery, the mean velocity index will be monitored 
continuously by the investigative team to confirm that treatments are instituted if mean 
arterial pressure falls below these limits. These same data will be collected in the Control 
Group but no specific measures for treating blood pressure will be advised. 
At the conclusion of surgery, patient steaming data files will be stored on a portable 
computer in the ICM+ file. The data files will be transferred to a departmental server with 
a password-protected file folder specifically designed for this study. Data on the server is 
backed up daily. The data from each patient will be copied to an excel spread sheet. This 
data will include the mean arterial pressure from a range of 0 to 115 mmHg and the 
corresponding mean velocity index and cerebral oximetry index as well as the percentage 
of time at each blood pressure. 
Blood Pressure Management 
To avoid hypotension during surgery, angiotensin converting enzyme inhibitors will not be 
given on the day of surgery. Patients randomized to the blood pressure Intervention 
Group will have their mean arterial pressure treated according to the protocol outlined in 
Appendix A when it is below the lower autoregulatory limits as determined by mean 
velocity index or cerebral oximetry index. Patients in the Control Group will receive the 
same treatment, but the lower threshold for treatment will be based on institutional 
practices and not mean velocity index or cerebral oximetry data. The threshold for treating 
high blood pressure is not specified and will be based on institutional practices. A 

treatment algorithm for treating high blood pressure is provided to ensure consistency in 
treatments between patients. To avoid a precipitous drop in mean arterial pressure on 
initiation of CPB, a 100-μg bolus dose of phenylephrine will be given intravenously 
immediately before drainage of blood from the patient to the CPB reservoir. Initiation of 
CPB will be begun gradually, at no more than 2 L/min, to allow slow equilibration. CPB 
will be increased by 0.5 L/min increments to the calculated full CPB flow. Phenylephrine 
boluses (50–100 μg) can be given when mean arterial pressure is below the lower limit, 
until it is stabilized. 
Hypotension for periods other than during CPB will be treated by first ensuring adequate 
cardiac preload with crystalloid or colloid. The decision will be dictated by examination of 
left and right ventricular end-diastolic areas with transesophageal echocardiography or 
based on central venous pressure or pulmonary capillary wedge pressure when a 
pulmonary artery catheter is in place and transesophageal echocardiography is not used. 
If cardiac filling is normal, as described above, and systemic vascular resistance is low, 
hypotension will be treated using the same algorithm as that for treating hypotension on 
CPB. If cardiac preload is adequate but cardiac function is poor (or cardiac index of <2.0 
L/min/m2), epinephrine will be started per hospital standard care. If cardiac 
function/cardiac index remains depressed, milrinone and dobutamine will be used per 
hospital standard care. Persistent low cardiac function/cardiac index, including that 
resulting from right ventricular dysfunction, will be treated according to institutional 
treatment guidelines. 
Patients will be evaluated at screening and sometime between postoperative day 5 and  
7 or at hospital discharge (whichever occurs first) with the National Institutes of Health 
Stroke Scale (NIHSS). The NIHSS is a standardized, validated neurologic examination 
used in clinical trials to evaluate change in neurologic status.105 The test quantifies 
neurologic deficits in 11 categories using a 42-point scale. This testing will be performed 
by a trained research nurse. Research personnel will be certified for performing the 
NIHSS using the American Stroke Association's Online NIH Stroke Scale Training 
Program (http://asa.trainingcampus.net/uas/modules/ trees/windex.aspx). Patients with a 
change from baseline in their NIHSS will be referred for evaluation by a neurologist per 
hospital standard of care by their medical team. An MRI of the brain will be obtained when 
stroke is likely based on the neurologist’s examination. Brain CT imaging will be 
substituted for MRI when MRI is viewed as clinically contraindicated. Central nervous 
system infarction will be defined based on the Expert Consensus Statement of the 
American Heart and Stroke Associations as ischemic injury to the brain, spinal cord, or 
retina based on pathological, imaging, or other objective evidence of cerebral, spinal cord, 
or retinal focal ischemic injury in a defined vascular distribution; or clinical evidence of 
cerebral, spinal cord, or retinal focal ischemic injury based on symptoms persisting for 
≥24 h or until death, and other etiologies have been excluded.36A stroke will be defined 
as an episode of neurologic dysfunction caused by focal cerebral infarction. An 
intracerebral hemorrhage will be defined as a focal collection of blood within the brain 
parenchyma or ventricular system that is not caused by trauma. A transient ischemic 

attack is defined as focal arterial ischemia with transient symptoms lasting < 24 h without 
evidence of infarction by pathology or imaging. 
Delirium Assessment: Delirium is characterized by an acute-onset, fluctuating disorder in 
level of consciousness associated with changes in cognition, attention, and perception 
not explained by pre-existing or evolving dementia.156 Trained examiners can diagnose 
delirium and quantify its severity with structured instruments (Appendix C). Examinations 
are followed by case-by-case adjudication.146 A Mini Mental Status Exam and 
Abbreviated Digit Span will be done preoperatively to establish a baseline. Delirium 
assessments will be made on three of the first four postoperative days using the following 
tools: 
a. 
Confusion Assessment Method (CAM) is a standardized method that is designed 
to allow trained non-psychiatrists to diagnose delirium. It shows high inter-rater reliability, 
sensitivity (94–100%), and specificity (90–95%) when compared to the gold standard of 
psychiatric diagnosis.142 The CAM diagnostic algorithm is based on assessing the four 
cardinal features of delirium: 1) acute onset and fluctuating course, 2) inattention, 3) 
disorganized thinking, and 4) altered level of consciousness. 
b. 
Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is a 
validated instrument used to diagnose delirium in critically ill intubated patients in the ICU, 
including those who are non-verbal due to mechanical ventilation. Inter-rater reliability is 
high (kappa 0.79–0.95), and it has high sensitivity (95–100%) and specificity (89–93%) 
when compared to the gold standard of psychiatric diagnosis. This test will be used for 
intubated patients in the ICU. 
c. 
Delirium Rating Scale-Revised-1998 (DRS-R-98) is a 16-item scale that has been 
validated as a measure of delirium severity. Inter-rater reliability is high (interclass 
correlation coefficient = 0.99), and the scale is one of the few that has been validated 
against a dementia group.39 
Trained delirium assessors (authorized research members) will obtain a history of current 
symptoms from the patient, care providers, and family; review medical records; and 
perform a mental status exam and cognitive screens that will include the Mini Mental 
State Exam (MMSE) and abbreviated digit span.68 This information will be used to rate 
the CAM, producing a binary outcome for the presence or absence of delirium in the past 
24 h. The DRS-R-98, which yields a delirium severity rating, will also be completed. If a 
patient is unable to respond verbally to questions because of intubation and mechanical 
ventilation, the CAM-ICU version will be administered. This instrument has sensitivities of 
76%–80% and a pooled specificity of 96% in the ICU.157,158 
Neurocognitive Function: A component of the endpoint of this study is cognitive decline 
after surgery compared with the patient’s baseline. Cognitive testing will be performed 
within two weeks before surgery, 4–6 weeks after surgery, and 1 year after surgery. Most 
elective cardiac surgical procedures are performed on patients admitted to the hospital 
the day of surgery. Assessing baseline cognitive status in patients during an outpatient 
visit is confounded by time constraints and anxiety that might bias the data and affect 
enrollment. Nonetheless, we have extensive experience in performing cognitive testing 

on the day before cardiac surgery. For patients already admitted to the hospital, cognitive 
testing and other preoperative assessments will be performed on the ward. For patients 
who will be admitted the day of surgery, testing will occur either after their preoperative 
visit with their surgeon or by a separate visit specifically for the purposes of the study. For 
outpatients, testing before surgery will be at NMH.  
 
Postoperative cognitive testing will be performed at the patient’s postoperative surgical 
clinic visit, in NMH which usually occurs 4–6 weeks after surgery, and again at 1 year 
after surgery. 
 
Our goal for cognitive testing is not to test hypotheses about specific types of cognitive 
decline or about injury to specific brain regions. We have selected neuropsychologic tests 
that assess a number of cognitive domains known to be affected by cardiac surgery.81-
83,159 They have the advantage of being standardized. They are also brief and easy to 
administer and score; the total administration time is approximately 35–45 min. Based on 
our previous experience, this focused approach is highly feasible for testing surgical 
patients. The battery is listed in Appendix B and consists of the Rey Auditory Verbal 
Learning Test,87,160 a test of verbal learning and memory; Rey Complex Figure Test121, 
an assessment of visual memory; Controlled Oral Word Association Test,87 a test of 
executive functions; Symbol Digits Modalities Test,162 a test of psychomotor speed and 
attention control; Trail Making A and B,163 tests of visuomotor speed, attention, and 
executive functions; Grooved Pegboard Test,34,164 a measurement of fine motor dexterity 
and speed; Beck Depression Inventory,105,165 a self-reported scale of depression 
symptom severity; and the State-Trait Anxiety Inventory,162 a measurement of anxiety 
symptoms. The patients are also evaluated with the SF-36 short form of the RAND 
Medical Outcomes Study (MOS) health-related quality of life questionnaire.166 This 
questionnaire is a multi-item scale that measures 8 health-related concepts: physical 
function, social function, physical role, emotional role, mental health, energy, pain, and 
general health perceptions.166,167 The standardized scores for each of the 8 quality-of-life 
domains range from 0 (worst) to 100 (best). The SF-36 has been used in previous studies 
to assess quality of life in cardiac patients and chronically ill populations. Cognitive decline 
will be defined as a decrement in performance from baseline to postoperative testing of 
at least 1 standard deviation (SD) in two or more tests, or 2 SD in one test. It has been 
shown that this definition is unlikely to classify random test-retest variability as decline but 
is nonetheless sensitive enough to detect actual postoperative change in cognitive 
performance.46 
 
Magnetic Resonance Imaging 
Brain ischemic lesions detected with diffusion-weighted imaging are a component of the 
primary outcome of this study. Brain MRI will be performed between postoperative days 
3 and 14. The imaging sequences will include oblique axial diffusion-weighted images 
from 
which 
apparent 
diffusion 
coefficient 
(ADC) 
maps 
will 
be 
calculated, 
perfusionweighted images, T2, FLAIR, and 3D spoiled gradient-echo (SPGR; which 
allows 3dimensional reconstruction, comparable to MPRAGE) scans. These data will be 
acquired on an instrument TBD.106 Diffusion-weighted trace images are obtained using a 

multi-slice, isotropic, single-shot EPI sequence, with bmax = 1000 s/mm2 and TR/TE = 
10,000/120 msec. Corresponding ADC maps will be used to identify infarcted tissue. For 
perfusion-weighted imaging, single-shot gradient echo EPI perfusion images (TR/TE = 
2000/60 msec) are obtained with a 20 mL Gd-DTPA (Gadolinium) bolus power injected 
at 5 mL/sec at the start of the scan. These scans are used to generate maps of the time-
to-peak arrival of contrast across voxels in the region of interest, relative to the 
homologous region of interest in the unaffected hemisphere. Given concerns about the 
potential for nephrogenic systemic fibrosis from gadolinium contrast in subjects with renal 
failure, the creatinine level of all patients will be measured before the MRI. Gadolinium 
will not be given to individuals with an estimated glomerular filtration rate ≤60 mL/min or 
to those who need dialysis after surgery (by FDA).107 In such patients, only diffusion-
weighted imaging without gadolinium administration will be performed as needed for 
determining the primary outcome. The FDA Web site states that “there are no reports 
received of individuals with normal or even moderately impaired renal function developing 
NSF http://www.fda.gov/cder/drug/infopage/gcca/qa_200705.htm. 
 
In previous work by members of the investigative team, inter-observer point-to-point 
agreement for analysis of the time-to-peak delay in each area for 12 scans was 83% for 
calculating the delay to the nearest 0.1 sec and 100% for calculating the delay within 0.2 
sec. We will register each image (first registering the corresponding SPGR scans) to a 
spatial standard, a digital form of the Montreal Neurological Institute atlas, using local 
registration methods or image warping, in which each voxel is individually displaced.108 
This technique results in better registration to an atlas than do global methods.109 
Registered images are first read by a neuroradiologist and reported in the patient’s 
medical record as part of standard Department of Radiology policy at Northwestern 
Memorial Hospital.  Any subject who enrolls in this study with a history of retained metal 
in their head and/or eye(s) will have an x-ray of the head done in order to determine if it 
will be safe to proceed with the MRI. If it is deemed safe for the subject the MRI will be 
obtained. 
Additionally, stored images will be independently analyzed by one of two investigators 
(TBD) blinded to patient outcomes. The images will be assessed for nonischemic 
pathology, the presence and location of prior cerebrovascular disease, new acute 
ischemic lesions, global cerebral edema, and hemorrhages. Acute ischemic lesions will 
be depicted as a hyperintense signal on the diffusion-weighted images and hypointense 
signal on the ADC map. ADC can be calculated on a pixel-by-pixel basis. Based on the 
location, size, and pattern of distribution, the ischemic infarct will be classified into one of 
four categories: small subcortical infarction (lesion that is <1 cm in diameter located in the 
basal ganglia, thalamus, or brainstem); territorial infarction (lesion located in a vascular 
distribution, usually resulting from large vessel occlusion); watershed infarction (lesion 
located in the border zone between vascular territories); or multiple emboli (multiple 
lesions in one or several different vascular territories). The number of acute lesions 
detected by diffusion-weighted imaging will be counted, and the total infarct volume will 
be traced and measured volumetrically by a technician using the Image J software.110 
The sum of infarcts and infarct volume will be recorded in addition to the categorization 

of the infarcts as described above. The primary MRI outcome will be a comparison of the 
number of diffusion-weighted imaging lesions for patients in the blood pressure 
Intervention Group with that of the Control Group.  
 
Secondary analysis will include total infarct volume, location in cortical or subcortical 
regions, and the ratio of diffusion-weighted imaging lesion size to perfusion-weighted 
imaging defect size.  
MRA will be obtained by contrast-enhanced MRA (CE MRA), using IV contrast at the time 
of brain MRI. In the event that gadolinium is not administered, MRA of the neck will be 
carried out with 2D time of flight (TOF) imaging. When gadolinium is administered, neck 
MRA will be 3D TOF of the neck. MRA of the head will be 3D TOF regardless of use of 
gadolinium. Measurements of arterial stenosis on MRA will vary depending on the 
location of the vessel; standard measurements are made by a neuroradiologist, and these 
will be replicated by one of the investigators (TBD). For extracranial carotid stenosis, the 
technique is that used in the North American Symptomatic Carotid Endarterectomy Trial 
(NASCET) (Fig 7). 
 
Intracranial arterial stenosis of the most clinically important major vessels (middle cerebral 
artery, basilar artery, intracranial internal carotid artery) and the extracranial vertebral 
arteries, will be measured based on the methods used in the Warfarin- Aspirin  
Symptomatic Intracranial Disease study.111 
 
The percent stenosis of a major intracranial artery will be defined as [(1 
(Dstenosis/Dnormal))] x 100, where  
stenosis = the diameter of the artery at the site of the most severe degree of stenosis and 
normal= the diameter of the proximal normal artery.  
 
For the middle cerebral, intracranial vertebral, and basilar arteries, normal will be defined 
as the diameter of the widest part of a normal segment of the proximal part of the artery. 
If this portion of the artery is not normal, then normal will be defined as the diameter of 
widest part of the distal portion of the artery. When the entire intracranial artery has 
atherosclerotic narrowing, the most distal part of the normal segment of the artery 
supplying the vessel will be used for determining normal. 
 
Brain imaging might result in the detection of an unexpected condition, such as a brain 
mass, aneurysm, or vascular malformation. In the event of such findings, the patient, and 
his/her family and clinical physicians will be notified, and the patient will be referred for 
clinical management. 
 

 
 
 
 
Frailty Assessments: 
 
We will evaluate frailty based on a validated scoring system1 that characterizes frailty 
as an age-associated decline in 5 domains: shrinking, weakness, exhaustion, low 
physical activity, and slowed walking speed.  
 
These measurements are described below based on the original paper. 
 
Each domain will yield a dichotomous score of 0 or 1. We will classify patients scoring 3 
to 5 as frail, 1 to 2 as intermediately frail (pre-fail), and 0 as nonfrail. We will also measure 
the Instrumental Activities of Daily Living scale as part of the frailty assessment. Research 
staff will undergo frailty screen training to allow consistent measurements of frailty 
domains in the study population. Frailty assessment will be held in clinic during the 
patient’s preoperative and postoperative visits, and again at the time of the 1 year follow-
up visit.  
Weight loss: “In the last year, have you lost more than 10 pounds unintentionally (i.e., not 
due to dieting or exercise)?” If yes, then frail for weight loss criterion.  
Exhaustion: 
Using the CES–D Depression Scale, the following question and the accompanying two 
statements are read:  
“How often in the last week did you feel this way?” (a) I felt that everything I did was an 
effort (b) I could not get going.  
The subject will respond to these questions using the following scale: 
0 = rarely or none of the time (1 day);  
1 = some or a little of the time (1–2 days);  
2 = a moderate amount of the time (3–4 days); or 
                                            
 

3 = most of the time.  
Subjects answering “2” or “3” to either of these questions are categorized as frail by the 
exhaustion criterion. 
Physical Activity: 
Based on the short version of the Minnesota Leisure Time Activity questionnaire, asking 
about walking, chores (moderately strenuous), mowing the lawn, raking, gardening, 
hiking, jogging, biking, exercise cycling, dancing, aerobics, bowling, golf, singles tennis, 
doubles tennis, racquetball, calisthenics, swimming. Kcals per week expended are 
calculated using standardized algorithm. This variable is stratified by gender:  
Men: Those with Kcals of physical activity per week <383 are frail. Women: 
Those with Kcals per week < 270 are frail.  
Walk Time: Table 3 (below) will be used to stratify Walk Time by gender and 
height (gender-specific cutoff a medium height). 
 
Grip Strength: Table 4(below) will be used to stratify Grip Strength by gender and body 
mass index (BMI) quartiles 
 
Instrumental Activities of Daily Living Scale will be used to provide additional information 
on functional status in the frailty assessment. Seven questions are asked to gauge 
participant difficulty with using the telephone, walking, preparing meals, managing 
money, shopping, doing housework, and taking medicines.  
Each study subject will participate in the study for approximately 1 year.  

Consent will be obtained before any study related events occur. Cognitive and quality of 
life testing, medical history, TCD measurements (to determine subject eligibility), National 
Institutes of Health Stroke Scale (NIHSS), ECG and psychomotor testing and Brief Smell 
Identification Test133will be performed within 1- 2 weeks before surgery. We plan to 
perform this testing in the outpatient center for most patients. Patients who are in-patients 
prior to surgery will have testing performed on the hospital ward. 
On the day of surgery after anesthesia induction the patients will be connected to a 
transcranial Doppler to monitor middle cerebral artery blood flow velocity and to a near 
infra-red spectroscopy machine to monitor cerebral oxygenation. Doppler probes are held 
in place with a fitted head band. The NIRS electrodes will be placed using manufacturer 
guidelines. Both devices are FDA approved. Transcranial Doppler and NIRS are used to 
monitor cerebral blood flow autoregulation. Subject randomization will also be done at 
this time. 
Before cardiopulmonary bypass is initiated (after sternotomy and pericardiotomy) the 
patients will undergo epiaortic ultrasound examination of the ascending aorta to examine 
for atherosclerotic changes. In many centers epiaortic ultrasound has replaced the 
traditional palpations by the surgeon of the aorta for the detection of atherosclerosis of 
the ascending aorta.  
The day of surgery during cardiopulmonary bypass the patients will undergo cerebral 
blood flow autoregulation monitoring using methods described in the preliminary data 
section. For individuals in the intervention arm, blood pressure targets during 
cardiopulmonary bypass will be determined by this monitoring and will be the blood 
pressure where the mean velocity index (Mx) is <0.2 or the cerebral oximetry index  
(COx) is< 0.3. This information will be communicated to the perfusionist, anesthesiologist 
and surgeon by the investigative team. In the control arm, cerebral blood flow 
autoregulation information will be monitored and saved but the data will not be provided 
to the surgical team.  
After surgery, visits will all be done in the ICU or postoperative unit. The patients will have 
an ECG which is to be done upon the subject’s arrival in the ICU after surgery. This 
procedure is routine care and only a copy of the ECG will be obtained for the study case 
report form. 
Each patient will be evaluated daily by the attending and resident physicians. Data will 
be collected from the patient record by a member of the study team. Every patient will 
have an ECG done each day postoperative days 1 through 3, per standard of care. An 
MRI will be done at some point between postoperative day three and postoperative day 
14 or at hospital discharge (whichever occurs first). In addition, all patients will be 
evaluated between postoperative days 5 and 7 or at hospital discharge (whichever 
occurs first) with the National Institutes of Health Stroke Scale (NIHSS) And Brief Smell 
Identification Test. 

Cognitive testing and the Brief Smell Identification Test will be repeated at the time the 
patient returns for follow-up with the cardiac surgeon, about 4 to 6 weeks postoperatively. 
Cognitive testing will be repeated at 1 year postoperative. 
Assessment Schedule  
The schemata of study procedures are listed in Table 5.  
 
SAEs/AEs 
----------------------------------------X------------------------------------------ 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Mx and C02 monitoring  
 
X 
X 
X 
 
 
 
 
 
 
 
 
Bispectral Index Monitoring  
 
X 
X 
X 
 
 
 
 
 
 
 
 
Urine Flow 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Brain MRI 
 
 
 
 
 
 
 
X1 
 
 
 
 
MMSE and Abbreviated Digit Span X 
 
 
 
 
 
 
 
 
 
 
 
Delirium assessments  
 
 
 
 
 
X 
X 
X 
X 
 
 
 
Electrocardiogram 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 

 
Clinicians caring for the patients will participate in managing blood pressure in the Blood 
Pressure Intervention Group and, thus, cannot be blinded. Individuals making the 
neurologic assessments and performing data analysis will be blinded to the intraoperative 
management group, providing effective double blinding. 
Participation in this study will not require discontinuation of a subject’s current therapy 
any more than would be required if the subject were to undergo CABG and/or valve 
surgery outside of the study. The Control Group will receive standard care practiced here 
at Northwestern Memorial Hospital. The Blood Pressure Intervention Group will be 
receiving investigational care. Blood pressure targets during surgery will be at least those 
of the standard care group or higher based on the individualized autoregulation 
measurements.  
Justification for inclusion of a placebo or non-treatment group. 
There will be a Control Group in which mean arterial pressure is maintained during 
surgery, including CPB, using institutional standard of care. This is being done in order to 
allow direct comparison of the current standard of care with the Blood Pressure 
Intervention Group. 
Definition of treatment failure or participant removal criteria. 
There is no definition for treatment failure. The subject will be excluded from further study 
if an adequate temporal window for TCD monitoring cannot be identified before surgery.  
Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
If a subject’s participation in the study were to end prematurely then that subject would 
be treated according to current standard of care. 
Study Statistics  
a. Primary outcome variable.  
Aim 1: To determine whether targeting blood pressure to a level above an individual’s 
lower CBF autoregulatory threshold during CPB reduces the frequency of the composite 
end point of clinical stroke, a diffusion-weighted MRI brain lesion, or postoperative 
cognitive decline 4 to 6 weeks after surgery, compared with patients who receive standard 
blood pressure management.  
Aim 1a: To assess whether extracranial and/or intracranial arterial stenosis (detected by 
MR angiography), or other patient characteristics such as age, gender, hypertension, 
diabetes, or prior stroke, modify the effect of maintaining blood pressure above an 

individual’s lower CBF autoregulatory threshold on the risk for the above composite 
neurological outcome.  
Aim 1b: To assess whether targeting MAP to a level above an individual’s lower CBF 
autoregulatory threshold during CPB reduces the frequency of cognitive decline 1 year 
after surgery compared with the use of standard blood pressure management. In Aim 1, 
we will test whether the Intervention and Control groups have the same risk of the primary 
composite neurologic endpoint of stroke, DWI lesion, or cognitive decline 4 to 6 weeks 
after surgery (i.e., null hypothesis). This will be done using a two-sided test of proportions 
at 5% significance level. We will first calculate and report the relative risk (RR) of 
composite neurologic outcome by comparing the Intervention and Control groups without 
adjusting for any potential confounders (i.e., the unadjusted RR). In addition, we will 
construct an adjusted estimate of RR using a generalized linear model (GLM) with 
Poisson distribution and robust standard errors.100 The candidate models will include 
study group as the primary independent variable as well as extra- or intracranial arterial 
stenosis determined by MRA, patient age, gender, and baseline risk factors that are 
assumed to be highly predictive of the outcome, such as history of hypertension, diabetes, 
or prior stroke. To assess potential effect modification by cerebral arterial stenosis, age, 
gender, hypertension, diabetes, or prior stroke (Aim 1a), we will calculate the unadjusted 
RR stratified by these variables. We will use a test of homogeneity to compare stratum-
specific estimates of RR.101 Finally, we will use the model developed in Aim 1 to report 
stratum-specific adjusted estimates of RR by introducing appropriate interaction terms of 
these variables and study group in the GLM model. We will compute the Z-score for the 
cognitive tests to normalize the distribution to the control data. The individual Z-scores 
will be combined into an average score and re-normalized.102 To assess postoperative 
change in cognitive function for up to 1 year (Aim 1b), we will use population-average 
marginal models estimated using generalized estimating equations (GEE) with 
exchangeable working correlation structure. The model will include assessment time with 
2 indicator variables for 1 year and 4 to 6 weeks postoperation and baseline as the 
reference group as well as Intervention Group, and their interaction to test whether 
postoperative trajectory of cognitive function differs by group.  
As a secondary analysis, we will develop logistic regression models on the binary 
outcome of the composite neurologic outcome and the time spent below the CBF 
autoregulatory threshold regardless of treatment assignment (i.e., data combined from 
both groups), while adjusting for other statistically and scientifically important covariates. 
This will allow for the development of a ”dose-response” relationship between blood 
pressure below the CBF autoregulatory threshold and outcome, whereby we can estimate 
the probability of an adverse neurologic event as a function of time spent in suboptimal 
perioperative conditions. In this analysis, we will consider the time spent below the CBF 
autoregulatory threshold as both an absolute time in minutes and as a percent of the total 
time on bypass, thereby allowing us to determine which measure of time below optimal 
threshold is more predictive of an adverse outcome. Note, the lower graph in Figure 6 
(above), depicts the data from a single patient showing the percent time at each blood 
pressure epoch. The program saves the data in a spreadsheet format.  

As an additional set of analyses for the multivariable logistic regression models, we will 
look whether there are interactions (e.g., effect modification) between gender or extra- 
and intra-cranial arterial stenosis on the composite neurologic outcome. In considering 
patient sex, we are particular interested in whether or not the effectiveness of the 
intervention applies equally to women as well as men. Similarly, we are interested in 
determining whether the association between the intervention and the neurologic end 
point differs in the presence or absence of clinically significant narrowing in the arteries 
of the neck and head. In considering the modifying effect of carotid arterial stenosis, we 
will dichotomize this variable with the cut point of <70% versus ≥70% narrowing based 
on the NASCET criteria, using the methods for measurement described in Magnetic 
Resonance Imaging.113 For intracranial arterial stenosis, we will dichotomize the 
stenosis as ≥50% or <50%. As a second step, we will also consider three categories of 
arterial stenosis (<50%, 50%–70%, and >70%), which considers the clinically important 
stenosis definition as defined by the Warfarin-Aspirin Symptomatic Intracranial Disease 
criteria.111 Interaction terms for both the binary definition of stenosis and the three 
categories of stenosis will be incorporated into the regression model, and any statistically 
significant effect modifications will be determined via standard Wald tests. Finally, we will 
also consider arterial stenosis in the multivariable logistic regression model as a 
continuous variable if the inter-rater reliability is high for this variable. Considering arterial 
stenosis as a continuous variable will allow us to consider possible thresholds of risk for 
the neurologic end point as a function of a continuous measure of stenosis. We will look 
for inflection points in the risk of stenosis on the outcome by incorporating linear (e.g., 
broken arrow regression) and cubic spline terms in the model. If the inter-rater reliability 
for the continuous measures of stenosis is low, we will consider only the above categories 
of mild, moderate, and severe stenosis in the regression models. 
Aim 2: To compare the accuracy of CBF autoregulation as determined by monitoring of 
the linear regression correlation between blood pressure and cerebral O2 saturation 
(cerebral oximetry index) and near-infrared reflectance spectroscopy (hemoglobin volume 
index) with the accuracy of that determined by TCD-measured CBF velocity (mean 
velocity index).  
We expect that the estimated lower CBF autoregulatory thresholds based on the cerebral 
oximetry index will be similar to those measured with both the mean velocity index and 
the hemoglobin volume index. Nevertheless, to quantify variance, we will first calculate 
the pair-wise differences in each of these estimate threshold levels per patient. 
Graphically, we will quantify these differences using histograms to assess the distribution 
of the discrepancy. In addition, we will create Bland-Altman plots to investigate if these 
differences are related to the absolute values of the threshold estimate. In other words, 
does this difference in estimates using either the hemoglobin value and cerebral oximetry 
or the mean velocity index and the cerebral oximetry increase (decrease) as one’s 
autoregulatory threshold increases (decreases)? We will also investigate whether the 
discrepancies in threshold estimates differ by the demographic or clinical variables in our 
patient sample using both univariate methods and linear regression modeling to examine 
the effect of these covariates on discrepancies in threshold estimates.  

This hypothesis has already been adequately addressed and will no longer be an aim of 
this study as we move forward. 
Aim 3: To perform secondary analysis to determine whether an association exists 
between abnormal perioperative TCD findings indicative of intracranial arterial stenosis 
and the risk for the composite neurologic outcome.  
Under this aim, we will assess whether perioperative TCD findings indicative of arterial 
stenosis of major cerebral vessels (see Transcranial Doppler Evaluation) are predictive 
of the composite adverse postoperative neurologic outcome. We will test for this possible 
association by considering - in the multivariable logistic regression model described under 
Specific Aim 1 - a dummy variable indicative for a positive finding for stenosis 
preoperatively. Results from this model in conjunction with determination of any potential 
effect modifications of stenosis on the outcome as described under Aim 1a will serve as 
a valuable tool for assessing the benefits and risks of this CBF-targeted intervention 
during CPB on patients found to have clinically significant narrowing of the intracranial 
arteries, as determined by either MRA or TCD examination before surgery. 
Aim 4: To assess whether targeting MAP during CPB to a level above an individual’s 
lower CBF autoregulatory threshold during CPB reduces the frequency of postoperative 
delirium, as assessed with a structured examination, compared with the use of standard 
blood pressure management.  
In Aim 4, we will compare Intervention and Control groups for proportion of patients with 
delirium. For the analysis, we will include only those patients who have undergone the 
more extensive delirium assessments as described in this proposal. This same structure 
assessment for delirium was initiated in year 4 of the prior grant and is consistent with 
other delirium studies performed by co-investigators (R01 AGO33615). We will estimate 
the unadjusted (without any other variable in the model) and adjusted RR of delirium by 
comparing the two study groups. We will adjust for potential confounders using a 
generalized linear regression model with Poisson distribution and robust standard 
errors.119 
Aim 5: To determine whether baseline frailty is independently associated with delirium or 
functional decline after cardiac surgery.  
In Aim 5, we will test the hypothesis that frailty is associated with postoperative delirium. 
The primary outcome will be the development of delirium at any time, as measured by 
CAM or CAM-ICU and coded as a binary variable. Secondary outcomes will be delirium 
severity from the DRS-R-98 scale. Bivariable and multivariable logistic regression 
analysis will be used to determine if frailty is associated with postoperative delirium. We 
will also test the hypothesis that frailty is associated with decreased function after cardiac 
surgery. The primary outcome will be proportion of patients with >1 IADL decline. 
Secondary outcomes will be change in gait speed and grip strength. Bivariable and 
multivariable linear and logistic regression analyses will be used. For each of these 
analysis, covariates to include in the model will be selected using a priori evidence, and 
may include age, gender, race, baseline cognitive status, education, medications, and 

type of surgery. We will also consider propensity score analysis to account for important 
confounding. 
Aim 6: To determine whether depth of anesthesia in frail patients is a modifiable risk 
factor for delirium and functional decline after cardiac surgery.  
In Aim 6, we will compare cumulative time of BIS<45 in frail vs. non-frail patients using 
bivariable and multivariable linear regression. The cumulative time of BIS<45 will also 
estimate the amount of potential anesthetic overdose in all patients. 
Rapid Dissemination of Clinical Research  
A major objective of this study is to disseminate new information to the medical and lay 
communities. We propose to fulfill this aim by presentations at national and international 
meetings and conventional publications in the medical literature. Full results of the study 
will be published as soon as possible, consistent with principles of peer-reviewed 
publication. National meetings of the AHA, American Stroke Association, Society of 
Thoracic Surgeons, and the Society of Cardiovascular Anesthesiologists are excellent 
venues for presenting clinical study results. We will continue to use MedDium, LLC (Silver 
Springs, MD) for a Web portal that provides the NIH and public with visibility into program 
activities and major scientific discoveries. Finally, the media relations department at 
Northwestern University will be utilized to coordinate press releases of study trial results 
as they become available. 
Secondary outcome variables.  
Included in Primary outcome variables (above).  
Statistical plan including sample size justification and interim data analysis.  
Sample size calculations are based on 
detecting differences in the proportion of patients with an adverse neurologic outcome 
(DWI lesion, stroke, or cognitive decline 4 to 6 weeks after surgery) between the Control 
and Intervention groups. We expect that approximately 45% of subjects in the Control 
Group will experience an adverse neurologic outcome after surgery based on the 
preliminary data analysis of outcomes of 176 patients. In comparison, we expect that the 
proportion of the Intervention Group that experiences adverse neurologic outcomes will 
be reduced by 40-45% (e.g. The frequency of neurologic adverse events will be between 
25% and 27%). This magnitude of reduction in the frequency of the composite outcome 
is within the range that is considered to be clinically important effect (20% to 45% 
reduction from control frequency) based on prior trials that have evaluated temperature 
manipulations, pH management, transfusion triggers, and pharmacologic strategies for 
improving neurologic complications of cardiac surgery 116-118. 
Postoperative MRI is not 
always feasible for reasons already discussed. According to our calculations, we will need 
to obtain MRI data on a total of 122 patients in each study arm (244 patients in total) to 
have 80% power to detect 40% reduction in the composite outcome of stroke, DWI lesion, 
or cognitive decline 4 to 6 weeks after surgery, assuming that 45% of Control Group 
patients experience adverse neurologic events. The Type I error is 5%. 

  
Our current enrollment trajectory suggests that at least 277 patients will have undergone 
the protocol of our study before the end of the funding period for the initial grant. At that 
point we would expect to have 101 patients who have undergone MRI for evaluation of 
DWI lesions. An additional143 patients with complete MRI, stroke, and cognitive endpoint 
data are needed to reach the target of 244 patients with the primary, complete endpoint 
data. To reach this target, we will need to enroll an additional 350 patients in this renewal. 
Our recruitment projections for our initial funded study are a conservative estimate, as we 
have enrolled 277 patients to our study (101 have MRI data). On average, 5 to 8 patients 
are enrolled per month. These projections confirm that the plan for this submission of 
studying 350 additional patients (a total of 630 patients) will ensure completion of the 
study with 244 patients having all study assessments, including MRI, at the completion of 
the proposed study funding period.  
In addition, we calculated the 
minimal sample size required to detect 0.2 SD difference in combined Z-score for 
cognitive tests normalized to the control group’s data between the Intervention and 
Control groups with 80% power 47. We assume 2 follow-up points (4 to 6 weeks and 1 
year after surgery) and an average within-patient correlation of 0.7 (observed in our 
preliminary data). The calculations indicate that we will need 177 observations per group, 
or 354 patients in total, to detect 0.2 SD difference with 80% power (assuming 5% Type 
I error). The study (first and second funding periods) will recruit a total of 489 patients to 
meet the MRI endpoint. Therefore, we will meet our goal of having 354 patients to detect 
the expected 0.2 SD difference in combined cognitive score seven with a 1-year drop-out 
rates high as 27%.Historically, the drop-out rate for cognitive testing at 1 year in similar 
populations has been between 3% and 24% 47. 
 
For Specific Aim 4, we assessed the level of statistical power to detect clinically 
meaningful differences in proportion of patients with postoperative delirium based on the 
sample size for Aim 1. Our preliminary data indicate a 50% reduction in this outcome 
when a structured instrument for delirium assessment is used (frequency of 33% vs. 66% 
in Intervention vs. Control Group). This marked decrease was based on n = 37 patients. 
Therefore, in the power assessment for this aim we conservatively assumed 50% 
frequency of delirium in the Control Group. We will expect to see a 40% reduction in 
frequency of this condition in the Intervention Group. Our calculations indicate that having 
a minimum of 122 patients in each group with thorough delirium assessments (not 
performed in all patients in the first cohort) will allow us to detect a 40% decrease in 
proportion of patients who develop delirium in the Intervention Group with 87% power, 
assuming a 5% level of statistical significance for the two-sided test. We have instituted 
careful delirium assessments in our current. Postoperative MRI is not always feasible for 
reasons already discussed. According to our calculations, we will need to obtain MRI data 
on a total of 122 patients in each study arm (244 patients in total) to have 80% power to 
detect 40% reduction in the composite outcome of stroke, DWI lesion, or cognitive decline 
4 to 6 weeks after surgery, assuming that 45% of Control Group patients experience 
adverse neurologic events. The Type I error is 5%. 

Our current enrollment trajectory suggests that at least 277 patients will have undergone 
the protocol of our study before the end of the funding period for the initial grant. At that 
point we would expect to have 101 patients who have undergone MRI for evaluation of 
DWI lesions. An additional 143 patients with complete MRI, stroke, and cognitive endpoint 
data are needed to reach the target of 244 patients with the primary, complete endpoint 
data. Our recruitment projections for our initial funded study are a conservative estimate, 
as we have enrolled 277 patients to our study (101 have MRI data). On average, 5 to 8 
patients are enrolled per month. These projections confirm that the plan for this 
submission of studying 350 additional patients (a total of 630 patients) will ensure 
completion of the study with 244 patients having all study assessments, including MRI, at 
the completion of the proposed study funding period. 
As of June 2016, we have enrolled 280 patients in the first five years and 244 patients in 
the second five year study. We need approximately 150 patients to complete enrollment.  
In addition, we calculated the minimal sample size required to detect 0.2 SD difference in 
combined Z-score for cognitive tests normalized to the control group’s data between the 
Intervention and Control groups with 80% power.47 We assume 2 follow-up points (4 to 6 
weeks and 1 year after surgery) and an average within-patient correlation of 0.7 
(observed in our preliminary data). The calculations indicate that we will need 177 
observations per group, or 354 patients in total, to detect 0.2 SD difference with 80% 
power (assuming 5% Type I error). The study (first and second funding periods) will recruit 
a total of 489 patients to meet the MRI endpoint. Therefore, we will meet our goal of 
having 354 patients to detect the expected 0.2 SD difference in combined cognitive 
scores even with a 1-year drop-out rate as high as 27%. Historically, the drop-out rate for 
cognitive testing at 1 year in similar populations has been between 3% and 24%.47 
For Specific Aim 4, we assessed the level of statistical power to detect clinically 
meaningful differences in proportion of patients with postoperative delirium based on the 
sample size for Aim 1. Our preliminary data indicate a 50% reduction in this outcome 
when a structured instrument for delirium assessment is used (frequency of 33% vs. 66% 
in Intervention vs. Control Group). This marked decrease was based on n = 37 patients. 
Therefore, in the power assessment for this aim we conservatively assumed 50% 
frequency of delirium in the Control Group. We will expect to see a 40% reduction in 
frequency of this condition in the Intervention Group. Our calculations indicate that having 
a minimum of 122 patients in each group with thorough delirium assessments (not 
performed in all patients in the first cohort) will allow us to detect a 40% decrease in 
proportion of patients who develop delirium in the Intervention Group with 87% power, 
assuming a 5% level of statistical significance for the two-sided test. We have instituted 
careful delirium assessments in our current protocol. Thus, our sample size projections 
are conservative estimates, as we will have at least 60 patients in each group with careful 
delirium assessments by the completion of the first 5 years of the study. At the completion 
of the second 5 years, we are likely to have 180 patients in each study treatment arm with 
careful delirium assessments. 

Missing data 
Two sources of missing data are anticipated: missing data on predictors and missing data 
on the primary outcome. The strategy of dealing with missing data on predictors will 
depend on the amount of missing data. If the overall number of observations with missing 
predictors is under 5%, a complete-case analysis will be performed by dropping 
observations with missing data. The pattern of missingness will be examined. If the 
amount of missing data is between 5% and 20%, we will calculate the main results based 
on the complete-case analysis, but we will perform a sensitivity analysis using multiple 
imputation strategy. No attempt will be made to impute variables that have more than 
20% data missing. Missing data on outcomes and the drop-out pattern will be assessed. 
No imputation of the outcome variables will be attempted. In addition to the primary 
analysis with the GEE approach, random-effects models have been shown to be a useful 
strategy in cases of non-equal number of measurements across individuals if missing 
data mechanism can be assumed to be ignorable. Therefore, the primary analysis will be 
supplemented by the random-effects approach. In addition, we will explore random-
effects pattern mixture models to assess the influence of missing data in these 
analyses.122 
Feasibility of Recruitment and Retention 
The investigative team has a track record of high enrollment in industry-sponsored and 
extramurally funded clinical trials in patients undergoing cardiac surgery. The original 
study end point of 280 patients over a 56-month enrollment period required approximately 
5 to be enrolled each month. The study endpoint of 350 patients in the second phase of 
the study requires enrollment of approximately 8 patients/month, a rate that we feel is 
attainable based on our success in the first phase of the study. The volume of surgical 
procedures performed at Northwestern Memorial Hospital (Table 6) will allow for the study 
to be completed in the planned timeframe. Procedures for retention of patients in the 
study will include visits by the nurse coordinators to the patients during hospitalization to 
reinforce the importance of the study. The patients will be contacted by phone before the 
4-to-6–week postoperative visit to confirm their testing session. 
Table 6: Number of Cardiac Procedures at Northwestern Memorial Hospital 
Type of procedure 
2014 
2015 
Coronary artery bypass graft surgery 
177 
144 
Mitral valve procedure 
134 
119 
Aortic valve procedure  
286 
264 
Multiple procedures 
198 
186 
Other CV (VAD, ECMO, Heart transplant) 
88 
124 
This surgical volume and the track record of the PI and other investigators in enrolling 
patients in clinical trials involving cardiac surgical patients ensures that an adequate 
number of patients will be enrolled to complete this trial in the funding period. 

Statistical Analysis Plan 
Tabular and graphical methods of data exploration will be used to evaluate variable 
distributions over the perioperative time period. When conducting modeling, we will 
determine the influence of the outliers on model fit. If the influence is high, we will consider 
excluding the outlier/s. We will explore the extent to which CBF autoregulation changes 
over the perioperative period. Univariate distributions for all study variables will be 
evaluated. We will explore potential confounders as variables strongly predictive of the 
outcomes (a priori and in the data) and differentially distributed between the study arms. 
Results of these analyses will be used to refine the analyses and guide model building 
and selection. 
 
The cognitive outcome will be assessed as change from baseline in a composite 
cognitive Z score 4 to 6 weeks after surgery.  The Z score will be calculated for 
individual tests at each testing time point with the mean and SD of baseline tests of 
all patients. Timed tests will be multiplied by ‘-1’ so that higher scores represent 
better performance. Individual Z scores will be combined into an average Z-score, 
calculated from the average of the non-missing individual test Z-scores. These will 
then be renormalized using the mean and standard deviation at baseline.  A 
difference between pre- and post-test > 0.3 is considered cognitive decline. 
Early stopping rules: N/A 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
Experimental Problems 
Hemodynamic perturbations are frequent preoperatively. Such events could potentially 
confound the results of this study if a patient suffers cerebral ischemia from hypotension 
postoperatively. To adjust for hypotension, patient clinical data will be reviewed daily by 
research staff, and episodes that meet the criteria for hypotension will be recorded in the 
case report form. Use of vasoconstrictive or inotropic medications will be recorded. One 
strength of the protocol is that blood pressure will be measured continuously via the IMx+ 
software during surgery rather being recorded by an observer. 
The use of gadolinium in subjects with renal failure has been implicated in the etiology of 
a rare condition called nephrogenic systemic fibrosis (NSF). As we state in Magnetic 
Resonance Imaging, a creatinine level will be measured in all patients before the MRI, 
and gadolinium will not be given to individuals with an estimated glomerular filtration rate 
of ≤60 mL/min or to those needing dialysis after surgery (by FDA and hospital 
recommendations).107 Diffusion-weighted MRI will still be performed as part the 

assessment of our primary end point. MRA will also be obtained of the head and neck; 
the neck MRA will be performed with gadolinium in individuals with adequate renal 
function and without other contraindications for gadolinium, but otherwise will be done 
without gadolinium. No cases have been reported to the FDA of NSF in individuals with 
normal renal function or with only mild renal insufficiency. Thus, we do not anticipate an 
increased risk in our study protocol. 
One challenge in this study will be the transport of patients who remain in the 
postoperative ICU to the MRI scanner, particularly those who require continued 
mechanical lung ventilation and infusion of vasoactive drugs. The PI or a critical care 
physician will accompany such patients to the scanner, along with the critical care patient 
transport team of The Northwestern Memorial Hospital. 
AEs will be reviewed by the investigative team at bi-monthly meetings and by the IRB to 
ensure that these safeguards are adequate to protect the safety of the enrolled patients. 
Patients will be excluded if a TCD trans-temporal window cannot be identified before 
surgery, as the primary intervention is dependent upon detecting the lower CBF 
autoregulatory threshold using this method. Regardless, monitoring with TCD in surgical 
patients is challenging for many reasons. Maintaining continuous monitoring is 
particularly difficult during certain portions of the procedures, such as during tracheal 
intubation, central venous line placement, transesophageal echocardiography 
examination, and especially during dissection of the left internal mammary artery, when 
frequent changes in the patient’s body position and the sternal retractor can lead to 
displacement of the transducers. Intermittent loss of the temporal window during surgery 
might lead to bias if blood pressure reductions below the autoregulatory threshold are not 
detected as such. Defining the lower autoregulatory threshold based on mean velocity 
index or oximetry index should minimize this bias, as the latter will be a continuous 
measurement not subject to intermittent loss of signal. 
Many factors can influence a surgical patient’s CBF, including anemia, temperature 
fluctuations, and volatile (but not intravenous) anesthetics.69 The effects of many of these 
variables on CBF autoregulation in this setting have not been examined extensively. 
Further, the effect of volatile anesthetics on CBF autoregulation is dose dependent. In 
low to moderate doses, as used clinically, the CBF autoregulatory plateau might be 
slightly attenuated and minimally shifted to the left. These clinical considerations 
emphasize the dynamic nature of CBF autoregulation and the need to monitor this 
parameter continuously when targeting blood pressure management to remain above the 
point at which CBF is pressure passive. The conditions of this study will enhance the 
external validity of the findings. 
The monitoring of the CBF autoregulatory threshold by a moving linear regression 
correlation (mean velocity index) requires first ensuring the fidelity of the TCD-derived 
measurements of middle cerebral artery CBF velocity. Intraoperative TCD monitoring will 
be performed by individuals with extensive experience in obtaining these measurements, 

including in cardiac surgical patients. Our experience is that the demarcation of the lower 
CBF autoregulatory threshold via mean velocity index is clearly indicated by the error bar 
graphing, as shown in Figures 3 and 5. 
Undergoing an MRI can lead to anxiety in some patients. The investigative team will take 
measures to reassure the patients during the MRI procedure. Image acquisition will be 
stopped at frequent intervals to query the patients about distress. A “panic button” will 
also be available to the patients to notify radiology and study personnel about distress. 
Some patients may have temporary cardiac pacemaker leads placed after surgery. Coiled 
pacemaker wires on the surface of the patient could potentially serve as antennae during 
MRI that might generate heat or induce premature cardiac beats. However, brain MRI will 
be obtained between postoperative days 1 and 5 or within the first 14 days after the 
procedure (whatever the patient is more comfortable with), usually after the patient has 
had the pacemaker wires removed. When necessary, brain MRI can be performed safely 
in patients with retained metallic materials128 by taping the pacemaker wires straight to 
the skin to avoid coiling. 
The location and extent of abnormality in perfusion-weighted imaging, diffusion weighted 
imaging, and conventional MRI are subject to inter-observer discrepancy. However, we 
have found a high degree of inter-judge reliability in evaluating volume and sites of 
abnormalities on diffusion-weighted imaging and perfusion-weighted imaging, calculating 
the number of seconds of delay in perfusion, and determining the affected regions of 
interest, as described above. We will evaluate effects of cerebral edema on both T2- and 
perfusion-weighted imaging. Edema is usually significant only in large strokes, is greatest 
at day 3–10, and is most visible on T2 images. Edema contributes to the hypoperfused 
region. Patients in whom edema is observed on T2 beyond regions of hypoperfusion on 
perfusion-weighted imaging will be excluded. 
We will obtain only postoperative brain MRI imaging rather than paired pre- and 
postoperative imaging. The logistics of obtaining preoperative MRI in surgical patients 
would be a major impediment to recruitment. In some patients, small, clinically undetected 
diffusion-weighted imaging lesions might result from cardiac catheterization performed 
before surgery. Such lesions would be mistaken to have occurred during surgery. 
Therefore, a careful neurologic examination using the NIHSS will be performed before 
surgery but after cardiac catheterization to ensure that there are no new major deficits. 
Acute strokes that may have occurred 1–2 weeks before surgery should no longer appear 
acute at the time of a postoperative DWI MRI (they will no longer be bright on DWI and 
dark on ADC, as occurs with new strokes). 
The significance of new diffusion-weighted imaging lesions to brain regions not involved 
with higher cerebral function might be debated. However, it is increasingly appreciated 
that the cumulative impact of a small area of injury on cognitive or other neurologic end 
points might only be manifest after long-term follow-up. Even if the impact of some 
diffusion-weighted imaging lesions is minor, development of strategies to improve 

neurologic outcomes after cardiac surgery should aim to detect all forms of injury using 
sensitive means. 
The use of 2D TOF MRA in the subset of individuals who cannot receive gadolinium will 
limit the resolution of this vascular imaging in this subset; however, we anticipate that we 
should still be able to make global measurements of stenoses. In addition, MRA may 
suggest stenoses that are not as narrow as they appear, because it measures flow.  
Unfortunately, alternative technologies that might give better vascular imaging (such as 
CT angiography or conventional angiography) expose patients unnecessarily to iodinated 
dye and, in the case of angiography, an invasive procedure. 
Although perfusion-weighted imaging provides an indication of whether a brain area is 
relatively hypoperfused, it cannot necessarily distinguish whether a brain infarct results 
from embolism and/or hypoperfusion. Small emboli in well-perfused areas might be 
transient, but those in areas of hypoperfusion might persist (slow “washout”). In this study, 
we will count the number of TCD-detected microembolic signals to adjust statistically for 
the number of emboli in patients with and without diffusion-weighted imaging lesions. 
Although this study will provide only inferential data on the mechanism of brain injury, the 
combination of MRI indices and our determination of duration during CPB that mean 
arterial pressure is below the individual’s CBF autoregulatory threshold, combined with 
emboli monitoring with TCD, will provide important clinical mechanistic insights. 
Failure to obtain study data after a patient is discharged from the hospital (i.e., at the 4- 
to 6-week postoperative testing sessions) could confound analysis of the secondary 
cognitive end points of the trial. Multiple reasons might cause patients not to comply with 
follow-up testing, including death, severe stroke, and discharge to a secondary care 
facility. Postoperative testing is coordinated to occur during the patient’s postoperative 
clinic visit with his/her surgeon.  
Off-pump CABG surgery is performed in <10% of patients at our institution but is not 
performed in patients undergoing combined CABG and valve surgery. Although 
performance of CABG surgery “on-” versus “off-pump” has not been shown to impact 
neurologic outcomes remarkably based on prospectively randomized trials, it is possible 
that new data may become available during this trial that might support the decision to 
perform more surgeries without CPB. Such a decision could conceivably influence 
recruitment. However, the number of procedures performed at our hospital and the 
number of patients projected for this study suggest that a sufficient number of patients 
will be recruited during the planned period of study. 
Providing additional information about functional capacity including performance of 
instrumental ADLs, as well as about ability to drive. This carries minimal additional 
medical risk to the participant beyond routinely held structured preoperative interview – 
increased anxiety due to extension of regular pre-operative interview time. 

Frailty testing which includes 15 feet walk and performance of hand grip strength. 
Performance of handgrip strength test using the dynamometer is associated with minimal 
risks including muscle strain (<1%), discomfort with muscle exertion (~1%), and elevated 
blood pressure as a response to physical exertion (~5%). 
Informed Consent 
Before the start of any study-related procedure, a signed and dated IRB-approved 
informed consent form (ICF) will be obtained and documented in the patient’s medical 
record. The investigator must 1) inform each patient accordingly and allow each patient 
sufficient time to decide whether or not to participate in the study; 2) give patients and 
relatives the opportunity to inquire about details of the study and to answer any questions 
regarding the study; and 3) ensure that the ICF is approved by the IRB when an 
amendment to the study protocol is made. 
A patient is free to withdraw consent for participation in the study at any time, without 
prejudice to further treatment. Every effort will be made to obtain complete follow-up 
information on subjects who discontinue from the study prematurely. The reason(s) for a 
subject’s discontinuation must be clearly documented in the subject’s medical records 
and in the case report form (CRF). A patient’s participation in the study may be 
discontinued at any time at the discretion of the PI. 
Data Management Methods 
Patient information relevant to this study will be recorded on case report forms customized 
for this study. Only the PI and authorized research staff according to the list of Authorized 
Study Personnel are entitled to make entries on the case report form. Completed case 
report forms will be dated and signed by the PI or Sub-PI. Personal patient data will be 
kept confidential. Case report forms or other documents will identify a patient by initials 
and study number only. The PI or authorized research personnel will keep the Patient 
Identification and Enrollment List separately. To allow compliance with GCP principles, 
each patient will be asked for consent regarding the access to source documents for 
monitoring, audits, and inspections. The agreement, also covering the use of the data for 
analyses, must be documented in writing, together with the written ICF for study 
participation. Data will be transferred from the case report form to a study database 
(Redcap). This database will include only the patient study number and will be devoid of 
patient identifying information. All information obtained during the conduct of this study 
will be regarded as confidential.  
Quality Assurance 
Before the start of the study, a training session will be conducted to familiarize team 
members with the protocol and case reporting processes. The protocol and all testing, 
including the cognitive tools, the NIHSS, and the process for reporting AEs, will be 
reviewed in detail. 
Quality control procedures for the cognitive testing include multilayered training of 
examiners, review of practice protocols by a board-certified neuropsychologist, and 

random selection and review of actual patient testing by a board-certified 
neuropsychologist during the study period. An initial training session with detailed 
discussion and demonstration of each test in the battery will be performed led by a 
member of the research team. All examiners will practice administration of the battery 
with colleagues. Next, all examiners will practice administration of the battery on three 
volunteers at the site. The same procedure will be followed if new examiners are added 
after the study period has begun. During the study period, similar quality control 
procedures will be in place. Research personnel will be certified for performing the NIHSS 
using the American Stroke Association's Online NIH Stroke Scale Training Program 
(http://asa.trainingcampus.net/uas/modules/trees/windex.aspx). 
All members of the team who assess delirium will undergo rigorous training prior to study 
enrollment. During the course of the study, team members will meet every two weeks to 
discuss the diagnosis and evaluation of individual cases of delirium. 
Data and Safety Monitoring Plan 
At the start of the study, a Data and Safety Monitoring Board (DSMB) will be appointed 
and will consist of a cardiac surgeon, two neurologist, an anesthesiologist/critical care 
physician, a statistician (Dr. McCarthy), an independent member from an outside 
institution and a member from the NIH all with expertise in the area of neurological 
complications after cardiac surgery. The DSMB members will not be direct participants in 
the study and they must attest to not having any conflicts of interest with the study or any 
of its investigators. A team member (TBD) will participate in the DSMB meetings as non-
voting member. The DSMB will be charged with oversight of the study’s safety and 
integrity and assessing the risk versus benefits of continuing the study if such questions 
arise. The DSMB will meet at least bi-annually in person or by conference call or more 
often, if necessary, based on the progression of the study, including any arising events 
as communicated by the PI. The DSMB will continue to meet until the completion of the 
study. 
 
The DSMB will review patient recruitment and patient follow-up, compliance with the 
protocol including protocol violations, timeliness and completeness of data entry, 
compliance with patient confidentiality and HIPPA regulations, and communications of 
adverse events to the IRB. The DSMB members should immediately review the data in 
order to make any requests for additional information or analysis in a time frame that can 
allow for such requests to be completed before the scheduled DSMB meeting. Members 
of the DSMB must maintain confidentiality of the study data until otherwise instructed. An 
interim analysis of the data looking at safety will be conducted by the DSMB when results 
from the first 140 subjects are available. If we are given continued funding a meeting of 
the investigative team will be held to discuss the validity of an additional interim analysis. 
Plan for reporting unanticipated problems or study deviations. 
Adverse Events 
For this study, an adverse event (AE) is any untoward medical occurrence (e.g., sign, 
symptom, disease, syndrome, intercurrent illness, or abnormal laboratory finding) that 

emerges or worsens relative to baseline during the study periods, regardless of the 
suspected cause. Untoward medical events that occur from the time the subject signs the 
ICF to the time of surgery are not considered AEs and should be recorded under medical 
history. AEs encountered during or after surgery will be recorded on the appropriate AE 
section of the CRF. All AEs will be evaluated by the PI for their intensity, frequency, 
relationship to study, and outcome. The intensity of both serious and nonserious AEs will 
be graded as mild, moderate, or severe. The definitions are as follows: 1) mild, transient 
event—does not require medical intervention; the normal clinical course for a subject 
undergoing cardiac surgery is not changed; AND/OR the subject experiences discomfort, 
but no disruption of normal daily activity; 2) moderate—event may require medical 
intervention; induces moderate deviation from the normal clinical course for a subject 
undergoing cardiac surgery; AND/OR the subject experiences sufficient discomfort to 
reduce or affect normal daily activity; and 3) severe—event requires significant medical 
intervention and constitutes a marked deviation from the normal clinical course for a 
subject undergoing cardiac surgery AND/OR the subject is incapacitated and unable to 
perform normal daily activities. 
An AE should be classified as SERIOUS if: 1) it resulted in death (i.e., the AE caused or 
led to death); 2) it was life threatening (i.e., the AE placed the subject at immediate risk 
of death); 3) it required or prolonged inpatient hospitalization (i.e., the AE required at least 
a 24 h inpatient hospitalization or prolonged a hospitalization beyond the expected length 
of stay); 4) it was disabling (i.e., the AE resulted in a substantial disruption of the patient’s 
ability to carry out normal life functions); or 5) it did not meet any of the serious criteria 
listed above but potentially jeopardized the patient or required medical or surgical 
intervention to prevent one of the outcomes listed above. Adverse events will be reported 
to the IRB, recorded in the study database, and reviewed at the weekly investigators’ 
meeting. Adverse events also will be reviewed at the quarterly Data Safety and Monitoring 
Board meeting. Serious AEs will be reported to NIH personnel. As soon as the research 
team notices that an enrolled patient has died or suffered as an adverse event the 
research team will report it within 24 h and within 72 h respectively. 
Financial risks to the participants. 
The only foreseeable financial risk for the study participant would be in the event that a 
referral was needed for something found on MRI scan. The study related MRI scan will 
be paid for by the study sponsor. However, since MRI scanning of the brain is not routinely 
done for cardiac surgery there is the potential that a pre-existing condition may be 
diagnosed that would not have ordinarily been found. In that case, the study participant’s 
insurance would need to cover the cost of further diagnostics and/or treatment. 
Benefits 
Description of the probable benefits for the participant and for society. 
Brain imaging might result in the detection of an unexpected condition, such as a brain 
mass, aneurysm, or vascular malformation. In the event of such findings, the patient, and 
his/her family and clinical physicians will be notified, and the patient will be referred for 
clinical management. 

Brain injury from cardiac surgery is an important source of operative mortality, prolonged 
hospitalization, increased health care expenditure, and impaired quality of life. 
Developing strategies to reduce the burden of this complication has wide public health 
implications. 
Brain imaging might result in the detection of an unexpected condition, such as a brain 
mass, aneurysm, or vascular malformation. In the event of such findings, the patient, and 
his/her family and clinical physicians will be notified, and the patient will be referred for 
clinical management. 
Payment and Remuneration 
The patients will receive a $100 stipend for participation at the time of their 4-6 week visit. 
Patients who return for the 1 year follow-up visit will receive an additional $100 stipend. 
Patients will also receive a $300 if the finish the MRI component of the study. These are 
meant to help defray the cost of parking and meals associated with the postoperative 
visit. 
Costs 
The subjects will not be charged for study procedures including TCD monitoring, blood 
pressure management, MRI/MRA (and x-ray of the head, where indicated), 
neurocognitive testing. In the event something is found on MRI and a referral to a 
specialist is made, that referral would need to be covered by the subject’s insurance. 
RESOURCES AVAILABLE: 
The research team includes personnel with vast experience in clinical research studies 
and some have been involved with other NIH funded projects and have published 
numerous papers in peer review journals. Dr Sorond is a neurologist with many years of 
experience with clinical trials. Dr. Nemeth is a neuroradiologist who has participated in a 
several clinical trials. Dr. Schrift is a neuropsychiatrist who has participated in clinical 
trials.  Research staff have over 15+ years of clinical research, GCP, and data analysis 
experience.  
PRIOR APPROVALS:  
Department of Anesthesiology Research 
Committee John Hopkins Institutional Review Board  
NUMBER OF LOCAL PARTICIPANTS:  
150 participants  
PROCESS TO DOCUMENT CONSENT IN WRITING: 
(Review “SOP: Written Documentation of Consent (HRP-091).” If you will not be following 
HRP-091, describe whether and how consent of the participant will be documented in 
writing.) 
We will be using documentation of consent checklist.   

DRUGS OR DEVICES: 
A near infrared spectroscopy machines (INVOS 5100, Covidien, Inc, Boulder, CO) with 
digital signal output capability, A/D converter for digitizing blood pressure data from OR 
hemodynamic monitors, and a laptop computer all on a mobile cart for acquisition and 
analysis of cerebral blood flow autoregulation data. The mobile cart will be stored at the 
5th floor or 7th floor of Feinberg pavilion in the anesthesia block room which is locked and 
requires key entry. It will only be used for research purposes.   

 

 

 

 

 

 

 
 
 
 
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