Cerebral Monitor Guided Therapy on Cerebral Outcomes After Cardiac Surgery

Neurologic and cognitive decline remain common complications that adversely affect patients'
outcome after cardiac surgery. By incorporating a brain monitor that measures cerebral oxygen
content into our perioperative management we aim to decrease postoperative neurologic and
cognitive deficits and improve quality of life in this patient population. We also aim to
uncover how the compromised brain alters its metabolism in response to ischemic injury and
how this new information can guide new preventive treatment methods for vulnerable patients.

Briefly, cerebral near-infrared spectroscopy (NIRS) or cerebral oximetry is a non-invasive
monitor that estimates cerebral oxygenation through measurements of regional venous
saturation. It is based on measuring intravascular oxyhemoglobin fraction in a small sample
of cerebral cortex through the skull using near-infrared light spectroscopy. Cerebral
oximetry examines all reflected light, from both pulsatile arterial and non-pulsatile venous
blood, without requiring pulsatility, hence cerebral oximetry can continue to monitor brain
oxygenation during both CPB and circulatory arrest. With this advantage, cerebral oximetry is
widely utilized in our daily cardiac anesthesia practice, routinely for surgeries requiring
circulatory arrest, and for other elective CABG and valve replacement/repair surgeries in
some institutions. Despite its wide use, controversy still exists in its interpretation and
ability to optimize cerebral outcome after cardiac surgery. Key questions to be answered are:
1) the desaturation threshold associated with poor prognosis; 2) the absolute desaturation
value at which adverse clinical outcome increases, and 3); if the relative trend is more
important to signal approaching deterioration. All of these questions are relevant to our
clinical practice yet remain unanswered. Our research study aims to take a first step towards
identification of the ideal method of utilizing cerebral oximetry in cardiac surgeries to
improve neurological outcome through increasing precision in managing hemodynamic as well as
laboratory values through a treatment algorithm.

The second component of this study incorporates metabolomic profiling as we refine the
perioperative management of cardiac surgery patient to improve their cerebral outcome.
Despite enormous research efforts over the last decades, currently there is no specific and
single neurologic biomarker (or panels of biomarkers) that has been validated for clinical
use. Meanwhile, neuro-imaging (CT and MRI) remains the gold standard for the diagnosis of
cerebral injury. Organ-specific biomarkers, if identified, have the potential to be a
reliable and cost-effective method to diagnose, guide management, classify severity of
stroke, anticipate cognitive function, and predict complications. Recently, metabolomic
profiling has enabled comprehensive analyses of changes in metabolic fuel selection in a
variety of models, including cardioplegic arrest. Advances in analytical technology have
enabled quantitative analysis of several hundreds of metabolites in a single measurement with
high throughput and sensitivity.

Metabolomic profiling entails quantitating small-molecule metabolites from body fluids or
tissues in a single step, and possesses the potential for early diagnosis, therapy monitoring
and investigating the pathogenesis of various diseases. This biomarker detection is conducted
in cells, tissues, or biofluids by either nuclear magnetic resonance (NMR) spectroscopy or
mass spectrometry (MS) which then undergoes multivariate data analysis. Jung et al., using
1H-NMR spectropy combined with multivariate statistical analysis assessed stroke patients. In
this study perturbed metabolic pattern in both plasma and urine from patients with known
cerebral infarction incidents were assessed to identify a specific proteome associated with
stroke. A similar investigation has been conducted with a wider quantification of
neuroproteomics using a rodent model. Biomarker prognostic of acute kidney injury in patients
undergoing cardiopulmonary bypass (CPB) has also been investigated. Despite its potential for
wide application, metabolomic profiling has not seen its utilization to guide neuroprotective
management in patients undergoing cardiac surgery. We believe the unique combination of these
two methods poses a valuable opportunity not only to improve the patient's neurocognitive
outcome, but also to gain insights on which biomarkers represent cerebral ischemia or other
signs of cerebral injury.

Our specific aims are to: 1. Assess the transcerebral metabolomic profile and neurocognitive
outcome in response to cerebral injury in patients monitored and treated according to
cerebral oximetry (NIRS) and those that are just monitored with NIRS.

Based on available literature, our working hypothesis is that compared to monitored only
patients, cerebral fuel utilization will be differentially affected in patients monitored and
treated by tightly following a specific neuroprotective algorithm.

1.a. Test the plasma concentrations of metabolites representing the amino acid, carbohydrate,
energy, lipid, and nucleotide pathways using nuclear magnetic resonance (NMR) and mass
spectrometry.

1.b. Compare the neurocognitive function of treated and untreated patients using a
comprehensive test battery consisting of 5 assessment modalities at baseline, at the time of
discharge and 6 weeks postoperatively.

Inclusion Criteria:

- Adult cardiac surgery patients undergoing cardio-pulmonary bypass (CPB) with
cardioplegic arrest (CABG, valves, CABG + valves).

Exclusion Criteria:

- History of a stroke within 90 days prior to enrollment, or a history of cerebral
vascular disease with significant (> 80%) extra cranial stenosis;

- Technical obstacles, which pose an inordinately high surgical risk, in the judgment of
the investigator;

- Existence of any ongoing mechanical circulatory support other than intra- aortic
balloon counter pulsation;

- Body Mass Index (BMI) > 50 kg/m2;

- Pregnancy;

- Psychiatric disease, irreversible cognitive dysfunction or psychosocial issues that
are likely to impair compliance with the study protocol;

- Presence of active, uncontrolled infection;

- Evidence of intrinsic hepatic disease as defined by liver enzyme values;

- Participation in any other clinical investigation that is likely to confound study
results or affect study outcome;

- Patient refuses to be enrolled in study;

- Institution inmates