 Good morning. I'm Kathleen Kibler, a certified clinical profusionist with the Texas Heart Institute School of Profusion. Today, I will be speaking on, can neurologic injury from cardiac surgery be prevented by hemodynamic optimization? I was previously a primary investigator on an industry-supported grant from Medtronic, Avcor, auto-regulation monitoring in the cardiac operating room. None of that data will be presented today. It will be different. Auto-regulation is thought to be a myogenic mechanism, whereby vascular smooth muscle constricts in response to increases in wall tension and relax to a decrease in wall tension. At the lower limit of auto-regulation, cerebral vasodilation is maximal. And below that level, the vessels collapse and cerebral blood flow falls passively with falls in blood pressure. At the upper limit, vasoconstriction is maximal, and beyond that point, elevated intraluminal pressure may force the vessels to dilate, leading to an increase in cerebral blood flow and damage to the blood-brain barrier. Physicists, neurosurgeons, and intensivists at Cambridge University have combined to create an out-of-the-box approach to finding the optimal perfusion pressure. They have developed a new way to monitor auto-regulation that is continuous. The basis of this approach is obvious. When the cerebral perfusion pressure is too low or too high, then the cerebral blood flow is pressure passive, and this causes death and disability. Finding the cerebral perfusion pressure or blood pressure where auto-regulation works best gives the best outcomes. This is a animal model in a neonatal piglet. The upper panel A is a patient with a blood pressure and blood flow sufficient to maintain cerebral auto-regulation. Note that the slow waves in the blood pressure tracing are in the opposite direction as the slow waves in the ICP and the cerebral blood volume traces. The blood vessels in the brain are reactive to the changes in blood pressure. Panel B is a scatter plot of ICP values across the range of blood pressures from Figure A. Note that as blood pressure increases, ICP decreases. This relationship can be correlated and is called the pressure reactivity index, the PRX, is negative when the brain is auto-regulating. Panel C is the same patient during a period of hypotension. Note that the slow waves are still present in the blood pressure, ICP, and the cerebral blood volume tracings. Also note that the slow waves in the blood pressure and the slow waves in the ICP and the cerebral blood volume are changing in the same direction at the same time. That means that changes in ICP and cerebral blood volume are passive to the changes in blood pressure. Loss of auto-regulation is occurring. Panel D is a scatter plot of the ICP values across the range of blood pressures from Figure C. Note that as blood pressure increases, ICP increases. The pressure reactivity is positive when the brain is not auto-regulating. A patient can now be monitored. New analysis of the interactions of physiologic variables can be displayed in real time at the bedside. And now the physician has a tool to guide care decisions. The auto-regulation industry is plotted in five millimeter bends of cerebral perfusion pressure or blood pressure, not by time. The bending allows for a rapid pictorial view to assess the auto-regulation curve across available blood pressures. This makes a U-shaped curve plot. The lowest values indicate the optimal cerebral perfusion or pressure or optimal blood pressure, and the positive areas indicate auto-regulation impairment. I showed auto-regulation in a piglet model. Is it relevant to human brains? Does it have value in predicting clinical outcomes in children? We applied this monitoring technique to traumatic brain injury children at Johns Hopkins Hospital in Baltimore, Maryland. A study of 21 patients with traumatic brain injury. Those patients that maintained a blood pressure sufficient for auto-regulation survived while patients with blood pressures too low had disturbed auto-regulation died. The limitations of the study are it's a single center. We included induced traumatic brain injury patients, but yet it's still a powerful indicator of the vital nature of the loss of auto-regulation on the brain. We stopped the study early at 21 patients because a patient arrived. He was an eight-year-old boy that was in a car accident. He arrived to Hopkins. He was riding his bike and was struck by a car. When he arrived, he was in a coma. He was eight years old and no one knew what blood pressure to maintain. So his parents asked that this monitor be applied. We had to stop our trial. We had to contact the IRB to suspend and ask if we could guide, not treat the physician as how to care for this child as far as pressure management. He fully recovered. He went, is now graduated from college and is in graduate school. So he was one of the lucky ones, but that's pediatrics to convince you a little more is auto-regulation and important in adults. This is an adult traumatic brain injury trial in Cambridge, England. With this 327 patients with severe TBI, they were managed when they were managed and their blood pressure was too low, up to 15 millimeters below their optimal CPP. There was 100% mortality. If they spent the majority of their time 15 millimeters above their optimal CPP, there was persistent vegetative state. So in an injured brain, that range of optimal blood pressure, optimal cerebral perfusion pressure is very small compared to a healthy brain. So we have this great way of monitoring auto-regulation. We should be able to do this on bypass, but auto-regulation monitoring using the pressure reactivity index during bypass is not without risk. Patients are hypernized prior to induction of bypass. Even if an invasive ICP catheter could be placed prior to bypass surgery, it's probably not a good idea. It would highly likely that the patient would develop that interest cerebral hemorrhage from the catheter placement. That would confound any auto-regulation measurement. A non-invasive surrogate for ICP needed to be developed to be able to safely measure auto-regulation while on bypass. The transcranial Doppler is possible during bypass, but its probe can be bombed or moved and give false readings. Also, the use of electric cottery can create too much noise and you wouldn't receive a good signal. We've decided, therefore, to investigate the feasibility of using NIRs, near-infrared spectroscopy, as a possible surrogate for blood flow in the brain. So back to the lab, this is a piglet study to validate the use of NIRs as a measure of auto-regulation. Notice that the slow waves in the total hemoglobin volume index changes mirror those in the ICP wave. This relative hemoglobin saturation is not calibrated value like ICP is, but that's not important. We are only correlating the changes in the direction of the slow wave in responses to changes in the slow waves and blood pressure. So when the waves are present in both the blood pressure and the blood volume index, a correlation gives a number between minus one and one. The slow waves in blood pressure and the slow waves in the BVI are changing in the same direction at the same time, then blood volume is passive to changes in blood pressure and auto-regulation is lost. So this is a good surrogate. So congenital heart defects, 1% of all babies born in the U.S. will have a congenital heart defect, that's about 40,000. 25% of those 10,000 will have a critical congenital heart defect requiring surgical intervention within the first year of life. Infant death due to congenital heart defects often occur when the baby is less than 28 days old. Half of the deaths due to congenital heart defects occur during infancy, younger than one year of life. Congenital heart defect survival, survival in infants with congenital heart defects depends on the severity of the defect when it's diagnosed and how it's treated. At one year, 97% of non-critical congenital heart defects survive where only 75% of critical congenital heart defect patients survive. At 18-year survival, it's 95% for non-critical congenital heart defects down to 83% with critical congenital heart defects. Much improved since the 1980s when only 67% of those patients survived. Half of those with critical congenital heart defects have some form of disability or impairment. Because of this, multi-study provided evidence of neurologic damage by comparing pre-surgical MRIs with post-op MRIs to evaluate the prevalence of neurologic injury among neonates undergoing bypass. And that ranged from some centers at 35% to 75%, so 3-8 out of 10 children having a new neurologic injury due to bypass. The majority of those lesions are located in the white matter, which suggests an ischemic mechanism related to low systemic oxygen delivery. This is called PVL, periventricular leukomalacia. PVL is highly associated with subsequent cerebral palsy, mental retardation, learning disabilities, visual motor defects and ADHD. Prolonged exposure to bypass with or without deep hypothermic circulatory arrest and hypoxemia and hypotension in the early post-operative periods were associated with PVL. I know I've been talking a lot about stroke and TBI, but this is a perfusion conference. As a perfusionist, we understand that the aortic outflow is not to a single vascular bed. The brain, the heart, the kidneys and viscera all receive varying amounts of blood depending on need. The brain circulation has multiple layers to protect its brain blood flow. It has systemic vasoconstriction, pressure auto-regulation, metabolic auto-regulation, CO2 reactivity, hypoxic vasodilation and hypoxic hypoglycemic vasodilation. But if the mean arterial pressure minus the central venous pressure is greater than the lower limit of auto-regulation, then the mean arterial pressure is adequate to maintain auto-regulation. Cerebral blood flow is dependent on what your blood pressure is, not what your cardiac output is, not what your flow is. This is the base, so neurosurgeons did a study in 1995 using baboons on bypass. They showed that it is pressure that is most important in maintaining cerebral blood flow, not how much you're flowing on the bypass pump. Both full flow and low flow had diminished cerebral blood flow based on pressure, not flow. We replicated this study in neonatal piglets. We showed that full flow does not protect the brain when the blood pressure is too low. Throughout the entire study, the flow was 150 cc per kilo per minute, yet as the patient became hypotensive, the blood flow to the brain decreased according to the blood pressure when the blood pressure lost adequacy. This study is an observational retrospective analysis of high resolution physiologic data that is collected at Texas Children's Hospital using an FDA cleared secure data warehouse that is used for alarm management and quality projects. The approval for the Institution Review Board was obtained prior to extracting, de-identifying and analyzing the subject data. Eligible subjects were neonates under 30 days of life at the time of surgery for congenital heart disease at Texas Children's Hospital with requisite physiological recordings to analyze auto-regulation with a hemoglobin volume index, arterial blood pressure, and blood pressure. The preoperative patient categories, 69 patients, median age of 9 days, weight 3.4, they're very small, very sick patients, hyperplastic, trans-post, great arteries, co-arctations, interrupted arch, TAPVRs, the surgeries, the procedures were Norwood's aortic switch operations, aortic arch operation co-arc repairs, TAPVRs. The surgery times, median time, surgery time 412 minutes with a bypass time 211 minutes, cross-clamp times of 2 hours. Short circarrest times as Texas Children's uses integrate cerebral perfusion to protect the brain. Analysis of the physiologic data was performed using ICM plus software. The following signals were analyzed, arterial blood pressure, neo-sopharyngeal temperature, blood volume index derived from the near-infrared spectroscopy. The hemoglobin volume index was calculated as a continuous correlation between blood pressure and the blood volume index. Hypothermic data was excluded. Blood pressure was rendered for each ABP op, blood pressure optimum, was rendered for each patient from the curve analysis. The median ABP op for this group was 50 millimeters of mercury. The younger the patient, the lower the ABP op. So day one, it was closer to 40 and as they approached 30 days out, they were closer to 50. So it was ABP op was determined for each patient as a function of age and blood pressure. So the effect of the deviation from ABP opt on the auto-regulation score is shown in figure A or B. As hemoglobin index of vascular reactivity has a negative value in health, small deviations from the optimal range of blood pressure rendered positive values of hemoglobin volume index in this cohort. The mean blood pressure for each subject was about 45 millimeters of mercury where they were maintained, so average 5 millimeters below that 50 op. The amount of time you spend at deviations from your op can be clinically significant. The cohort spent 43% of the surgery greater than 10 millimeters of mercury below their optimum, which is about 120 minutes. They spent 28% of that time greater than 15 millimeters of mercury, about a little over an hour, and 17% of that recorded time was spent 20 millimeters below the optimum or about 35 minutes. The amount of deviation from opt in adults has shown to lead to neurologic damage. So that's pediatrics, but stroke occurs in adults as well. Stroke can occur reportedly 1 to 3% of adults having cardiac surgery have a stroke. Yet another 30 to 65% of patients experience postoperative cognitive decline at one month and 20 to 40% experience residual cognitive effects five months later. So even though you're not scanning every patient for an MRI, there seems to be a clear neurologic effect from bypass. My colleague, Dr. Charles Ho, has a randomized control clinical trial, which was not blinded. It occurred at two different institutes. It's funded by the NIH. The perfusions were involved in the study where half of the patients received auto-regulation monitoring and half of the patients did not. The patients that did not receive auto-regulation monitoring, the perfusions maintained their protocols of how they normally flow. If the patients that were monitored, the monitor says that the blood pressure needed to be higher, the first order was to increase flow up to 20%. If they could not reach that optimal blood pressure, then they were to give vasoconstrictors as the secondary treatment. In these patients, there were 94 that did not get auto-regulation monitoring and 105 that did. Their bypass times were relatively similar. They were mostly cabs, valves, or other. The amount of pressures used was similar within the groups, and the mean arterial pressure was very similar, 71 versus 73. The mean arterial pressure at the lower limit of auto-regulation between the groups was very similar, 68 to 65. But there was a difference in outcomes. When studied for postoperative delirium, the auto-regulation monitoring in adults, there was a 17% reduction in postoperative delirium. 174 patients were in this category. 90 received auto-regulation monitoring and 84 did not. The perfusions was instructed to keep the blood pressure above the lower limit of auto-regulation. So there seems to be a pressure requirement to protect the brain. Further into the data, the auto-regulation monitoring in adults on bypass, there was a decrease in renal injury, significant decrease in renal injury, a significant decrease in sepsis, a significant decrease in multi-system organ failure in the treatment group, and there was a reduction in mortality rate. So protecting the brain protects the body. When you increase your flow and then increase your blood pressure, you're protecting the brain. By increasing your flow, you're improving your flow to the viscera, so less likely to help with stroke or sepsis, which also increases your flow to your kidneys and your kidneys are very flow dependent. Thank you very much for your time and allowing me to speak on this subject, and I thank all my collaborators who we have worked together for many, many years.