Cerebral Function And CNS

Updated 11/26/07

1. Biomarkers of Hyperthermia in Sudden Infant Death

D. S. Jardine, M.D.

In 2002, the last year for which statistics are available, SIDS claimed the lives of 2295 infants (more infants died from SIDS than from accidents or congenital anomalies). The cause of SIDS remains unknown, but a group of factors that increase the risk of SIDS has been identified. Among these are prone sleeping, cold weather, and excessive sweating, to name only a few. Many of these risk factors appear to increase the risk of overheating (hyperthermia). Therefore, we hypothesize that lethal hyperthermia causes some (but not all) SIDS deaths. Con­sequently, we hypothesize that biomarkers of hyperthermia can be found in some SIDS victims.

In order to maintain thermal homeostasis, an infant must be able to transfer heat to the environment at a rate that equals heat production. Because a young infant lacks the motor coordination to remove blankets when he is too hot, he is at greater risk of overheating compared to an older child. An overheated, sweating infant is critically dependent upon evaporative losses, because the quantity of heat lost from evaporation is far greater than heat lost from convection, conduction and radiation. Blankets of modest thickness greatly reduce evaporative heat loss in a sweating infant, so the crucial factor determining heat loss is usually the quantity of uncovered skin rather than the thickness of the blankets. We have developed a mathematical model of heat balance which indicates that an infant’s temperature may rise to injurious or lethal levels in as little as 90 minutes without excessively thick blankets.

Death from heat injury does not produce recognizable postmortem or histologic changes, so other evidence for overheating must be found in order to understand the role of hyperthermia in SIDS. Gene expression, which can be quantitated through microarray analysis, has great potential for this application, and to distinguish between SIDS caused by hyperthermia and SIDS caused by other stresses such as hypoxia.

If we can demonstrate that a substantial proportion of SIDS deaths are caused by hyperthermia, education and intervention could be directed at eliminating this problem by modifying bedding and sleep environments. This has the potential to be far more effective than public awareness campaigns aimed at avoiding risk factors that may contribute to hyperthermia.

2. CPP Management – Information Feedback and Nursing (C)

P. Mitchell,PhD, RN, FAAN,  M. S. Vavilala,  M.D.,    A.M. Lam, M.D.

This study is predicated on the assumption that there may be optimal levels of cerebral perfusion pressure (CPP) and systematic arterial blood pressure (ABP), that help prevent or reduce secondary brain injury in critically ill patients.  Since CPP can be influenced by nursing care such as positioning, suctioning and the like, refining the ability for nurses to manage CPP on a minute-to-minute basis is currently being tested for the ability to demonstrate measurable improvement in short and long-term outcome for late adolescents and adults.  We propose to extend the observation to children, for whom no adequate threshold has yet been determined, to examine complexity of physiologic waveforms to better understand the variations that may underlie clinical outcome differences or better predict outcome variation, and to conduct a cost-analysis of this improvement in technology.  The specific aims are: 1) Determine if CPP threshold can be defined for children less than 16 years of age, based on 3, 6 and 12 month outcomes;  2) Characterize ICP and ABP complexity and HRV for both adults and children in relation to predicting outcome at discharge and 6 and 12 months (for children);  3) Estimate hospitalization cost across the life span for children, adolescents and adults monitored for CPP;  4)  Estimate the value, in quality adjusted life years (QALY) for varying outcomes of care across the life span for children, adolescents and adults monitored for CPP.

Computer interfaces that provide visual information about CPP will be allocated to beds in each of the pediatric intensive care units used for children ages 1-16 years with traumatic injury, in whom ICP and blood pressure monitoring has been instituted as part of medical management.  Data regarding CPP and 3, 6, and 12 month functional outcome will be evaluated to determine if a threshold for CPP can be determined for differing grades of outcome (from death to very good physical and social function).  Continuous ICP, ABP and electrocardiographic data from these children and from the adults in the parent study will be analyzed using a variety of non-linear approaches to determine waveform factors that are predictive of outcome.  Hospital data regarding costs and charges during acute care hospitalization will be examined in both children and adults to determine if the use of the computer interface is associated with greater or lesser acute care costs.  Finally, a survey of survivors of acute brain injury and of community peers will be conducted to estimate the value (in quality adjusted life years) placed on differing outcomes states after both traumatic brain injury and aneurismal subarachnoid hemorrhage.

3. Hemodynamics and Outcome in Pediatric Brain Injury (C)

M. S. Vavilala, M.D.

Traumatic brain injury (TBI) is the leading cause of mortality in children over one year of age. Evidence suggests that hypotension after initial brain injury contributes to secondary brain injury and worsens outcome. Cerebral ischemia due to impaired cerebral autoregulation and hyperemia may both also contribute to poor outcome following pediatric TBI. Therefore, knowledge of optimal cerebral hemodynamics immediately following severe pediatric TBI is important. The objective of the proposed research is to describe the relationship between cerebral hemodynamics following severe pediatric TBI and outcome. The specific aims proposed here will provide new information regarding the early cerebral hemodynamic management of children with severe TBI. Therefore, we propose a logical series of investigations to: 1) determine the optimal blood pressure following severe pediatric TBI by examining the relationship between cerebral perfusion pressure (CPP) and outcome, 2) ascertain whether persistent impairment of cerebral autoregulation is associated with poor outcome, and 3) examine whether hyperemia is more common following severe TBI in children compared to adults.

It is important to conduct these studies in children of various ages because: 1) cerebral hemodynamics change significantly during development, 2) optimal cerebral hemodynamics following severe TBI may differ in young children compared to older children, 3) there is a paucity of physiologic data in children and 4) pediatric practice is currently extrapolated from adult practice,.

The results and experience gained in this research may aid in the future study of cerebral hemodynamics in children at risk of cerebral ischemia both with and without TB.

4. Cerebral Edema in Pediatric Diabetic Ketoacidosis (C)

M. S. Vavilala, M.D., A. M. Lam, M.D.

Nearly 22,000 children are hospitalized annually for complications of insulin dependent diabetes mellitus (IDDM). Diabetic ketoacidosis (DKA) is a life threatening condition and is the number one reason for IDDM related admissions. Cerebral edema occurs in 1-3% of pediatric DKA episodes and accounts for 30 - 90% of DKA deaths. Although several studies document cerebral edema in children with DKA, the cause of cerebral edema is unknown. The lack of understanding of the pathophysiology of cerebral edema leaves children with IDDM at risk for death or permanent disability, and health care providers without the necessary knowledge to prevent this complication. Epidemiologic data suggest an association between cerebral ischemia and cerebral edema in pediatric DKA. However, limited clinical studies document cerebral hyperemia NOT cerebral ischemia. Therefore, the overall goals of this study are to characterize cerebrovascular changes in children critically ill with DKA, and to determine the relationship between laboratory markers, cerebrovascular changes and the presence or absence of cerebral edema.To do this, we propose three specific aims: 1)To examine the relationship between cerebral hyperemia and cerebral edema in children with critical and severe DKA, 2) To determine the incidence of impaired cerebral autoregulation in critical and severe DKA and 3) To explore the relationship between potential clinical and laboratory predictors and cerebral hyperemia and cerebral edema in critical and severe DKA. The findings of this study will lead to: 1) a greater understanding of the pathophysiology of DKA related cerebral edema, 2) the innovative use of existing methodologies to examine cerebrovascular changes in pediatric DKA (new scientific area), and ultimately through further study, 3) the development of a clinically useful scoring system and screening program that identifies children at risk for cerebral edema, and 4) the identification of management strategies needed to prevent cerebral edema.

5. Determination of Risk Factors for Ischemic Optic Neuropathy After Spine Surgery

Lorri A. Lee, M.D.K. Domino, MD,MPH, K. Posner, PhD, et al.

One of the most devastating iatrogenic complications that can occur perioperatively is postoperative visual loss (POVL). Data from the American Society of Anesthesiologists (ASA) POVL Registry has provided important information on the perioperative characteristics of patients who developed ischemic optic neuropathy (ION) after spine surgery. However, it is unclear from these data if co-existing diseases, gender, hematocrit, blood pressure management, and other factors increase the risk of developing ION because there are no denominator data. We therefore propose to evaluate potential risk factors for ION after spine surgery using a multi-center randomized case control study in which patients with ION from the ASA POVL Registry (n = 80) will be compared to matched controls who did not develop ION after spine surgery. Determination of risk factors for perioperative ION after spine surgery could potentially identify 1) high risk pre-existing patient characteristics; and 2) perioperative events that may increase the risk of ION such as blood pressure management, type of fluid replacement, blood transfusion / hematocrit management, anesthesia / prone duration,  or and use of vasopressors. These data could also be used to determine the odds ratio for developing ION for every additional hour of anesthesia and every liter of blood loss.     These results could be used by both spine surgeons and anesthesiologists to improve patient safety by influencing appropriate patient selection and perioperative anesthetic and surgical management of prolonged spine operations with the goal of reducing the incidence of this devastating complication.

6. Basal Ganglia Modulation of Trigeminal Intralaminar Nuclei Thalamic Activity

Eric Chudler, Ph.D., M. Byers, Ph.D.

The motor symptoms and underlying neuropathology resulting from damage to the basal ganglia such as that in Parkinson's disease (PD) have been described extensively.  However, the basal ganglia role in somatosensory function, including that of pain and nociception, has been largely ignored.    The proposed use electrophysiological methods to explore how the basal ganglia modulate the response of nociceptive neurons in the intralaminar nuclei of the thalamus to persistent trigeminal nociceptive stimuli.  Our long range goal is to establish a framework to understand how the basal ganglia modulate nociceptive information.   Dopaminergic degeneration of the nigrostriatal pathway is expected to enhance the response of thalamic neurons to persistent nociceptive trigeminal stimuli.   The first specific aim is to analyze the connectivity between the caudate-putamen (CPu) and intralaminar nuclei of the thalamus by testing the effects of electrical CPu stimulation on the responsiveness of nociceptive neurons in the intralaminar nuclei of the thalamus. Activation of the CPu by electrical stimulation is expected to alter the discharge frequency of nociceptive thalamic neurons to noxious chemical and mechanical stimulation of the face.  These electrophysiological experiments will also permit functional characterization of a nociceptive thalamostriatal pathway.  This thalamostriatal pathway has not been described previously.  The second specific aim is to test the effects of dopamine depletion on the responsiveness of trigeminal nociceptive neurons in the intralaminar nuclei of the thalamus and investigate how dopamine depletions affects pain behavior.  Unilateral injection of 6-hydroxydopamine into the CPu to destroy dopamine-containing neurons is expected to alter the evoked discharge frequency of nociceptive neurons in the intralaminar nuclei of the thalamus and increase nociceptive behavioral responses.  These experiments will provide new insights about the role of the basal ganglia in pain and nociception and will shed light on a new dopaminergic pain modulatory system.   It is possible that damage to the basal ganglia, such as that which occurs in patients with PD, will cause an increase risk of pain because of the impairment of this pain modulatory system. These studies will help explain the complex sensory symptoms exhibited by patients with PD and may suggest new treatment strategies to alleviate such pain. 

7. Pharmacokinetics of Intrathecal Drug Infusions

C.M. Bernards, MD, S. Flack, MBChB

Human clinical studies of intrathecal bolus drug distribution demonstrate that baricity (i.e., the density of the injected fluid relative to the density of CSF) is the most important determinant of drug distribution in CSF.  However, the effect of baricity during very slow continuous drug infusions has never been studied in humans or animals.  In vitro studies of drug distribution in the Medtronic spinal model suggest that baricity is also the overwhelming determinant of drug distribution during very slow chronic drug infusions.  However, the in vitro model cannot account for the effects of drug clearance from CSF, which is a critical determinant of drug distribution during very slow continuous drug infusions.  Consequently, to determine the effect of baricity on drug distribution during chronic slow intrathecal infusions it is necessary to study distribution in an animal model.

* (C) denotes clinical investigation.

 

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