ICOS PAFASE Trial

Funding Agency: ICOS Inc.
Total Project Period: Jun 01, 2002 - May 31, 2006
Principal Investigator: Derek Angus, MD

Project Summary:
ICOS Corporation (ICOS) is conducting a phase III clinical trial (BAR03) to evaluate the efficacy and safety of recombinant Platelet Activating Factor Acetylhydrolase (Pafase) in patients with severe sepsis and/or septic shock. ICOS wishes to assess the impact of Pafase on extended patient outcomes and costs concurrently with this phase III trial -- in other words, to assess the health economics of Pafase in severe sepsis.

The CRISMA Laboratory will coordinate the Health Economics Sub-study and directly perform the collection of billing data and the final economic analyses. ICOS and its agents will provide CRISMA with other clinical and resource use data.

CRISMA will execute a state-of-the-art analytic and modeling plan that will provide a detailed assessment in keeping with current and pending guidelines for the conduct and reporting of health economic studies. The specific aims of this health economics sub-study will be achieved by augmenting BAR03 data collection with detailed information on hospital costs, extended survival follow-up for a minimum of seven months, and patient interviews at discharge and at 7 months post enrollment to determine quality of life and resource use. We will also construct a microsimulation model calibrated by results from BAR03 and published data on life-expectancy and costs and then adjusted to reflect a broader patient case-mix in routine clinical practice.

Recombinant human activated protein C worldwide evaluation in severe sepsis

Funding Agency: Eli Lilly & Co. Inc.
Total Project Period: Oct 01, 1997 - Dec 31, 2002
Principal Investigator: Derek Angus, MD

Project Summary:
Coagulation Markers & Mediators in Sepsis" GlaxoSmithKline Supplemental funding to NIH 1R01 GM61992-03.

Anemia and Transfusion Practices in Hospitalized Community Acquired Pneumonia

Funding Agency: Ortho Bioteh, Inc.
Total Project Period: May 16, 2003 - May 16, 2006
Principal Investigator: Derek Angus, MD
Co-Investigator(s): Gilles Clermont, MD; Kelly Wood, MD

Project Summary:
This is an agreement with Ortho Biotech. The goals of this project are to provide Ortho Biotech with report data in accordance with the protocol titled, "Anemia and Transfusion Practices in Hospitalized Community-acquired Pneumonia" Analysis of incidence and outcome in a large US Cohort."

Myocardial Ischemia and Vasospasm in Aneurysmal Subarachnoid Hemorrhage (SAH)

Funding Agency: National Institutes of Health
Total Project Period: April 4, 2004 – March 31, 2005
Principal Investigator: Dr. Michael Horowitz
Co-Investigator(s): Dr. Marie Baldisseri

Project Summary:
This project will prospectively evaluate the incidence of myocardial ischemia and infarct in the subarachmoid hemorrhage (SAH) population and determine whether the presence of myocardial ischemia significantly increases the risk of symptomatic vasospasm, a major complication following SAH. The central hypothesis is that there is a catecholamine surge of norepinephrine and epinephrine immediately after SAH. This provides a common mechanism associated with both vasospasm of the cerebral and myocardial vessels that increases secondary cerebral and myocardial infarct.

Improving the Diagnosis and Prognosis of Inflicted Head Trauma in Infants

Funding Agency: Center For Disease Control
Total Project Period: Sep 01, 2003 - Aug 31, 2004
Principal Investigator: Huyla Bayir, MD

Project Summary:
Inflicted Traumatic Brain Injury (iTBI) is a leading cause of serious TBI in infants and young children. Diagnosing iTBI is difficult, and misdiagnosis is common yet there are no established diagnostic adjuncts to help physicians properly identify iTBI. We have developed an international reputation for the study of biochemical markers in both non-inflicted (n)TBI and iTBI. In light of the exciting potential for this approach to lead ultimately to a clinical breakthrough, we propose a case-control study evaluating the utility of novel biochemical markers in the serum of infants at risk for iTBI as the centerpiece of a collaborative project by our group. We will determine whether biochemical markers can serve as diagnostic adjuncts in a high-risk target population to identify potential infant victims of iTBI.

Therapeutic Hypothermia and Nitrosative Stress After Sev

Funding Agency: Laerdal Medical Foundation
Total Project Period: Jan 01, 2003 - Dec 31, 2003
Principal Investigator: Huyla Bayir, MD
Co-Investigator(s): Valerian Kagan, P. David Adelson

Project Summary:
Traumatic brain injury (TBI) sets into motion a deleterious secondary cascade of biochemical and molecular events. Oxidative damage plays a key role in secondary damage after TBI. Oxidative damage results from production of reactive oxygen (oxidative stress) and nitrogen species (nitrosative stress). Our recent report shows attenuation of oxidative stress by hypothermia after severe TBI in infants and children, suggesting that hypothermia is beneficial. In contrast to oxidative stress, which contributes to secondary damage, nitrosative stress may confer both detrimental and beneficial effects. To date there has been no experimental or clinical study addressing the effect of therapeutic hypothermia on nitrosative stress after TBI. Therefore we hypothesize that hypothermia will attenuate nitrosative stress after severe TBI in infants and children. Using an IRB approved protocol, ventricular CSF samples (n = 120) from 30 infants and children (15 normothermia 15 treated with hypothermia) will be collected within the first 8 h and for the initial 4 d then immediately frozen until analysis. This will allow assessment during hypothermia (48 h) and re-warming. CSF will also be obtained from age-matched controls (n=15, children who underwent lumbar puncture to rule out meningitis [confirmed negative cultures and no pleocytosis]) for analysis. Nitrotyrosine and S-nitrosothiols will be quantified by ELISA and fluorescent assay respectively. Time course and association of CSF nitrotyrosine and S-nitrosothiol levels with demographic and clinical parameters (age, gender, mechanism of injury [accidental vs. abuse], admission GCS, outcome, head CT scan, ICP, CPP) will also be determined.

Transfusion Medicine Hemostaisis Clinical Research Network

Funding Agency: National Institutes of Health
Total Project Period: Sep 30, 2002 - Aug 31, 2007
Principal Investigator: Joseph Carcillo, MD

Project Summary:
In year 6 (2003-04), we propose to explore in dogs in study I slower exsanguination over 30 min. to near-CA, and to maximize preservation time for transport and repair. For study I-A we hypothesize that survival time after near-CA followed by hypotensive FR is longer under 34°C by external cooling than under normothermia, and longer with the novel poikilothermia inducing peptide neurotensin, as compared to morphine. In study I-B we hypothesize that following exsanguination to near-CA, a period of prolonger hypotensive FR at 34°C is less preservative than the same period of CA at 10°C by aortic cold flush of a special solution. In study I-C we propose to maximize preservation time after exsanguination to near-CA over 30 min, by combining in sequence hypotensive FR for uncontrolled HS of 30 min vs 60 min vs 90 min followed by SA for CA of 90 min at 10°C.

Study II in rats on the limits of resuscitability will use brain mitochondrial proteomics. We will identify indicators of cell death during CA and reperfusion at various temperatures.

Myocardial Ischemia and Vasospasm in Aneurysmal Subarachnoid Hemorrhage (SAH)

Funding Agency: Army
Total Project Period: Sep 15, 2002 - Sep 14, 2007
Principal Investigator: Joseph Carcillo, MD (Peter Safar, MD – Principal Investigator)

Project Summary:
In year 5 (2002-03), we propose to conduct three studies simultaneously. Study I: To maximize resuscitability in dogs from traumatic Exs CA of 60 minutes (now partially successful) to CA of 120 minutes no-flow. Study II: To help increase feasibility of SA induction in the field by tests in dogs. 1) Reducing flush volume requirement by recirculating diluted venous blood via cooler without oxygenator or using ice slush solution. 2) Exploring flush and resuscitation via thoracotomy without CPB. 3) Testing new prototype devices developed by industry guided by us: novel catheters for rapid vessel access with and eithout thoracotomy; miniaturized portable cooling/pumping devices for induction of mild hypothermia (34 degree C) under spontaneous circulation and profound hypootheriic aortic cold flush (10 degrees C) under CA, portable CPB. Study III: To start exploring the limits of resuscitability during prolonged clinical death in rats in a systematic basic science pilot project to identify chemical markers (proteomics) and histologic markers of cell deatah (fluorojade) during CA without reperfusion by focusing on mitochondria in brain and other vital organs under various temperatures.

Efficacy and Safety of Drotrecogin Alfa Activated in Pediatric Severe Sepsis

Funding Agency: Lilly Research Labs
Principal Investigator: Joseph Carcillo, MD

Caspase-mediated Neuronal Death After Head Injury

Funding Agency: National Institutes of Health
Total Project Period: Feb 01, 1999 - Jan 31, 2003
Principal Investigator: Robert Clark, MD
Co-Investigator(s): Patrick Kochanek; Simon Watkins, Patrick M. Kochanek, M. Chen, K.L. Jin, Steven H. Graham, C. Edward Dixon,
Timothy R. Billiar, Donald W. Marion

Project Summary:
Caspase activation is the first committed step in the programmed-cell death cascade, a tightly regulated sequence of cellular and molecular events that systematically leads to the death of a cell. Specific aims will: 1) characterize the temporal, regional, cellular and subcellular expression and activity of Caspase-3 using a rat model that mimics severe human TBI, 2) examine the upstream regulation of caspases by cytosolic Cytochrome c and nitric oxide after severe TBI in rats and mice, 3) test the effects of several pharmacologic caspase inhibitors on neuropathologic and functional outcome after severe TBI in rats, 4) examine the expression of other caspases after severe TBI in rats, and 5) examine the expression of currently identified caspases after severe TBI in humans.

PARS Activation After Traumatic Brain Injury (PP - Project #5)

Funding Agency: NIH/Neurological Institute
Total Project Period: May 11, 2000 - Feb 28, 2005
Principal Investigator: Robert Clark, MD
Co-Investigator(s): Jun Chen

Project Summary:
Cellular energy failure contributes to cell death seen after traumatic brain injury. Recent studies using cell cultures and in vivo experimental models suggest that a key participant in cellular energy failure is the abundant nuclear enzyme poly (ADP-ribose) synthetase (PARS). The aims of this project are to establish the role of PARS in traumatic brain injury. Pharmacologic inhibition of PARS may prove to be a powerful means of reducing energy failure, cell death, and neuropathologic sequelae after traumatic brain injury.

Divergent Pathways of Cell Death After Brain Injury

Funding Agency: National Institutes of Health
Total Project Period: Feb 01, 2003 - Jan 31, 2008
Principal Investigator: Robert Clark, MD
Co-Investigator(s): Patrick Kochanek; Jun Chen, C.Edward Dixon, Steven G. Graham, Donald W. Marion, Hector R. Wong, Joseph A. Carcillo, Simon C. Watkins

Project Summary:
The major goals of this project are to identify divergent pathways of cell death in experimental in vitro models, in vivo models of traumatic brain injury in adult rats, and in humans after traumatic brain injury. Variations within these pathways in the response to pharmacological and molecular therapies targeting cell death will also be examined. This represents a competitive renewal application for 1R01 NS38620.

PARS Activation After Traumatic Brain Injury (PP - Project #4)

Funding Agency: NIH/Neurological Institute
Total Project Period: May 11, 2000 - Feb 28, 2005
Principal Investigator: Robert Clark, MD
Co-Investigator(s): Jun Chen

Project Summary:
Cellular energy failure contributes to cell death seen after traumatic brain injury. Recent studies using cell cultures and in vivo experimental models suggest that a key participant in cellular energy failure is the abundant nuclear enzyme poly (ADP-ribose) synthetase (PARS). The aims of this project are to establish the role of PARS in traumatic brain injury. Pharmacologic inhibition of PARS may prove to be a powerful means of reducing energy failure, cell death, and neuropathologic sequelae after traumatic brain injury.

Ultrapotent PARS Inhibitor for CBS Trauma

Funding Agency: INOTEK CORPORATION
Total Project Period: Sep 15, 2002 - Sep 14, 2003
Principal Investigator: Robert Clark, MD
Co-Investigator(s): Larry Jenkins

Project Summary:
Cellular energy failure is a key contributor to cell death seen after traumatic brain injury. Recent studies using cell cultures and in vivo experimental models suggest that a key participant in cellular energy failure is the abundant nuclear enzyme poly (ADP-ribose) synthetase (PARS). Recently, novel and potent PARS inhibitors have been developed that are likely to reduce cellular energy failure and cell death, thus impacting outcome after traumatic brain injury. The aims of this project are to test promising PARS inhibitors using an experimental model of traumatic brain injury, using a long-term and stringent battery of histological and functional outcome tests. Pharmacologic inhibition of PARS may prove to be a powerful means of reducing energy failure, cell death, and neuropathologic sequelae after traumatic brain injury.

Modeling Host Immunity to Agents of Biological Terrorism

Funding Agency: National Institutes of Health
Total Project Period: Jul 01, 2002 - Jun 30, 2006
Principal Investigator: Gilles Clermont, MD
Co-Investigator(s): Carson Chow, Yoram Vodovotz, G Constatine, S Iyengar, W Troy

Project Summary:
A large effort to develop an effective strategy against agents of bioterrorism has been undertaken by our nation. TIlis strategy is multifaceted and includes source control, intelligence, disease prophylaxis preveiitionlnhalational and gastrointestinal infection with Bacillus cmihrucis (anthrax) can cause an inflammatory reaction leading to multisystem organ failure and death. Various clinical cues and diagnostic tests are used to confirm suspected anthrax infection, and it is likely that emerging molecular diagnostic techniques will yield more accurate and quicker confirmation of anthrax infection. Drs. Vodovotz. Clermont and Chow have developed a mathematical model incorporating cellular, molecular, and physiological details of the acute inflammatory responses to infection, and have begun to simulate the response to anthrax infection This model can be used to predict an individual patient's course of disease, as well as to test the efficacy of a given intervention in a simulated clinical trial. In this Phase I proposal. We propose the following: 1) to adapt and calibrate, based on existing data. Our mathematical model of the innate inflammatory response to a inhalational and gastrointestinal anthrax infection and its treatment: and 2) to develop a software tool designed for the input- visualization, and manipulation of (lie this mathematical model. This model and software too will be adaptable to incorporate the results of multiple diagnostic and clinical tests. The results of the research proposed herein will not only impact the treatment of victims of anthrax infection, but will also yield valuable tools for the treatment of sepsis in general.

International Conference on Complexity in Acute Illness

Funding Agency: National Institutes of Health
Total Project Period: Apr 01, 2004 - Mar 31, 2005
Principal Investigator: Gilles Clermont, MD

Project Summary:
As medical science enters the 21st century, an enormous amount of new data is emerging from technological advances in genomics and proteomics, high-density data acquisition hardware, computational power and algorithm development. However, there exist huge cognitive and cultural obstacles to translating this data into new knowledge, and to patient care. Mathematical modeling is emerging as a desirable approach by which to describe and predict the behavior of complex biological phenomena. A key barrier to the widespread implementation of complex modeling in acute illness is the gulf separating clinicians and bench researchers on the one hand, and modelers on the other. Further skepticism as to the utility of this integrated approach exists in the pharmaceutical industry, stung by the failure of therapies targeting inflammation in the setting of acute illness. To improve collaboration and dialog among these groups, we propose a yearly meeting entitled “International Conference on Complexity in Acute Illness”. The goals of this conference are to 1) facilitate open exchange among clinicians, biological scientists, and modelers, 2) present original research in complex modeling of biological events relevant to acute illness, 3) provide a forum for young and underrepresented investigators to present and learn from interdisciplinary research, 4) promote collaboration between industry and academia, and 5) promote scientific diffusion of these efforts by the publication of highlight presentations in a suitable scientific journal. We request support for four yearly conferences, to begin November 7-9, 2004, and to be held at the University of Pittsburgh, a nucleus for extensive basic and applied research in acute illness in combination, and a leading center in computational biology and simulation. For the 2004 conference, we propose to evolve from the workshop format of three prior meetings, to a larger scale thematic conference with open registration. Themes to be covered include 1) molecular modeling of acute inflammation, 2) organ function and dysfunction, 3) methodological and validation issues in modeling complex systems, 4) application of complex modeling to patient care, and 5) modeling, Industry, and Academia.

Each thematic session, under the direction of a chair and co-chair, includes formal presentations by an international group of established scientists, followed by questions and discussion. Half a day will be devoted to seminar-type presentations by young researchers. Scientific abstracts will be sollicited.

Molecular Biology of Hemorrhagic Shock Project V

Funding Agency: National Institutes of Health
Total Project Period: Apr 01, 2004 - Mar 31, 2005
Principal Investigator: Gilles Clermont, MD

Mathematical Models of Anthrax Infection

Funding Agency: NIH/Immunex
Total Project Period: Sep 01, 2002 - Feb 20, 2003
Principal Investigator: Gilles Clermont, MD
Co-Investigator(s): Yoram Vodovotz, PhD, Rukmani Kumar

Project Summary:
Sadly, bioterrorism is no longer an emerging possibility, but rather a daily fact of American life. Inhalational and gastrointestinal infection with Bacillus anthracis (anthrax) can cause an inflammatory reaction leading to multisystem organ failure and death. Various clinical cues and diagnostic tests are used to confirm accurate and quicker confirmation of anthrax infection. However, all diagnostic modalities fail in one crucial respect: while they identify the presence of anthrax infection, they do not point to the status of the individual patient nor do they indicate how this person will fare in the immediate future. Drs. Vodovotz, Clermont, and Chow have developed a mathematical model incorporating cellular, molecular, and physiological details of the acute inflammatory responses to infection, and have begun to simulate the response to anthrax infection. This model can be used to predict an individual patient's course of disease, as well as to test the efficacy of a given intervention in a simulated clinical trial. Immunetrics, Inc., is in the process of commercializing the applications of this model to the treatment of sepsis, a healthcare problem affecting over 750,000 Americans each year with a cost of over $17 billion. In this Phase I proposal, we propose the following: 1) to adapt and calibrate, based on existing data, our mathematical model of the innate inflammatory response to an inhalational and gastrointestinal anthrax infection and its treatment; and 2) to develop a software tool designed for the input, visualization, and manipulation of this mathematical model. This model and software tool will be adaptable to incorporate the results of multiple diagnostic and clinical tests. The results of the research proposed herein will not only impact the treatment of victims of anthrax infection, but will also yield a valuable tool for the treatment of sepsis in general.

Validation of Criteria Identifying Candidates For Non-Heart Beating Organ Donors

Funding Agency: Health and Service Administration
Total Project Period: Sep 01, 2003 - Aug 31, 2004
Principal Investigator: Michael DeVita, MD

Project Summary:
There are several major obstacles to proliferation of NHBOD programs. First, identification of patients likely to die within an hour after discontinuation of life supporting medications and treatments is difficult because there is no data upon which to base donor criteria. The second issue is impairing the growth of non-heart beating organ donation is the notion that so few organs are likely to be procured from non-heart beating cadavers that it is not worth the effort. Third, and finally, there is an impression that organs from NHBOD are inferior to those obtained from brain-dead (also known as heart-beating) cadavers. The few centers in the U.S. that are doing a large number of transplants of organs procured from NHBOD are starting to reverse this opinion. Thus the critical data required to answer two of the three major obstacles to non-heart beating organ donation do not exist, and are unlikely to be obtained without a funded study. Fortunately, all three questions can be answered with data derived from a single set of patients. A prospective, observational study of patients who are to have life support removed is required. 500 of these patients who also meet the UNOS Critical Care Advisory Council NHBOD Criteria, will have life support removed according to routine. Other demographic information like age, type of disease and co-morbidities, APACHE 3 score, gender, will be recorded. The patients should be observed from the time of withdrawal of support to death. Data collected will include ICU physiologic data obtained from devices already in place, as well as the medications delivered during the dying process. No investigators need be in the room, and data can be collected by the patient’s own ICU nurse easily without disrupting family.

Molecular Mechanisms of Gut Barrier Dysfunction

Funding Agency: National Institute of General Medical Science
Total Project Period: Jul 01, 1999 - Jun 30, 2003
Principal Investigator: Russell Delude, PhD

Project Summary:
Although the mechanisms promoting intestinal injury in sepsis and endotoxemia remain to be elucidated, extensive data obtained by our group as well as others suggests that one important factor is probably overproduction of the pluripotent ediator, nitric oxide (NO-). Although some clues exist in the literature, the mechanisms whereby NO modulates intestinal epithelial barrier function in inflammatory conditions, such as sepsis or inflammatory bowel disease, are poorly understood. Accordingly, the goal of the studies proposed herein is to improve our understanding of the fundamental cellular and molecular mechanisms underlying alterations in intestinal epithelial permeability inducted by NO and/or other related reactive nitrogen intermediates (RNIs). The project has been organized under four specific aims 1) Engineer a tetracycline-regulated expersion plasmid to permit tightly controlled transcriptional regulation of inducible nitric oxide synthase (iNOS) gene expression in a well-differentiated enterocytic cell-line. Caco-2, in order to test the hypothesis that excessive endogenous generation of NO is sufficient (even in the absence of other pro-inflammatory mediators) to increase intestinal epithelial permeability. 2) Using (i)cytokine-stimulated cultured eneterocytes (Caco-2 and T84 cells), (ii) the engineered cell line described under Aim 1, (iii) an in vivo model system for monitoring gut mucosal respiration in rats; and (iv) mucosal samples from endotoxemic wild-type or iNOS "knockout" mice, test the hypothesis that up-regulation of NO production in the intestinal epithelium leads to cellular ATP depletion on the basis of mitochrondrial dysfunction and/or activation of the enzyme, poly(ADP)-ribose polymerase. Aim 3: The cell lines described under Aim 2 will be used to test the hypothesis that exogeneously supplied or endogenously produced NO promotes the phosphorylation or dephosphorylation of key cytoskeletal proteins and that NO mediated alterations in protein tyrosine phosphorylation lead to changes in cytoskeletal integrity and epithelial permeability. Aim 4: Test the hypothesis that exogenously supplied or endogenously produced NO promotes mono (ADP)-ribosylation of one or more key regulatory or cytoskeletal proteins (including actin, itself)in enterocytes; determine the mechanism whereby NO modulates mono(ADP)-ribosylation; and identify the NO sensitive elements responsible for this phenomenon. The proposed experiments will provide powerful new tools (e.g., the Caco-2 cell line expressing iNOS in a Tc-regulated fashion) for studying the effects of NO on epithelial function. In addition, the proposed studies should open up a fruitful lines of investigation regarding the fundamental mechanisms (e.g. mono(ADP)-ribosylation of cytoskeletal proteins)underlying the regulation of intestinal epithelial permeability under physiologic and pathophysiologic conditions.

Howard Hughes Med Institute Research Training Fellow/Med Students

Funding Agency: Howard Hughes Medical Institute
Total Project Period: Jul 01, 2003 - Jun 30, 2004
Principal Investigator: Joshua Englert

Project Summary:
Howard Hughes Medical Institute Research Training Fellowships for Medical Students.

Prospective, Randomized, Double-Blind Comparison of Efficacy & Safety Sequential Treatment with Intravenous (IV)/ (PO) Oral Moxifloxacin

Funding Agency: Bayer Corporation
Total Project Period: Sep 15, 2001 - Mar 15, 2003
Principal Investigator: Mitchell Fink, MD

Project Summary:
Prospective, Randomized, Double-Blind Comparison of Efficacy and Safety of Sequential Treatment with Intravenous (IV)/Oral (PO) Moxifloxacin (BAY 12-8039) Versus Ceftriaxone IV/PO Cefuroxime-axetil in Patients with Nosocomial Pneumonia?

Protocol #100244

Prospective Randomized Double Blind Comparison of Efficacy & Safety Sequential Treatment with Intravenous (IV)/ Oral Moxifloxacin

Funding Agency: ICOS Inc.
Total Project Period: Jul 25, 2001 - Dec 31, 2002
Principal Investigator: Mitchell Fink, MD

Project Summary:
A Randomized, Double-Blind, Double Dummy, Phase III Comparative Study of Cidecin (Daptomycin) and Zyvox (Linezolid) in the Treatment of Hospitalized Adults with Suspected Vancomycin Resistant Enterococcal Infections.

IND #57693

Protocol # DAP-VRE-00-07

Intestinal Perfusion and Permeability in Sepsis

Funding Agency: National Inst of Gen Med Science
Total Project Period: Apr 01, 1987 - Jun 30, 2004
Principal Investigator: Mitchell Fink, MD

Project Summary:
Our long-term goal is to elucidate the fundamental mechanisms responsible for intestinal barrier dysfunction in states associated with acute tissue hypoxia and/or inflammation. Our unifying hypothesis is that derangements in cellular energy metabolism cause or contribute to alterations in epithelial barrier function in critical illness. Aim I is to study cytokine mediated repression of hypoxia-inducible factor-1 (HIF-1)-dependent adaptive epithelial responses in hypoxia during sepsis. Aim II is to evaluate one potential way that an increase in cytosolic ionized calcium concentration, [Ca2+], could act to increase intestinal epithelial paracellular permeability. Aim III is to investigate the effect of cytokines, hypoxia, or metabolic inhibition on the polarized basolateral-to-apical transport of complex carbohydrates and other hydrophilic compounds across the intestinal epithelium.

Pathogenesis of Experimental Necrotizing Enterocolitis

Funding Agency: National Institutes of Health
Total Project Period: Dec 01, 2001 - Nov 30, 2006
Principal Investigator: Mitchell Fink, MD
Co-Investigator(s): Henri R. Ford, MD (Project Director); Rosemary A. Hoffman, Ph.D.; Ronald Jaffe MB, BCh; Ruben Zamora, PhD; Timothy Billiar, MD; Simon C. Watkins, PhD; Seth J. Corey, MD, MPH; Ian J Reynolds, PhD; Anthony J Bauer, PhD

Project Summary:
Necrotizmg enterocolitis (NEC) is the most frequent and the most lethal disease that affects the gastrointestinal tract of the premature infant. The exact etiology of the disease is undefined. The only consistent identifiable epidemiologic precursors for NEC are prematurity and enteral alimentation. We have previously shown up-regulation of inducible nitric mde (NO) synthase (NOS-2) mRNA and protein in intestinal segments from infants with acute NEC. NOS-2 co-localized with enterocyte apoptosis and nitrotyrosine immunoreactivity. NOS-2 was down-regulated at the time of intestinal stoma closure when the acute inflammation had subsided. We have developed a reproducible model of gut
inflammation in neonatal rats that mimics many of the morphological changes characteristic of human NEC. We simply formula-feed hypoxic neonatal rats thereby simulating the conditions associated with human NEC. These pups show NOS-2 mRNA up-regulation, nitrosative stress, increased enterocyte apoptosis and decreased enterocyte proliferation in the crypts. Intraepithehal lymphocytes (IEL) from hypoxic formula-fed rats secrete more TNF-D and IFN-D compared to breast-fed rats. In vitro studies suggest that co-culture of IEL with the rat intestinal epithelial cell line IEC-18 in the presence of IL-lp induces IFN-y, TNF-a and NOS-2 production which can be abrogated with antibody to IFN-y, furthermore, peroxynitrite (ONOO) induces apoptosis and inhibits proliferation ofIEC-6 cells. The data suggests that intestinal necrosis in NEC may be the result of NO-induced imbalance between tissue injury and repair mechanisms. Mucosal injury resulting from perinatal insults leads to bacterial-epithelial interactions, local release of cytokines such as [FN-y and TNF-a by IEL and lamina propria (LP) lymphocytes. These mediators induce NOS-2 up-regulation with production of NO and ONOO by enterocytes or LP macrophages. NO or ONOO in turn promotes further tissue injury enterocyte apoptosis) and concurrent inhibition of tissue repair mechanisms (enterocyte proliferation) leading to gut earner failure and NEC. To test our hypothesis, we propose the following Aims: I) To define the mechanism of NOS-2upregulation in human and experimental rodent NEC. II) To define the mechanisms by which NOS-2 up-regulation promotes intestinal epithelial injury and alters tissue repair mechanisms in rodent NEC. Ill) To determine the effects of scavengers of NO or inhibitors of NO production on the development of experimental rodent NEC.

Effect/NOX100 Physical and biochemical parameters/pig model of LPS induced acute lung injury

Funding Agency: Medinox, Inc.
Total Project Period: Aug 15, 2001 - Apr 30, 2003
Principal Investigator: Mitchell Fink, MD

Project Summary:
LPS-induced acute lung injury (ALI) in pigs. One of the most characteristic features of sepsis and septic shock in humans is the development of acute lung injury (ALI) of the acute respiratory distress syndrome (ARDS). Virtually 100% of patients with septic shock develop at least some evidence of acute pulmonary dysfunction, and many manifest the full-blown syndrome of ARDS characterized by severe arterial phyoxemia, pulmonary hypertension, noncardiogenic pulmonary edema, alveolitis, and diminished pulmonary compliance. Many of the features of this syndrome are reproduced when pigs are infused intravenously with LPS. Our laboratory has extensive experience using this model. This experiment will be a relatively short-term study carried out for 5 hours following the injection of either LPS (experimental animals) or the saline vehicle (nonendotoxemic controls). The primary goal of this experiment will be to test the hypothesis that pre- or post-treatment with NOX-100 can provide protection against pulmonary dysfunction induced by infusing pigs with LPS.

Pathogenesis and Treatment of Experimental Peritonitis

Funding Agency: National Institutes of Health
Total Project Period: Apr 01, 2002 - Mar 31, 2007
Principal Investigator: Mitchell Fink, MD
Co-Investigator(s): Henri R Ford, MD; Richard L Simmons, MD; Rosemary A Hoffman, MD; Simon C. Wakins.

Project Summary:
Derangement in the intestinal mucosal 'barrier may play an important role in the pathogenesis of systemic infection in critically ill patients. Perturbations in me host defense mechanisms that result in sustained regulation of inducible nitric oxide synmase (iNOS) in the gut may lead to profound alterations in intestinal mucosal barrier function. Evidence suggests that peroxynitrite (ONOO'), a potent oxidant formed by the reaction 3fNO with superoxide, may be a key reactive nitrogen intermediate responsible for the cytopathic effects of NO in inflammatory conditions such as endotoxemia, inflammatory bowel disease (IBD), or necrotizing enterocolitis. Our objective is to determine the mechanisms by which overproduction of NO or ONOO' may promote tissue injury (enterocyte apoptosis) and inhibit tissue repair mechanisms (epithelial restitution via enterocyte migration and proliferation), thereby leading to gut barrier failure. We propose two specific aims. Aim I: To elucidate the potential mechanisms by which ONOO' induces enterocyte apoptosis. We will examine the cytotoxic effect of ONOO' in various enterocytic cell lines and the biochemical pathways that may be involved (mitochondrial dysregulation, caspases, and PARS activation). Aim II: To investigate the mechanisms by which NO or ONOO'inhibits tissue repair mechanisms, epithelial restitution and proliferation. We will examine how ONOO' affects epithelial restitution by enterocyte migration, the critical phase mat precedes the proliferative response to repair the mucosal injury. Migration may be regulated in part by Rho-GTPases which modify the actin cytoskeleton. We will determine whether Rho is required for enterocyte migration and stress fiber formation in vitro. We will test the hypothesis that ONOO' can inhibit migration and proliferation by nitrating critical tyrosine residues of key members of the Src family of tyrosine kinases: Src; focal adhesion kinase (FAK); and PI3K. We will attempt to modulate Rho, Src kinase, or mitochondrial signaling pathways with various cytoprotective agents to enhance intestinal barrier function in conditions associated with excessive NO/ONOO' production (endotoxemia,BD) in vivo.

Ethyl Pyruvate: A Novel Treatment for Sepsis

Funding Agency: National Institute of General Medical Science
Total Project Period: Jul 01, 2003 - Jun 28, 2008
Principal Investigator: Mitchell Fink, MD
Co-Investigator(s): Russell Delude, PhD

Project Summary:
Ethyl pyruvate (EP)* is the ester formed from pyruvic acid and ethanol in preliminary studies, we have documented that EP ameliorates intestinal and hepatic injury or improves survivial when it is used as a therapeutic agent to treat rodents subjected to mesenteric ischemia and reperfusion (I/R), hemorrhagic shock (HS), endotoxemia, or polymicrobial bacterial sepsis. In addition, we have demonstrated that EP is an effective scavenger of reactive oxygen species (ROS), and we have shown that this compound is also an anti-inflammatory agent that inhibits activation of the pro-inflammatory signaling factors, NF- and p38 mitogen-activated protein kinase (MAPK). EP also inhibits release of a novel cytokine, high mobility group box 1 (HMGB1). Prompted by these exciting observations, we propose to carry out a series of experiments that are designed to better elucidate the mechanism(s) responsible for the anti-inflammatory and therapeutic effects of EP.

Resuscitation Fluids for Treatment of Battlefield Casualties

Funding Agency: Defense Advanced Research Project Agency
Total Project Period: Sep 29, 2000 - Sep 28, 2003
Principal Investigator: Mitchell Fink, MD
Co-Investigator(s): M. Kameneva, A. Russell, H. Borovitz, T. Chapman, J. Wu, S. Hutcherson, J. Luly, K. Heimlich

Project Summary:
Hemorrhagic shock (HS) remains a major cause of morbidity and mortality for combat casualties. The pathological consequences of HS are myriad. Many of the deleterious effects of HS are a direct consequence of cellular energy starvation secondary to the inadequate delivery of oxygen through the microcirculation. Other adverse effects of HS, however, occur during and after the resuscitation phase, and can be attributed to the release of highly reactive partially reduced derivatives of molecular oxygen. The research proposed in this proposal will address both of these issues and lead to the development of an improved resuscitation fluid for the treatment of injured combat casualties.

Development of the DARPA Superfluid for Resuscitation from Hemorrhagic Shock

Funding Agency: Defense Advanced Research Project Agency
Total Project Period: Apr 01, 2003 - Mar 31, 2004
Principal Investigator: Mitchell Fink, MD
Co-Investigator(s): Russell Delude, PhD; Marina Kameneva, PhD

Project Summary:
This project is a continuation of the project to develop novel resuscitation fluids for the treatment of battlefield casualties.

Prospective Randomized, Double-Blind Comparative Efficacy & Safety Sequential Treatment w/IV Oral Moxifloxacin

Funding Agency: Bayer Corporation
Total Project Period: Jul 25, 2001 - Dec 31, 2002
Principal Investigator: Mitchell Fink, MD

Project Summary:
A Randomized, Double-Blind, Double Dummy, Phase III Comparative Study of Cidecin (Daptomycin) and Zyvox (Linezolid) in the Treatment of Hopitalized Adults with Suspected Vancomycin Resistant Enterococcal Infections.

IND #57693

Laerdal

Funding Agency: Laerdal Foundation
Total Project Period: Jan 01, 2003 - Dec 31, 2004
Principal Investigator: Kyle Gunnerson, MD

Project Summary:
This project will determine the effect of different etiology of metabolic acidosis on outcome in critically ill patients. The etiology of metabolic acidosis is a predoctor or outcome, independent of the magnitude of acidosis.

Dynamics of Peritoneal Dialysis Associated Peritonitis

Funding Agency: National Institutes of Health
Total Project Period: Jul 01, 2003 - Jun 30, 2005
Principal Investigator: John Hotchkiss, MD

Project Summary:
This multidisciplinary pilot proposal focuses on interactions between dynamics of bacterial growth and optimal bacterial clearance in the setting of peritoneal dialysis associated peritonitis (PDAP). In the proposed work, we will 1) use in vitro models to define the dynamics and nutrient dependence of fluid phase bacterial growth and antibiotic-induced bacterial killing in peritoneal dialysate (PDF); 2) develop and validate mathematical models of bacterial growth and killing in PDF as functions of time, growth rate, and nutrient availability; 3) Develop mathematical models of bacterial clearance (antibiotic and non-antibiotic related) during peritoneal dialysis. Dynamics guided optimization of bacterial clearance during peritonitis will allow reduction in the antibiotic exposure “burden” for these dialysis patients and their bacterial flora. In addition, this work may provide preliminary data regarding bacterial growth dynamics and antibiotic susceptibility in other “stressful” environments having single or multiple nutrient deficiencies. In peritoneal dialysis, the abdominal cavity is intermittently filled with a fluid (PDF) that is allowed to dwell in the peritoneal cavity. During this dwell time, waste products, excess salts, and water diffuse into the PDF. The PDF is subsequently drained, carrying with it the accumulated waste products and water, and the peritoneal cavity is refilled. Bacteria in fresh PDF represent a starved population, with consequent and profound suppression of bacterial division; starved S. aureus may require 2-2.5 hours to resume active cell division following provision of adequate nutrients. As the dwell times commonly used in peritoneal dialysis are in the 4-6 hour range, this delay in growth onset could be clinically significant, both because it may offer a means to augment non-antibiotic-mediated bacterial clearance (“flushing out” the peritoneal cavity), and because slowing or halting bacterial growth may decrease the antibacterial activity of commonly used antibiotics. Moreover, the significant impairment of host peritoneal defenses due to the non-physiologic milieu in PD fluid renders non-host factors, such as antibiotic efficacy and dialysis prescription, more important in clearing peritoneal infection. Prolonged courses of antibiotic therapy required by compromised host defenses may render the dialysis population an effective “incubator” for drug resistant microorganisms.

Blood Purification in Experimental Sepsis

Funding Agency: Renaltech International, LLC
Total Project Period: Sep 01, 2001 - Aug 31, 2004
Principal Investigator: John Kellum, Jr, MD

Project Summary:
This investigation tests two closely related general hypotheses: 1) That hemo-adsorption will reduce the inflammatory cytokine response and improve survival time compared to sham-treatment in experimental sepsis. 2) That hemoadsorption will reverse sepsis-induced immuno-paralysis. We will test both hypotheses using established animal models of sepsis (IV endotoxin injection and cecal-ligation and puncture in the rat) and using an established cell culture line (mouose macrophage-like rAW 2647 cells). The results of this investigation will significantly improve our understanding of the effects of hemoadsorption on immuno-paralysis and on survival from sepsis. These results may, by themselves, strengthen the clinical rationale for the use of hemo-adsorption in the treatment of severe sepsis, a condition inflicting more than 450,000 Americans every year. These studies will serve as an important platform for future investigation and as benchmarks against which other devices and sorbents can be measured.

A Phase 1 lb Study to Determine the Efficacy and Safety of LY3

Funding Agency: PPD Development
Total Project Period: Jan 01, 2002 - Feb 28, 2003
Principal Investigator: John Kellum, Jr, MD

Project Summary:
A Phase Iib Study to Determine the Efficacy and Safety of LY315920 in Patients with Severe Sepsis (J4A-MC-EZZI, 5/14/01), (Amendment (a), 8/15/01), (CTP3 JK-01-001) The objective of this study is to compare the efficacy of this drug in comparison with placebo in the treatment of patients with sepsis and prevention of organ damage associated with sepsis. The other objectives are to reduce mortality, assess if it has an acceptable safety profile, evaluate the effects of LY315920 on intensive care unit (ICU)-free days, ventilator-free days, hospital-free days, and organ failure-free days during the 28 days study period.

Phase 3 Study Determine the Safety and Efficacy of Recombinant Platelet Activating Factor Acetylhdrolase

Funding Agency: ICOS Inc.
Total Project Period: Jul 20, 2001 - Jan 31, 2004
Principal Investigator: John Kellum, Jr, MD

Project Summary:
A Phase 3 Study to Determine the Safety and Efficacy of Recombinant Platelet-Activating Factor Acetythydrolase (rPAF-AH, Pafase) for Reducing 28 Day All Cause Mortality in Patients with Severe Sepsis.

Long Term F/U of Survivors of the Prowess Trial. An Observational Study

Funding Agency: Eli Lilly & Co. Inc.
Total Project Period: Apr 01, 2002 - Mar 31, 2003
Principal Investigator: John Kellum, Jr, MD

Project Summary:
Long-Term Follow-Up of Survivors from the PROWESS Trial (An Observational Study)

Drotrecogin Alfa (Activated) (LY203638)

Cytosorb Clinical Trial Development

Funding Agency: Renaltech International, LLC
Total Project Period: Jan 01, 2004 - Dec 31, 2004
Principal Investigator: John Kellum, Jr, MD

Project Summary:
We propose to develop a clinical study plan that will address the following: feasibility, cost sample size, patient types and study endpoints. The focus of these studies will be on safety and feasibility. Phase I Clinical trial development will be carried out in conjunction with the sepsis advisory board and the research teams at the University of Pittsburgh and RenalTech International. This proposal covers the design of Phase I Clinical Trials; conduct and management of these trials is beyond the scope of the current project.

Hemadsorption To Improve Donor Organ Recovery

Funding Agency: Health and Service Administration
Total Project Period: Sep 01, 2003 - Aug 31, 2004
Principal Investigator: John Kellum, Jr, MD
Co-Investigator(s): David J Powner, MD

While brain-dead organ donors represent the majority of the organ donor pool, it appears that graft survival is independently adversely affected by brain-death itself. In addition to disturbances in the hormonal, hemodynamic and metabolic homeostasis, immunological changes have recently been shown to occur after brain-death and these changes contribute both to vascular collapse and organ injury. Increased expression of proinflammatory cytokines and their receptors have been demonstrated consistently in the organs and in the circulation of brain-dead animals and humans. Furthermore, the increased inflammatory response seen during and immediately after brain death has also been associated with poor allograft function. Thus, we hypothesize that down- regulating this inflammatory response will lead to improved organ function in the donor and thereby increase organ recovery and subsequent allograft function.

While drug therapy has not shown significant attenuation on the entire inflammatory response, we have shown in preliminary studies highly efficient removal of several inflammatory mediators from the blood of experimental animals using a novel hemoadsorption device. This device is safe in humans with chronic renal failure and increases survival time in animals exposed to lethal endotxemia. Therefore the purpose of this proposal is to determine whether short-term attenuation of the inflammatory response using CytoSorb can reduce pre-explantation organ dysfunction and thereby improve organ recovery. Our specific goals (with outcome measures) are: 1. to reduce circulating cytokine levels in potential organ donors (IL-6 levels), 2. to improve organ function in those donors (reversal of shock) and, 3. to increase organ recovery per donor (number of organs recovered per donor).

Intensive vs. Conventional Renal Support in Acute Renal Failure

Funding Agency: VA Connecticut Healthcare System
Total Project Period: Nov 01, 2003 - Oct 31, 2007
Principal Investigator: John Kellum, Jr, MD

Blood Purification in Experimental Sepsis

Funding Agency: Renaltech International, LLC
Total Project Period: Sep 01, 2001 - Aug 31, 2004
Principal Investigator: John Kellum, Jr, MD

Project Summary:
This investigation tests two closely related general hypotheses: 1) That hemo-adsorption will reduce the inflammatory cytokine response and improve survival time compared to sham-treatment in experimental sepsis. 2) That hemoadsorption will reverse sepsis-induced immuno-paralysis. We will test both hypotheses using established animal models of sepsis (IV endotoxin injection and cecal-ligation and puncture in the rat) and using an established cell culture line (mouose macrophage-like rAW 2647 cells). The results of this investigation will significantly improve our understanding of the effects of hemoadsorption on immuno-paralysis and on survival from sepsis. These results may, by themselves, strengthen the clinical rationale for the use of hemo-adsorption in the treatment of severe sepsis, a condition inflicting more than 450,000 Americans every year. These studies will serve as an important platform for future investigation and as benchmarks against which other devices and sorbents can be measured.

A Phase Iib Study to Determine the Efficacy and Safety of LY315920 in Patients w/Severe Sepsis

Funding Agency: PPD Development
Total Project Period: Jan 01, 2002 - Feb 28, 2003
Principal Investigator: John Kellum, Jr, MD

Project Summary:
A Phase Iib Study to Determine the Efficacy and Safety of LY315920 in Patients with Severe Sepsis (J4A-MC-EZZI, 5/14/01), (Amendment (a), 8/15/01), (CTP3 JK-01-001) The objective of this study is to compare the efficacy of this drug in comparison with placebo in the treatment of patients with sepsis and prevention of organ damage associated with sepsis. The other objectives are to reduce mortality, assess if it has an acceptable safety profile, evaluate the effects of LY315920 on intensive care unit (ICU)-free days, ventilator-free days, hospital-free days, and organ failure-free days during the 28 days study period.

Phase 3 Study to Determine the Safety and Efficacy of Recombinant Platelet-Activating Factor Acetylhdrolase

Funding Agency: ICOS
Total Project Period: Jul 20, 2001 - Jan 31, 2004
Principal Investigator: John Kellum, Jr, MD

Project Summary:
A Phase 3 Study to Determine the Safety and Efficacy of Recombinant Platelet-Activating Factor Acetythydrolase (rPAF-AH, Pafase) for Reducing 28 Day All Cause Mortality in Patients with Severe Sepsis.

Cytosorb Clinical Project Development

Funding Agency: Renaltech International, LLC
Total Project Period: Jan 01, 2004 - Dec 31, 2004
Principal Investigator: John Kellum, Jr, MD

Project Summary:
We propose to develop a clinical study plan that will address the following: feasibility, cost sample size, patient types and study endpoints. The focus of these studies will be on safety and feasibility. PHase I Clinical trial development will be carried out in conjuction with the sepsis advisory board and the research teams at the University of Pittsburgh and RenalTech International. This proposal covers the design of Phase I Clinical Trials; conduct and management of these trials is beyond the scope of the current project.

Xigris Evaluation In the United States

Funding Agency: Eli Lilly & Co. Inc.
Total Project Period: Sep 08, 2003 - Mar 31, 2004
Principal Investigator: John Kellum, Jr, MD

Project Summary:
"Xigris Evaluation in the United States" This study is an observational study for subjects who are receiving Xigris as their standard of care to evaluate outcomes and potential adverse events.

Adenosine and Traumatic Brain Injury

Funding Agency: NIH/Neurological Institute
Total Project Period: Aug 01, 1999 - Jul 31, 2008
Principal Investigator: Patrick Kochanek, MD
Co-Investigator(s): C Edward Dixon, Larry Jenkins, Edwin Jackson, Stephen Wisniewski, Xaiopeng Zhang

Project Summary:
Adenosine is a purine nucleotide that acts as a powerful endogenous neuroprotectant during ischemia-induced energy failure by decreasing neuronal metabolism and increasing cerebral blood flow (CBF), among other mechanisms. Two strategies to achieve this are particularly relevant to TBI and this application, namely, 1) the inhibition of adenosine metabolism or 2) the local administration of adenosine analogs. Defining four specific aims, we will use an

established rat model of TBI and applying cerebral microdialysis, contemporary MRI tools, functional outcome testing, and histology, we will first determine the magnitude of the adenosine response (brain interstitial levels of adenosine and purine degradation products) to experimental TBI.

We will then examine effects of augmenting adenosine effects both on key mechanisms of secondary damage and both functional and histopathological outcome. Finally, we will bridge bench to bedside by using cerebral micro dialysis methods to define the participation of adenosine after severe TBI in

humans. If successful, these studies will set the stage for a clinical trial, and provide important mechanistic information on the role of adenosine after TBI in humans.

Molecular Mechanisms of TBI: Bench to Bedside-Core C-Animal Modeling and Outcome

Funding Agency: NIH/Neurological Institute
Total Project Period: May 11, 2000 - Feb 28, 2005
Principal Investigator: Patrick Kochanek, MD
Co-Investigator(s): C. Edward Dixon

Project Summary:
In this Core we will provide rat and mouse Traumatic Brain Injury modeling (Controlled Cortical Impact model) functional outcome assessment (motor and Morris water maze test) to projects 1-5 in the University of Pittsburgh Brain Trauma Research Center program project grant application.

Training in Pediatric Neurointensive Care and Resuscitation Research

Funding Agency: NIH Nat Inst Child Health Human Dev
Total Project Period: Sep 25, 2000 - Apr 30, 2005
Principal Investigator: Patrick Kochanek, MD
Co-Investigator(s): Peter Safar, P.David Adelson, Timothy Carlos, Patricia Crumrine, Steven DeKosky, C.Edward Dixon, Heidi Feldman, Steven H. Graham, Chen Ho, Gregg Homanics, Edwin Jackson, Larry Jenkins, P Lee, P Levitt, Donald Marion, B. Pitt, I. Reynolds, E. Ricci, N. Schor, R. Simon, Ann Thompson, S. Watkins, S. Wisniewski, H. Yonas, Y. Xu

Project Summary:
This postdoctoral program will train pediatric critical care medicine,

neurological surgery and neurology fellows in basic and clinical research focused on neurointensive care and cerebral resuscitation, thus establishing an important link between bedside neurointensive care providers and senior scientific investigators. The research focus of the trainees is on mechanisms of secondary damage after two insults germane to pediatric neurointensive care, namely, TBI and CA. The training program capitalizes on the unique interaction that has developed between the CCM, neurosurgical, and child neurology training programs at Children's Hospital of Pittsburgh and the Safar Center for

Molecular Mechanisms in TBI: Bench to Bedside Project 3 INOS and TBI

Funding Agency: NIH/Neurological Institute
Total Project Period: May 11, 2000 - Feb 28, 2005
Principal Investigator: Patrick Kochanek, MD
Co-Investigator(s): Timothy Carlos, Hong Yan, Valerian Kagen, Simon Watkins

Project Summary:
Inducible nitric oxide synthase (iNOS) is a NOS isoform that was initially speculated to play an important role in traumatic brain injury (TBI). The hypothesis of this proposal is that iNOS is expressed after TBI and is a powerful endogenous neuroprotectant.

Improving the Diagnosis and Prognosis of Inflicted Head Trauma in Infants

Funding Agency: Center For Disease Control
Total Project Period: Jul 01, 2003 - Aug 31, 2004
Principal Investigator: Patrick Kochanek, MD

Project Summary:
Inflicted Traumatic Brain Injury (iTBI) is a leading cause of serious TBI in infants and young children. Diagnosing iTBI is difficult, and misdiagnosis is common yet there are no established diagnostic adjuncts to help physicians properly identify iTBI. We have developed an international reputation for the study of biochemical markers in both non-inflicted (n)TBI and iTBI. In light of the exciting potential for this approach to lead ultimately to a clinical breakthrough, we propose a case-control study evaluating the utility of novel biochemical markers in the serum of infants at risk for iTBI as the centerpiece of a collaborative project by our group. We will determine whether biochemical markers can serve as diagnostic adjuncts in a high-risk target population to identify potential infant victims of iTBI.

Novel Resuscitability From Lethal Hemorrhage Suspended Animation for Delayed Resuscitability

Funding Agency: United States Army
Total Project Period: Sep 15, 1998 - Sep 14, 2003
Principal Investigator: Peter Safar, MD
Co-Investigator(s): Patrick Kochanek, Samuel Tisherman, Ala Nozari, Xianren Wu, S. William Stezoski, Larry Jenkins, Edwin Jackson, C. Edward Dixon, Joseph Carcillo, Franklin Bontempo, Edwin C. Klein, Ann Radovsky, Robert Garman, A. Hale, Miro Klain, Valerian Kagan, Sheryl Kelsey, John Gorcsan, D. Triuizi, R. Wagner, Andrew Peitzman, Paul Paris

Project Summary:
To maximize resuscitability in dogs from traumatic Exs CA of 60 min to CA of 120 min no-flow. Study II: To help increase feasibility of SA induction in the field by tests in dogs. Study III: To start exploring the limits of resuscitability during prolonged clinical death in rats in a systematic basic science plot project to identify chemical markers and histologic markers of cell death during CA without reperfusion, by focusing on mitochondria in brain and other vital organs under various temperatures.

Textbook on Resuscitation Medicine in the 20th Century

Funding Agency: Laerdal Foundation
Total Project Period: Jan 1, 1997 – Dec 31, 2007
Principal Investigator: Peter Safar/Patrick Kochanek

Project Summary:
To create a textbook on resuscitation medicine.

Ultrapotent PARS Inhibitor for CBS Trauma

Funding Agency: INOTEK CORPORATION
Total Project Period: Sep 15, 2002 - Sep 14, 2003
Principal Investigator: Patrick Kochanek, MD
Co-Investigator(s): Larry Jenkins, MD

Project Summary:
Cellular energy failure is a key contributor to cell death seen after traumatic brain injury. Recent studies using cell cultures and in vivo experimental models suggest that a key participant in cellular energy failure is the abundant nuclear enzyme poly (ADP-ribose) synthetase (PARS). Recently, novel and potent PARS inhibitors have been developed that are likely to reduce cellular energy failure and cell death, thus impacting outcome after traumatic brain injury. The aims of this project are to test promising PARS inhibitors using an experimental model of traumatic brain injury, using a long-term and stringent battery of histological and functional outcome tests. Pharmacologic inhibition of PARS may prove to be a powerful means of reducing energy failure, cell death, and neuropathologic sequelae after traumatic brain injury.

Phase 2 Evaluation of the VitaGen Extracorporeal Liver Assist Device System

Funding Agency: Vital Sci, Inc.
Total Project Period: Jan 14, 2002 - Dec 31, 2006
Principal Investigator: Peter Linden, MD

Project Summary:
Phase 2 Evaluation of the VitaGen Extracorporeal Liver Assist Device (ELAD) System in the Management of Patients with Pulminant Hepatic Failure (CR-202, 11/30/00; Amendment II, 8/22/01) and Post Surveillance Protocol to Evaluate the Long-Term Safety of the VitaGen Extracorporeal Liver Assist Device (ELAD) System in Patients Previously Enrolled in VitaGen Protocol Number CR-202 (CR-203, 8/22/01)

Linezolid vs. Vancomycin/Oxacillin/Dicloxacillin in treatment of catheter

Funding Agency: Pharmacia
Total Project Period: Sep 11, 2002 - Dec 31, 2002
Principal Investigator: Peter Linden, MD

A Randomized Double Blind Double Dummy Phase II Comp Study of Cidecin

Funding Agency: Cubist Pharmaceutical, Inc.
Total Project Period: Jul 25, 2001 - Dec 31, 2002
Principal Investigator: Peter Linden, MD

Project Summary:
Protocol # DAP-VRE-00-07

IND #57693

A Phase I/II, Double Blind, Randomized, Placebo Controlled Clinical Study of NOX 100 Treatment of Distributive Shock Due to Sepsis.

Funding Agency: Medinox, Inc.
Total Project Period: Sep 15, 2001 - Jan 31, 2004
Principal Investigator: Peter Linden, MD

Project Summary:
A Phase I/II, Double-Blind, Randomized, Placebo-Controlled, Clinical Study of Nox-100 for the Treatment of Distributive Shock Due to Sepsis.

LY333328 Dose Finding In Subjects With S. Aureus Bacteremia H4QMCARRM

Funding Agency: Eli Lilly & Co. Inc.
Total Project Period: Aug 01, 2003 - Oct 30, 2003
Principal Investigator: Peter Linden, MD

Project Summary:
Protocol: H4Q-MC-ARRM

Study Entitled:

Heart-Lung Interactions & Cardiovascular Insufficiency

Funding Agency: National Institutes of Health
Total Project Period: May 01, 2002 - Apr 30, 2007
Principal Investigator: Michael Pinsky, MD

Project Summary:
This postdoctoral training program proposal is designed to train fellows, for a period of 2 or 3 years each, in basic science research relevant to cardiopulmonary and renal responses to stress. The overall research focus of the trainees is on four inter-related levels of basic science investigation: 1) cell and molecular immunobiology; 2) cellular basis of organ injury; 3) organ-system interaction; and 4) outcomes-based research. This approach underscores the essential basis of critical care medicine, requiring an integration of cell and molecular biology to organ-system monitoring, and following therapies to define their effects on socially relevant outcomes. These areas of research coincide with extramural research grants on which the faculty collaborate. The research plans are excellent vehicles for training because they ask broad questions on which precise, well-targeted individual research training efforts can be staged. The faculty reflect an experienced and dedicated group of senior academicians, and all have extramural research training support and training experience. Upon completion of the training program, the fellow will understand how to design, execute, and complete experiments to answer specific questions derived from critically ill patients. Thus, the fellow will be trained not only in advanced laboratory methodology, but also in the thought processes needed to apply future experimental problems as they relate to real life problems in critically ill patients. All trainees will take formal postgraduate courses offered by the basic science departments of the University of Pittsburgh. Some may complete coursework necessary to receive advanced degrees. Most training will take place in the laboratories of the principal trainers using a carefully thought-out version of the master-apprentice system. This training technique combines weekly meetings between the trainee and trainer as well as a one-hour research training seminar. Furthermore, formal research presentations by the trainees will be given biannually to the local research community.

Evaluation of the Hemosonic 100

Funding Agency: Arrow International
Total Project Period: Mar 01, 2002 - Aug 30, 2003
Principal Investigator: Michael Pinsky, MD

Project Summary:
This is a clinical study to evaluate the efficacy of the Arrow Hemosonic 100 to determine beat-to-beat stroke volume.

Experimental Therapeutics in Critical Illness

Funding Agency: National Institutes of Health
Total Project Period: Sep 01, 2002 - Aug 31, 2007
Principal Investigator: Michael Pinsky, MD
Co-Investigator(s): Arthur M Feldman, MD, John Gorcsan, III, MD, Edwin K Jackson, PhD, Candace S Johnson, PhD, John P Johnson, MD; Judith R Lave, PhD; Bruce R Pitt, PhD; Theresa L Whiteside, MD PhD; Mark L Zidel, MD

Project Summary:
The goal of this proposal is to provide post-doctoral fellows (Trainees) with research training in the basic sciences relevant to unsolved problems in the treatment of various cardiopulmonary insufficiency states. The primary goal is to train clinicians to redefine clinical problems in terms of essential biological questions that can be answered through laboratory investigation. In general, however, such questions are so complex that even sophisticated approaches using immunology, molecular biology, cell biology, or biochemistry alone cannot resolve them. Time-dependent factors, organ-specific changes, and organ-organ interactions necessitate the integration of these powerful basic science molecular- and cellular-based tools with large-animal acute physiological models and clinical outcome-based studies. Significant strides forward in our understanding of the processes of cardiovascular insufficiency, multiple organ dysfunction and their response to specific therapies will require more than detailed physiological monitoring of precise animal models with specific therapies or identification of a specific regulator gene in cultured cells. Despite efforts to understand the time course and host response to cardiopulmonary insufficiency, and to improve knowledge of the molecular basis for many aspects of diseases, we still have little tangible evidence of benefit in terms of the quality or length of patients' lives. A basic science approach alone is insufficient to address the complexity that continues upward through macroscopic interactions. Integration of various levels of investigation is essential for the efficient and rational development of effective treatment strategies for the critically ill.

Metabolic Inflammatory Systems

Funding Agency: National Institutes of Health
Total Project Period: Apr 01, 2004 – Mar 31, 2008
Principal Investigator: Juan Puyana, MD
Co-Investigator(s): Michael R. Pinsky, MD; Gilles Clermont, MD; Yoram Vodovotz, PhD; Mitchell Fink, MD; Johnathan Rubin, PhD; Steven Chang, MS; John Bartels, BS.

Project Summary:
Current therapy for severe hemorrhagic trauma patients consists of hemorrhage control and volume expansion. Depending on the severity of the hemorrhage and the time lag between injury and hemostasis, some patients with hemorrhagic shock may enter into irreversible circulatory collapse, despite resuscitation. We now understand that circulatory shock, through rheological and ischemic processes, induces hemodynamic, metabolic, and hyper-acute inflammatory responses that interact in a complex fashion and may lead to the development of refractory hypotension and irreversible shock. We have demonstrated that “real-time” monitoring of pH, oxygenation, and capnometry in skeletal muscle and other organs correlates with the severity of the hemorrhagic insult. However, these measurements have not been correlated directly with the inflammatory process, nor is the contribution of acute inflammation to irreversible shock well understood. In parallel, we have developed and calibrated a mathematical model that describes the mediators of acute inflammation in hemorrhagic shock. Though informed by circulating mediators, this model expresses the physiological derangement experienced by individual organs in terms of a global, currently theoretical, tissue dysfunction equation. We hypothesize that the magnitude of tissue dysfunction associated with circulatory collapse is a reflection of a global energetic failure and ensuing acute inflammation, which we can measure and model mathematically. Irreversible shock may result from severe exsanguination of short duration, or a more subdued, continuous hemorrhage, and/or delayed or inadequate resuscitation. We propose a systematic series of experiments in mice and swine to delineate irreversible shock. These experiments will be integrated within the mathematical framework previously developed. We propose the following two Specific Aims: 1) to characterize circulatory collapse in mice, and to augment a mathematical model of post-shock inflammation to include relevant neuroendocrine, cardiovascular and tissue metabolic elements; and 2) to validate the ability of several markers of tissue hypoperfusion to inform a mathematical model of post-shock inflammation in swine, and to provide specific outcome predictions. Within the scope of these Specific Aims, we will test the therapeutic efficacy of Ringer’s Ethyl Pyruvate Solution (REPS), hypothesizing that the proven anti-inflammatory properties in moderate hemorrhagic shock will improve outcome in irreversible shock. These novel approaches to hemorrhagic shock may save lives on the battlefield by identifying high risk, high mortality victims and by aiding in assessing the severity or irreversibility of cell function in a multiple casualty scenario. On a more basic level, this research will advance the use of complex systems in biology. Our approach of mathematical modeling integrated with data in relevant animal models, and the associated data analysis, fitting, and statistics problems, will define new methodologies for systems biology research.

Clinical Centers for the Clinical Network for the Treament of Adult Respiratory Distress Syndrome

Funding Agency: National Institutes of Health
Total Project Period: Oct 31, 2000 - Oct 31, 2004
Principal Investigator: Juan Puyana, MD (Michael Donahoe, MD, Program Director)
Co-Investigator(s): Mitchell P. Fink, MD

Project Summary:
The close correlation between the output of the mathematical model of inflammation and animal data suggests that a common metabolic and inflammatory response underlies diverse shock states, raising the possibility of modeling the inflammatory process in vivo. In contrast, circulatory collapse involves the inflammatory processes we have modeled, but also neuro-endocrine and cardiovascular derangements not currently in our mathematical model. The literature suggests two main paradigms of cardiovascular collapse: severe hemorrhage of short duration (approximately 1-2 hours), and a more subdued, continuous hemorrhage lasting 4-8 hours.{Peitzman, Billiar, et al. 1995 113 /id} This proposal will address both of these paradigms, in a systematic fashion in mice under Specific Aim 1 and in a more focused, therapeutically relevant fashion in swine under Specific Aim 2. Our studies show that we can, on the one hand, use a mathematical model informed by inflammatory parameters to predict dysfunction, and, on the other hand, measure dysfunction non-invasively in terms of clinically relevant parameters but without clear correlation with underlying inflammation. We hypothesize that inflammation is a crucial component of circulatory collapse. We further hypothesize that our current mathematical model, augmented to include relevant neuroendocrine, cardiovascular, and metabolic components, can predict the point at which this collapse is irreversible.

Schizophrenia Patient and Family Continuity of Care

Funding Agency: National Institutes of Health
Total Project Period: Sep 01, 2001 - Aug 31, 2004
Principal Investigator: Armando Rotondi, PhD
Co-Investigator(s): Rohan Ganguli, M.D.; Matcheri Keshevan, M.D.; Carol Anderson, Ph.D.; William Gardner, M.D.; Michael Spring, Ph.D.; Gretchen Haas, Ph.D.; Christina Newhill, Ph.D.

Project Summary:
One of every 100 people has schizophrenia statistic consistent from region to region, and country to country. In the US, more than two million adults are affected by schizophrenia in any given year, and up to 100,000 are in public mental health hospitals on any given day.1-2 Those with schizophrenia usually require medication for management, and though paramount, this is only one component of optimal treatment.2-4 The common issue of lack of adherence with medications dictates that treatment programs include outreach, preferably with family involvement, otherwise medications regardless of their effectiveness, are often not taken. The Patient Outcomes Research Team (PORT) study of schizophrenia concluded that medical treatment needs to be embedded in a comprehensive psychosocial, rehabilitative, and family treatment program.2,4,5

Relatives who care for a family member with schizophrenia are often under great stress, face a heavy emotional burden, and are at increased risk for both physical and psychological illnesses.6-7 Approximately 75% of these family members report feeling chronically overloaded and strained.8-10 The evidence indicates that these caregivers may feel helpless in dealing with, and adjusting to the illness.11 In order to reduce family distress, and improve patient outcomes, it is important that family members learn about schizophrenia, ways to minimize the chance of relapse, coping strategies to minimize crises, problem-solving skills to solve day-to-day problems, and effective ways to promote social functioning of the patient. Programs that provide this type of family psychoeducation have shown significant improvements in patient and family outcomes.12,13 Unfortunately, the long-term effectiveness and availability of these programs varies widely.

The overall goal of this project is to assess the feasibility of using the World Wide Web (Web) and in-home computers to provide patients with schizophrenia and their families a comprehensive psychoeducational program. This will include guidance from mental health professionals, social support, information, and easy access to professional expertise. The purposes of this intervention are to improve: 1) the availability, convenience, and use of needed mental health services; 2) family support for their ill family member; 3) patient adherence to treatment, and; 4) patient and family outcomes.

Families in the intervention group will participate in an initial 4-hour Psychoeducational Survival Skills Workshop (PSSW) and will then be provided with continuing mental health support services via our website. The website will contain six modules: 1) a library of reading materials to reinforce the PSSW; 2) a combined patient and family member, multi-family support group, which is facilitated by a mental health professional; 3) a support group for the patients with schizophrenia that is facilitated by a mental health professional; 4) an ability to e-mail questions to our group of experts and receive answers within 24 hours; 5) a question and answer library of the previously asked and answered questions, and; 6) a library of community resources.

A working prototype of the Web intervention, with initial feasibility data on user acceptance and utilization, and data to estimate the size of the interventions effects on patient and family outcomes, will be essential to further evaluate this approach, and develop a full-scale clinical trial of this intervention. This proposal has the following specific aims.

Specific Aim 1. To obtain effect size estimates, using a randomized treatment and control group design, of the influence of the intervention on the primary family caregivers. psychological distress, and knowledge of schizophrenia.

Specific Aim 2. To obtain an estimate of the size of the interventions effect on patient relapse rate.

Specific Aim 3. To evaluate patient and family reactions to the Web intervention, including, satisfaction, utilization, perceptions of the ease of use and the value of the intervention, both overall, and for each module.

Improving access to service for individuals with TBI

Funding Agency: Commonwealth of PA
Total Project Period: Jun 28, 2001 - Mar 31, 2003
Principal Investigator: Armando Rotondi, PhD
Co-Investigator(s): William Gardner, M.D.

Project Summary:
Those who have suffered a traumatic brain injury (TBI) may experience long-term loss of function, and their rehabilitation after returning home may last from several years to a lifetime. During this period, family caregivers play a vital role, often at great personal cost. Yet historically, most resources have been directed at in-patient care, where the greatest initial gains will occur. Far fewer programs and resources have been directed either at meeting family needs while the member with a TBI is receiving in-patient care, or meeting the needs of patients and family caregivers once patients return home, and face the challenges of continuing health care needs, and rebuilding their lives.

To identify where interventions and new initiatives should be undertaken, the needs and barriers faced by those with a TBI and their families must be understood. This project will perform a comprehensive needs assessment. The needs assessment will employ focus groups and individual interviews, to systematically identify and prioritize unmet needs, barriers, and issues, primarily from the perspectives of patients and families, but also from the perspectives of health care providers, insurers, and employers.

TBI Model Systems-Joystick

Funding Agency: National Institute on Disability & Rehabilitation Research
Total Project Period: Dec 01, 2002 - Nov 30, 2007
Principal Investigator: Armando Rotondi, PhD
Co-Investigator(s): Rohan Ganguli, MD; M. Keshevanm MD; Richard Schulz, PhD; Carol Anderson, PhD; Stephen Wisniewski, PhD; Michael Spring, PhD.

Project Summary:
The overall goal of this project is to assess the feasibility of using the World Wide Web (Web) to help provide patients suffering from schizophrenia, and their families, with a comprehensive, long-term psychoeducation program which includes education, social support, information and guidance from mental health, social services and medical professionals. This intervention is aimed at facilitating rehabilitation of patients with schizophrenia, and improving the well being of their families.

A Test of Two Online Interventions for Child Brain Injury

Funding Agency: Cincinnati Children's Medical Center (National Institues of Health)
Total Project Period: Sep 30, 2003 – Aug 31, 2009
Principal Investigator: Armando Rotondi, PhD
Co-Investigator(s): Susan Beers, PhD; Christina Newhill, PhD, David Adelson, MD

Project Summary:
Moderate to severe traumatic brain injury (TBI) in children is a significant family stressor resulting in increased caregiver burden, impaired psychological adjustment among caregivers, and deteriorating family functioning. Empirically based interventions to address family needs following TBI are limited, and access to skilled therapists can be restricted by distance and finances. The current project seeks to address these needs by testing the efficacy of two contrasting models of online intervention for families of children with moderate to severe TBI: individualized online Family Problem Solving Therapy (FPS) and online Case Management and Multi-Family support group (CM). Although both treatments have the goal of reducing caregiver stress and burden, they differ with respect to their primary targets (FPS-cognitive appraisals and problem solving; CM – information and support), the intensity of therapeutic contact, and the cost of implementation. We propose to examine the efficacy of these two online treatments in a randomized trial comparing the effects of FPS and CM to standard care (SC). Primary outcomes include: 1) problem-solving skills; 2) injury-related stress and burden; 3) caregiver depression and anxiety; and 4) parenting stress. Participants will include the families of children, aged 5 - 16, who have experienced a moderate to severe TBI between 1 and 12 months prior to study participation. Families will be randomly assigned to one of three conditions: FPS, CM, or SC. Group differences will be examined using a multivariate approach to analysis of covariance, controlling for injury severity, child’s age, sociodemographic status, and time since injury. We hypothesize less injury-related stress, lower levels of anxiety and depression, and less parenting stress in the two intervention groups compared to the standard care group. We further hypothesize that FPS will be associated with better outcomes relative to CM in families with high levels of child-related stress and family dysfunction at baseline. Our overarching goal is to identify effective treatments for reducing psychological distress in caregivers, thereby enabling the family to optimally support the child's recovery from TBI.

A systems approach for improving region wide patient safety

Funding Agency: National Institutes of Health
Total Project Period: Sep 26, 2001 - Aug 31, 2004
Principal Investigator: Carl Sirio, MD
Co-Investigator(s): Janice Pringle, Ph.D.; Robert Weber, Ph.D.; Carlene Muto, M.D.; Levent Kirschi; Ph.D.; Edward Harrison, M.B.A.; Donna Keyser, Ph.D.; Shan Cretin, Ph.D.; Denise Rousseau, Ph.D.; Ranga Ramanujam, Ph.D.; Susan Skledar, Ph.D.

Project Summary:
Preventable adverse events, including nosocomial infections (NI) and medication errors (ME), are among the nations most pervasive patient safety problems. Establishing effective reporting systems capable of compiling credible data is a necessary but insufficient condition for creating the capacity for sustainable change. In 1997, the Pittsburgh Regional Healthcare Initiative (PRHI) was created, a collaboration of leaders from all major healthcare stakeholder groups in a 6 county metro region representing diverse patient populations. PRHI goals include achieving the world’s best patient outcomes by identifying and solving problems at the point of patient care including the elimination of NIs and MEs. Under PRHI, the regions 30 hospitals have instituted a close collaboration with the US Pharmacopeia (USP) and the Centers for Disease Control (CDC) to implement MedMARxO and components of the National Nosocomial Infection Surveillance System (NNIS). All healthcare facilities participating in this research demonstration have agreed to share their data locally, thus providing an important opportunity for cross-organizational comparisons. Based on shared analysis of regional outcomes data, prevention strategies and interventions are being developed for both nosocomial infections and medication errors. These will be implemented through a variety of mechanisms including PRHIs existing Center for Shared Learning. Error reduction in organizations involves exploration and evaluation of multiple interrelated systems. Using multiple metrics described herein we have three sets of study aims: 1) To understand how well the Reporting Systems associated with NIs and MEs succeed in creating usable information. 2) To understand how well the Feedback Review Systems function. 3) To understand the Problem-Solving Systems through which knowledge is translated into organizational learning. Taken together, these systems inform and shape the conventional learning model: Data = Information = Knowledge = Learning. In order to accomplish this evaluation, we will establish and operate an investigative Data Coordinating Center. Our assessment of this unique collaboration may provide a generalizable model for regional, systems based approaches to patient safety.

Improving Outcomes in Mechanically Ventilated Patients

Funding Agency: National Institutes of Health
Total Project Period: Jan 01, 2001 - Dec 31, 2003
Principal Investigator: Carl Sirio, MD
Co-Investigator(s): Leslie A. Hoffman, R.N., Ph.D.; John Clochesy, R.N., Ph.D.; Michael P. Donahoe, M.D.

Project Summary:
The provision of critical care has changed markedly since its inception. Intensive care units (ICU's)developed to provide highly skilled care for critically ill patients during a brief illness, now also provide care for a substantial number of patients who survived their initial illness but require extended support due to their dependence on mechanical ventilation(MV). The primary aim of this study is to test an intervention (ACNP-managed care) designed to improve outcomes in patients who require extended MV support. The secondary aim is to identify factors which promote weaning progression and weaning success in this population.

Evaluation Outcomes/Treatment Patterns & Cost of Care w/AMI Using Statewide Database

Funding Agency: American Heart Association
Total Project Period: Jul 01, 2000 - Jun 30, 2003
Principal Investigator: Carl Sirio, MD
Co-Investigator(s): Judith Lave, Ph.D; Steven Wisniewski, Ph.D.

Project Summary:
The proposed evaluation is designed to investigate longitudinal outcomes associated with the care of patients suffering from acute myocardial infarction (AMI) in the state of Pennsylvania. We plan to take advantage of a unique, existing data source containing 130,581 admissions created by the Pennsylvania Health Care Cost Containment Council (PHC4) for all patients admitted in the state to an acute care hospital with AMI during calendar years 1993, 1995 and 1997. This data source contains detailed clinical and administrative information on all included patients. To our knowledge no similar rich, population based resource for patients sustaining AMI is available. It was designed, with limited exception, to represent all AMI admissions within the state for each of the 3 twelve month periods, providing the ability to assess longitudinal changes in care over time. PHC4 is the state agency responsible for public reporting of health care outcomes in the Commonwealth.

The evaluation will consist of five focused analyses designed to address four questions with implications for health care delivery and policy development for patients with AMI. These include:

PROJECT #1. Outcomes of AMI over time.

Specific Aim #1: To determine how the outcomes for AMI have changed over time.

PROJECT #2: Outcomes, Treatment Patterns and Costs for AMI Across Geographic Areas

Specific Aim #2: To determine whether there are differences in outcomes for patients with AMI living in different geographic locations, with different levels of access to clinical services; and to determine whether those differences were reduced over time. Our primary effort will be to focus on the differences between those who live in urban and rural areas.

PROJECT #3: The Effect of Payment Source On Costs and Outcomes of Care for Patient with AMI

Specific Aim #3: To determine whether hospital costs, processes of care and patient outcomes vary by payment type for patients sustaining an AMI.

PROJECT #4: Evaluating the Impact of Inter-hospital Transfers on Outcome in AMI

Specific Aim #: To determine differences in rates and timing of inter-hospital transfer across institutions in order to determine the impact these disparities have on length of stay, resource utilization and mortality outcome for patients with AMI.

PROJECT #5: Evaluating the Impact of Age and Gender on Care and Outcome for Patients with AMI

Effecting Change in chronic Care: The Tipping Point

Funding Agency: American Medical Association (AHRQ)
Total Project Period: Oct 1, 2002 – Sep 30, 2006
Principal Investigator: Carl Sirio, MD
Co-Investigator(s): Karen Kemetik, PhD (Program Director); Mark Antman (AMA)

Project Summary:
Chronic conditions have become the leading cause of illness, disability, and death in the United States, affect almost half of the U.S. population, and account for the majority of health care expenditures in this country. Despite efforts to enhance the quality of care delivered to chronically ill patients, studies continue to reveal tremendous variability in both practice and outcomes in this population. This study proposes to bring together a unique collaboration of physicians, employers, health plans, and payers from the private and public sector both regionally and nationally, to achieve a ‘tipping point’ in health care and, thereby, accelerate the rate at which improvement in the quality of care delivered in outpatients settings for a substantial portion of the chronically ill patient population in the U.S can occur. Specifically, the American Medical Association, Pittsburgh Regional Healthcare Initiative, Iowa Foundation for Medical Care, Blue Cross and Blue Shield Association, Centers for Medicare and Medicaid Services, and the Midwest Business Group on Health are cooperating in a partnership to identify the infrastructure necessary to make relevant data and clinical performance measurement tools available to physicians at the point of care for patients with diabetes, major depressive disorder, or coronary artery disease; to enable data collection, retrieval, and transfer within and across physician offices, health plans, and laboratories; to identify the perceived obstacles, burdens, as well as incentives for physicians and others who participate in efforts to improve the quality of care for patients with chronic diseases through the use of performance measurement; and to determine the feasibility of creating an integrated data registry that will enable the provision of benchmarking data to physicians and aggregate data to health plans and third party payors. The methods by which these aims will be achieved include adaptation and implementation of performance measurement sets developed by the Physician Consortium for Performance Improvement for diabetes, major depressive disorder, and coronary artery disease in a select sample of primary care physician offices in two regions of the U.S.; on-site identification of data capabilities for physicians, health plans, and laboratories participating in the study; and evaluation of physician, plan, laboratory, and employer experience with measurement tools and data collection and delivery processes.

Consequences of surviving critical illness in childhood

Funding Agency: National Institutes of Health
Total Project Period: Jun 8, 2004 – Mar 31, 2009
Principal Investigator: R. Scott Watson, MD
Co-Investigator(s): Derek Angus, MD (Mentor)

Project Summary:
The purpose of this project is to provide Dr. Scott Watson with the means and structure to transition to an independent investigator. His long-term career goal is to optimize the long-term, multi-dimensional patient- and family-centered outcomes of critical illness in childhood. This career award application contains a well-defined curriculum in psychometric, quantitative, and clinical research methods, has the institutional support of the Department of Critical Care Medicine, and has the commitment of an experiences, successful mentor, Dr. Derek C. Angus. The candidate will study long-term outcomes of an inception cohort of critically ill children at the Children’s Hospital of Pittsburgh.

A quarter million children aged 1 to 19 years receive care in an intensive care unit (ICU) in the US each year. Although most survive, the survivors are at risk of impairment in multiple domains. The need for additional research evaluating long-term outcomes and functional status after critical illness in children was highlighted at a recent NIH-sponsored conference.

The goals of the research portion of this proposal are to determine the incidence and extent of patient morbidity, the impact of illness on families, and risk factors for adverse sequelae following critical illness in children. The candidate will build a stratified prospective cohort of 300 previously healthy children who survive critical illness in the Children’s Hospital of Pittsburgh Pediatric ICU. He will perform assessments of 3 primary domains: 1) Functional status and quality of life, 2) Neuropsychologic sequelae, and 3) Family effects. Patients and their families will be evaluated in the hospital and followed for a minimum of 12 months, with evaluations 1, 6, and 12 month post-discharge and every 12 months thereafter. Teachers of school aged children will also be contacted.

Microarray Determinants of Outcome In Community Acquired Pneumonia

Funding Agency: National Institutes of Health
Total Project Period: Apr 01, 2003 - Mar 31, 2008
Principal Investigator: Kelly Wood
Co-Investigator(s): Derek Angus, MD; Mitchell Fink, MD (Co-Mentors)

Project Summary:
The research proposal, "Microarray Determinants in Community-Acquired Pneumonia (MADCAP), will focus on Community-Acquired Pneumonia (CAP) which is a major public health problem, frequently fatal in the elderly. Genetic analysis of elderly caucasian males with CAP will be performed with microarray technology in order to construct a model with additive predictive value over currently existing predictive tools and to identify genes involved in the progression of the infected state. Three subject cohorts will be analyzed: 1. a group of phenotypically similar elderly caucasian males obtained from a query of the pre-existing database of the NIH funded, "Genetic and Inflammatory Markers of Sepsis (GenIMS) study (survivors n=20; non-survivors n=20); 2. a group of normal elderly caucasian males (n=10); and 3. a prospective cohort of elderly caucasian males with pneumococcal CAP (n=40). Temporal patterns of gene expression at various time points (0, 1, and 6 hours) of both unstimulated and stimulated (with pneumoccocal vaccine) whole blood samples will be determined to evaluate if individuals who have a poor clinical outcome can be identified early in their clinical course. This proposed study will generate a new predictive tool of clinical outcome based on gene expression analysis in the narrowly defined cohort of elderly caucasian males with CAP. Information will also be generated regarding the pathophysiology of infection and possible points of early intervention with medical therapy that may alter the course of the disease process.