SCCM-Weil Research Grant Recipients

Sheila Alexander, BSN, PhD, RN, FCCM
Associate Professor of Nursing
University of Pittsburgh
Pittsburgh, Pennsylvania, USA

Topic: Temporal Inflammatory Gene Methylation Profiles and ICU Delirium

Abstract: Intensive care provides lifesaving monitoring and intervention. However, extensive literature reports intensive care unit (ICU) survivors too often experience significant deficits following discharge. Delirium, which presents in 30-80% of ICU patients, has been associated with worse outcomes in survivors and, therefore, has been a focus of intervention studies to improve ICU survivor outcomes. While important, these studies do not target the underlying mechanism that leads to delirium. The pathophysiologic underpinnings of delirium are not well understood and there are no known efficacious treatments.

This proposal focuses on increasing understanding of the complex pathophysiologic mechanisms, and specifically persistent inflammation, contributing to ICU delirium. Identifying mechanisms that contribute to ICU delirium can provide information crucial to improving the outcome profile for ICU survivors. Our preliminary data and reports in the literature have identified a prolonged inflammatory state associated with ICU delirium. Additionally, we have found select inflammatory genes may have distinct methylation patterns, indicating low level expression, related to ICU delirium early after ICU admission. We hypothesize that there is variable inflammatory gene methylation during critical illness and, in addition, distinct inflammatory gene methylation profiles characteristic to patients who develop ICU delirium. Identification of these profiles will clarify time dependent changes in inflammatory status important for brain function and recovery. The aims of this project will identify changes in select inflammatory gene methylation during the first 10 days after ICU admission, and the specific changes occurring before and during ICU delirium. This project capitalizes on the experience and expertise of a multi-disciplinary investigative team including representation from the fields of nursing, genetics, statistics and critical care medicine. 

Scott Weiss, MD, MSCE
Children’s Hospital of Philadelphia
Department of Anesthesiology and Critical Care Medicine
Philadelphia, Pennsylvania, USA

Topic: Role of the Intestinal Microbiome in Mitochondrial-Induced Immune Dysregulation in Pediatric Sepsis

Abstract: Septic shock is a dysregulated host response to infection that results in circulatory and metabolic dysfunction that often progresses to death. Recent evidence shows that the intestinal microbiome helps to regulate immune homeostasis, and that altered microbial diversity (or dysbiosis) contributes to immune dysregulation. These data provide strong biologic plausibility that intestinal dysbiosis may influence outcomes in pediatric sepsis through direct effects on the immune response. One mechanism by which the intestinal microbiome may affect immune function is through alterations in microbial-derived short chain fatty acids (SCFAs) released from the intestine into the systemic circulation. Notably, changes in SCFAs are known to impair mitochondrial respiration. We have previously demonstrated that mitochondrial respiration is decreased in immune cells in pediatric septic shock and that the resulting bioenergetic failure is associated with immunoparalysis in a rodent model. However, no clear precipitant of mitochondrial-induced immune dysregulation has been identified. To date, a potential link between intestinal dysbiosis, microbial metabolites, and mitochondrial dysfunction in circulating immune cells in sepsis has not been tested. Through a strong collaboration within the Penn-CHOP Microbiome Program, we will serially sample the intestinal microbiome and blood/stool SCFAs in pediatric sepsis to identify patterns of microbial SCFAs that are associated with depressed mitochondrial respiration in circulating immune cells (Aim 1), determine the impact of intestinal dysbiosis on changes in SCFA patterns (Aim 2), and test the association of intestinal dysbiosis with sepsis-induced immunoparalysis (Aim 3). This work will provide the key foundational data linking intestinal dysbiosis, microbial SCFAs, and mitochondrial dysfunction in circulating immune cells to guide future studies of the microbiome effect on immune function in sepsis and other critical illnesses.

Lara Nelson, MD
Children's Hospital Los Angeles
Department of Anesthesiology Critical Care
Los Angeles, California, USA
Topic: The Association between Delirium in Critically Ill Children and Long-term Cognitive Dysfunction
Abstract: This proposed research study will investigate the incidence of delirium in the pediatric intensive care unit (PICU) and the relation to long-term cognitive dysfunction. Delirium is an acute neurologic dysfunction, similar to other end-organ dysfunction seen in critical care. It is well established in the adult literature that rates of delirium are high and there are significant morbidities and mortalities associated with delirium. Additional studies have also shown an association between delirium and long-term cognitive dysfunction. Research examining delirium in children following admission to the PICU is sparse. Our central hypothesis is children with prolonged delirium during their PICU admission will have more long-term dysfunction than those with no or less delirium. We will enroll children into a prospective, longitudinal, multi-informant observational cohort study of children admitted to a large, urban, ethnically-diverse, academic PICU in Los Angeles, CA. Inclusion criteria will be children ages 5-17 years-old admitted to the PICU, English- or Spanish-speaking and with an anticipated PICU stay of >24 hours. They will be excluded if they have developmental delay or cognitive deficits, neurologic injury, severe psychiatric disorder, or inability to complete the measures in English or Spanish. Children will be assessed daily for delirium with the two available pediatric delirium screening tools. The Behavior Rating Inventory of Executive Function and Children's Memory Scale will be done while the child is in the PICU and at three-month follow up to assess for cognitive dysfunction. Current practice in the PICU does not include screening or treatment of delirium, or any anticipatory guidance for parents regarding potential long-term problems, such as poor school performance. It is imperative for pediatric critical care to catch up to our adult colleagues in our understanding and ability to treat an understudied area of end-organ dysfunction in the ICU, delirium.

Michael Kurz, MD, MS-HES
University of Alabama Medical Center
Department of Emergency Medicine
Birmingham, Alabama, USA
Topic: Coagulopathy Following Cardiac Arrest
Abstract: Background: Out-of-hospital cardiac arrest (OHCA) is a major public health problem affecting greater than 325,000 persons in the U.S. annually, of which only one in ten victims survive to hospital discharge despite widespread adoption of therapeutic hypothermia (TH). After achieving ROSC, OHCA patients experience a brief period of systemic fibrinolysis which is rapidly replaced by a prolonged hypercoagulable state causing micro-circulatory occlusion, lactate formation, and progressive multi-organ failure. The mecahnisms of these coagulation derrangements following OHCA and how they are effected by TH are poorly understood.
Goals: Describe the mechanism(s) by which TH attenuates the severity of the hypercoagulable state observed after OHCA. Specific Aim I: Describe the biological mechanisms of coagulation abnormalities associated with OHCA patients. Specific Aim II: Evaluate the impact of Therapeutic Hypothermia (TH) upon the coagulation abnormalities resulting from OHCA.
Methods: The PI proposes a single center prospective observational trial in 45 consecutive post-cardiac arrest patients where traditional (PT/PTT/INR/d-dimer/fibrinogen) and novel assays of coagulation (thromboelastography, platelet aggreometry, activated protien C, factors V, VIII, and Xa, PAI-1, thrombin-anti-thrombin complex, syndecan, heparan sulfate) will be measured at five important clinical intervals during the first three days of care to comprehensively describe the coagulapathy observed following OHCA. These data will be combined with clinical and demographic data collected in the Utstein style and analysis will focus upon relationships of injury severity (time pulseless, lactate levels, organ dysfunction) and coagulation abnormalities and how that these abnormalities are affected by TH.
Future Steps: Findings from this pilot effort will support a lager R01 application to validate these coagulation markers in a multi-center fashion.

Faheem W. Guirgis, MD
University of Florida
Department of Emergency Medicine
Jacksonville, Florida, USA
Topic: The Role of Dysfunctional HDL in Severe Sepsis
Abstract: High-density lipoprotein (HDL) has antioxidant, anti-inflammatory, and antithrombotic properties and is protective in sepsis. This project aims to determine the presence of dysfunctional HDL (Dys-HDL) in adult patients with early severe sepsis, and to  examine the relationship between Dys-HDL and cumulative organ dysfunction via the Sepsis-related Organ Failure Assessment (SOFA) score.

Krzysztof Laudanski, MD, PhD, MA
University of Pennsylvania
Department of Anesthesiology and Critical Care
Philadelphia, Pennsylvania, USA
Topic: Long-Term Decline of Acquired Immunity After Sepsis in Humanized Mice
Abstract: The objective is to determine whether sepsis induces a long-term aberration of the acquired immunity function. More specifically, we hypothesize that sepsis triggers a persistent defect in monocyte to dendritic cell differentiation (MODC) due to an aberrant, sustained a ctivation of the macrophage colony stimulation factor (M-CSF). This unrelenting M-CSF influence is caused by the abnormal activity of a PU.1-dependent mechanism. Consequently, we propose that interfering with M-CSF production or providing the autologous transplant of the naïve monocytes (never exposed to sepsis) can mitigate post-sepsis long-term aberrations in immune function. To increase clinical relevance of the study, a humanized model of cecal ligation and puncture (CLP) will be used.

Azra Bihorac, MD, MS, FCCM, FASN
University of Florida, Division of Critical Care Medicine
Department of Anesthesiology
Gainesville, Florida, USA

Critical Connections Feature
Topic: Database Communication Enables Machine Learning Classifiers to Predict Postoperative Acute Kidney Injury in Intensive Care Unit (Delcare)
Abstract: In the United States, where the average American can expect to undergo seven surgical operations during a lifetime, each year at least 150,000 patients die and 1.5 million develop a major complication after surgery. Postoperative complications (PC) not only cause a two-fold increase in ICU admission, mortality and cost, but are associated with long-term consequences. Reducing preventable complications by 20% could save thousands of lives and reduce costs by 5 billion dollars annually. Our group has demonstrated that postoperative acute kidney injury, characterized by even small increases in routinely measured serum creatinine levels, is not only one of the most common PCs but is also associated with up to a 10-fold increase in hospital mortality and decreased survival for up to 15 years after surgery. Acute kidney injury (AKI) complicates the postoperative hospital stay for up to 50% of all patients admitted to the ICU. The risk for AKI, as with any other PC, arises from the interaction between a patient's preoperative health and the physiologic capacity to withstand surgery-related stress, modulated by the type and quality of surgery. Today we do not have the ability to quantify for a given patient a "personal" risk for PC. The major obstacle to advancing the development of an automated process for "on-the-fly" risk assessment has been the lack of available technologies for real-time data integration and appropriate analytic methods. Our long-term goal is to build a collaborative research partnership between experts in computing, engineering, health informatics, medicine and patients to develop, evaluate and implement an "intelligent perioperative system" that integrates electronic medical records (EMR) data-driven, model-based computational algorithms with clinical reasoning to improve clinical decision-making in perioperative medicine.

Selina Mary Parry, B.Physio (Hons)
PhD Candidate at the University of Heidelberg, Australia
ICU Physiotherapist at Austin Health
Heidelberg, Australia
Topic: An Early Intervention to Prevent Muscle Weakness in Intensive Care: A Pilot Randomized Controlled Trial
Abstract: The goal of this project is to investigate the benefits of functional electrical stimulation in addition to in-bed cycling on muscle mass, strength, and physical function compared to standard care. This project combines both clinical and basic sciences to evaluate cellular and molecular mechanisms responsible for muscle mass and strength changes, together with measuring patient-centered outcomes.

Christopher Seymour, MD
Assistant Professor, Departments of Critical Care and Emergency Medicine
University of Pittsburgh
Pittsburgh, Pennsylvania​​, USA

Critical Connections Feature
Topic: Tiered Regionalization of Critically Ill Patients During Out-of-Hospital Care: An Impact Analysis
Abstract: Tiered regionalization of critical care may reduce variability in the quality of critical care and prevent thousands of avoidable deaths. As demonstrated among traumatically injured patients, out-of-hospital providers play a key role in early triage of high-risk patients to referral centers for definitive care. A similar approach is feasible for noninjured patients, but little data exists to support pilot studies and demonstration projects. The goal of this proposal is to determine the impact on hospitals, patients, and emergency medical services (EMS) agencies of a tiered regionalization strategy that begins with out-of-hospital triage. We will perform an advanced simulation with a unique, population-based cohort of linked EMS records and hospital discharge data. Our results will address important barriers to implementing a regionalized approach to intensive care.

Theodore Iwashyna, MD, PhD
Assistant Professor of Internal Medicine
University of Michigan Health System
Ann Arbor, Michigan, USA
Topic: The Contribution of Functional Decline in Long-Term Costs of Severe Sepsis
Abstract: This proposed work will inform practice, research, and policy in important ways. Understanding long-term outcomes after severe sepsis is essential to allowing patients and families to make informed choices about their care in the ICU. Understanding the long-term consequences of severe sepsis may provide new and rich targets for emerging therapies, much as research on functional status after acute respiratory distress syndrome has done.

Scott Halpern, MD, PhD
Assistant Professor of Medicine & Epidemiology
University of Pennsylvania School of Medicine
Division of Pulmonary & Critical Care Medicine
Philadelphia, Pennsylvania​, USA

Critical Connections Feature
Topic: Effects of ICU Census on Rationing and Patient Survival
Abstract: As the U.S. population ages and the output of critical care physicians and nurses plateaus, the demand for critical care is increasingly outpacing its supply. Intensivists face pressures to ration ICU services, and the time they have available to spend on each patient may be decreasing. This research explores how the increased demand for critical care may influence the withholding of potentially beneficial services and the survival of ICU patients. We will use the more than 150,000 patients admitted to 123 ICUs included in the Project IMPACT database to determine whether demand for critical care (as represented by ICU census) is associated with patients' probabilities of receiving potentially beneficial services or with their survival. We will also determine whether changes in survival are mediated by the withholding of examined services. The results will help increase public acceptance of rationing and will inform considerations of the optimal organization of critical care delivery.

Jeremy Kahn, MD, MSc
Instructor of Medicine
University of Pittsburgh
Philadelphia, Pennsylvania​, USA
Topic: Attitudes Toward Regionalization of Adult Critical Care
Abstract: Regionalization of critical care has been proposed as a strategy to expand access to high-quality critical care. No information about the perceptions of regionalization among national care providers currently exists. The goal of this project is to survey critical care practitioners and other stakeholders regarding their attitudes toward critical care regionalization. A validated survey instrument will be administered to critical care physicians, non-critical care physicians, ICU directors, and ICU nurse managers. The survey will uncover the important potential barriers to researching, designing, and implementing a regionalized system of intensive care.

B. Robert Gibson, MD
Johns Hopkins Bayview Medical Center
Department of Surgery
Baltimore, Maryland, USA
Topic: The Efficacy of GLP-1 (7-36) Amide for Glycemic Control in Critically Ill Surgical Patients
Abstract: This study will examine reduction or diminution in amount of insulin infusion required to maintain normal glycemic levels (80-110 mg/dL) in patients who are in the surgical ICU when treated with the naturally occurring insulinotropic hormone glucagon-like-peptide (GLP-1). Additionally, we hypothesize that the number of hypoglycemic events will be totally eliminated or substantially reduced with GLP-1 administration.