SCCM-Weil Research Grant Recipients

Topic: Racialization of ICU Notes and Debiasing Strategies to Lead to Fairer ICU Mortality Prediction

Abstract: Biased data lead to unfair and inequitable algorithms. Artificial intelligence (AI) models in non-medical domains have shown definitive examples of bias, prejudice, and direct consumer harm. Specifically, AI algorithms using natural language processing (NLP) or the quantitative study and classification of language, have also shown bias and prejudicial outputs, such as associating certain occupations with particular genders and associating certain races with stigmatizing words. However, examples of bias in NLP have not been well-studied in healthcare. This is particularly important given the rapid adoption of NLP for clinical outcome prediction. Hence, there is real risk of transmission of disparities, perpetuation of inequities and even possible patient harm if bias in NLP algorithms remains unaddressed.

Here, we seek to understand how text encodes intrinsic race and ethnicity information that if fed unaltered into AI models could lead to unfair and biased algorithms. As a first step to ensure that NLP use in healthcare does not worsen or reinforce existing disparities, the proposed research will focus on whether explicit (e.g. “Black”) and implicit aspects (e.g. “Spanish-speaking”) of notes are predictive of social constructs – specifically race and ethnicity.  Implicit descriptors may also represent how words are contextually related to one another and still encode for race or ethnicity patterns. By recognizing how written language encodes for social constructs and could be racialized, we seek to demonstrate that clinical notes are not immune to human biases and that structural racism exists in language itself. To ensure that NLP-based clinical prediction tools do not contribute to a racist healthcare structure, we seek to identify structurally racist and racialized elements, eliminate them and then construct mortality prediction models. We will determine to what extent mortality predictive performance is affected by debiasing notes. This will directly inform ways we can intervene on the note writing process, use NLP-based tools to promote antiracism in notes and construct fair and equitable note-based algorithms for risk prediction in the ICU.

Topic: Unraveling long COVID pathophysiology: insights from ICU perspectives

Abstract: The COVID-19 pandemic has impacted intensive care medicine significantly and a substantial part of patients develop long COVID syndrome after initial SARS-CoV-2 infection. Symptoms include dyspnea, fatigue and post exertional malaise and can be severely invalidating. Understanding the pathophysiology and long-term effects of long COVID syndrome is crucial for developing targeted treatments which are lacking now. Here we hypothesize a key role for disturbances in microcirculatory function and tissue oxygenation. We investigate how this is caused by an interplay between inflammation, endothelial dysfunction and microvascular dysfunction. This comparative, non-randomized, observational study will include 25 patients who have been admitted to the ICU with COVID-19 and now have long COVID syndrome, from a large cohort at our post-COVID outpatient clinic.  The control group will consist of patients who have been admitted to the ICU with COVID-19, but do not have symptoms of long COVID syndrome. For this study sublingual microcirculatory function and tissue oxygenation measurements will be performed with handheld vital microscopy sublingually before and after exercise. With the same method we are able to visualize leukocyte rolling and adhesion to the blood vessels, to study persistent inflammation. In addition, blood samples will be taken to determine markers of endothelial activation and finally questionnaires will be taken to characterize clinical symptoms. Unraveling the pathophysiology of long COVID from this systemic perspective will provide valuable insights for targeted treatments, which are urgently needed considering the large burden long COVID syndrome has on society.

Topic: Developing a Treatment for Delayed Cerebral Injury After Aneurysmal Subarachnoid Hemorrhage

Abstract: Delayed cerebral injury (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (SAH) that results from a ruptured aneurysm in the cerebrospinal fluid (CSF) space of the brain. DCI leads to long-standing cognitive and memory deficits in patients. Because it occurs 4 to 14 days after the aneurysm ruptures, it is potentially reversible. Our laboratory and others have shown that DCI is the result of inflammation that begins in the coverings of the brain (the meninges) and is directed by an inflammatory cell called a neutrophil. We have found that a neutrophil enzyme, myeloperoxidase (MPO), is critical for the development of DCI. In this proposal, we ask two important questions that will make it possible to develop therapeutic interventions against DCI. First, if the neutrophils accumulate in the meninges, how do they signal brain cells to become inflamed? Our laboratory has found evidence that the cells of one layer of the meninges, the meningothelial cell, may be an important conduit for inflammatory information to the brain. In this proposal, we will investigate how MPO interacts with meningothelial cells through a series of cell culture experiments. Second, can a specific MPO blocker improve DCI in a mouse model of SAH? We will test two MPO blockers by administering them in the CSF space (where the meningothelial cells reside) to attempt to improve the behavioral deficits of the disease. With these two experiments, we will better understand how MPO sends signals from the meninges to the brain and whether administration of MPO blockers into the CSF space is a potential therapeutic intervention for preventing or ameliorating DCI.

Topic: Metabolic Crosstalk in Acute Lung Injury Between Alveolar Macrophages and Epithelium

Abstract: Uncontrolled inflammation is a hallmark of acute lung injury (ALI). Alveolar type II (ATII) cells are key players in ALI. Alveolar macrophages (AMs) are critical to the pathogenesis of ALI, in which local microenvironmental cues shape their inflammatory properties, which can be fluent and amenable to manipulation. The mechanisms of how metabolic intermediates (e.g., lactate, the end product of glycolysis) can affect AM phenotypes are unknown in the setting of ALI. This proposal aims to delineate how lactate produced by alveolar epithelial type II cells is protective in ALI by shifting the AM toward an antiinflammatory phenotype. An innate protective mechanism in ALI involves enhanced glycolysis in ATII cells via induction of phosphofructokinase-2/fructose-2,6-bisphosphatase (PFKFB) 3. Our preliminary data show that macrophages co-cultured with ATII cells display a blunted response to LPS stimulation, which is dependent on lactate produced by the alveolar epithelial cells. Furthermore, locally intratracheally applied lactate can attenuate ALI. Our data suggest that this is associated with an increase in histone lactylation. Histone lactylation is a recently described histone modification that renders promoters of genes accessible to transcription. We hypothesize that lactate released by ATII cells dampens the AMs' excessive generation of proinflammatory cytokines in ALI via a lactate-mediated epigenetic regulation. In this application, we will test whether lactate produced by ATII cells shifts the AM phenotype toward an antiinflammatory, proresolving phenotype and we will determine whether in animals with ATII specific deletion of Pfkfb3 (decreased glycolytic capacity), AMs exhibit a more proinflammatory phenotype (aim 1). We will study how lactate induces the expression of antiinflammatory cytokine transcription by altering histone lactylation (aim 2). Acid aspiration and intratracheal LPS will be used as murine models of ALI. We will use primary human AMs for translational studies. ELISA assays and qPCR will be used to characterize AMs. We will study H3 histone lactylation modifications and transcription factor analysis experiments. This proposal is novel by expanding the scope of understanding of the role of epimetabolic crosstalk between ATII cells and AMs in ALI. It involves state-of-the-art experimental approaches and incorporates a therapeutic approach with potential for translation.

Topic: The Impact of a Metabolic Syndrome Phenotype in ARDS

Abstract: Acute respiratory distress syndrome (ARDS), a highly morbid and often fatal form of acute hypoxic respiratory failure, is common, with approximately 200,000 cases per year in the United States. However, the presentation, diagnosis, and clinical course of ARDS remain heterogeneous. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic increased the incidence of ARDS and as a result highlighted predisposing factors not studied before, such as metabolic syndrome (MetS). Similar to ARDS, MetS is a heterogeneous inflammatory state, often referred to as meta-inflammation and characterized by insulin resistance, obesity, dyslipidemia, and hypertension. ARDS develops as a systemic inflammatory response to certain risk factors and, although some metabolic determinants of health (e.g., obesity) are associated with non-COVID-19 ARDS, emerging data on COVID-19 ARDS clearly demonstrate a link with MetS. The need to better classify ARDS is well recognized. The overall objective of this proposal is to determine how a MetS phenotype alters ARDS risk and response to treatment. The central hypothesis is that a MetS phenotype will identify ARDS patients at increased risk for severe disease and worse outcomes. The rationale is based on our own evidence from COVID-19 ARDS and MetS as well as prior data from others on sepsis-related ARDS. To test this hypothesis, we propose two specific aims: 1) identify the effects of a MetS phenotype on ICU outcomes in patients with ARDS, and 2) determine how ARDS patients with a MetS phenotype respond to adjunctive therapies for ARDS (corticosteroids, prone positioning, ventilator strategies, or neuromuscular blockade) compared to patients without MetS. For the first aim, ARDS patients with MetS will be identified and compared to a matched cohort of control ARDS patients without MetS, using a subset of patients from SCCM Discovery’s SAGE trial and VIRUS registry. For the second aim, we will compare how outcomes differ for adjunctive ARDS therapies in patients with and without MetS. This project is innovative because it explores a never-before-tested hypothesis using existing data to discover new mechanisms and treatments for ARDS. The proposal is significant because it will facilitate harmonization of two robust datasets and will provide strong scientific justification for a follow-on R01 application to the NHLBI to study the biologic mechanisms underpinning how metabolic determinants of health contribute to ARDS.

Topic: Geographic Access to Pediatric Healthcare According to Social Determinants of Health

Abstract: Social determinants of health (SDOH) such as socioeconomic status (SES), race, ethnicity, and urbanism profoundly influence child health access and outcomes. Because of health access disparities, diverse or disadvantaged children are more likely to die from critical illness and less likely to undergo lifesaving therapy. SDOH are necessarily shaped by policies and resource distribution. While centralization may achieve economies of scale and promote quality, for critically ill children timely access to care can mean the difference between life or death. Our limited understanding of the complex interplay between SDOH, access, and outcomes represents a barrier to eliminating disparities.

Health resource allocation is susceptible to systemic discrimination. Social gradients and racial gaps in geographic access to high-quality acute pediatric care resulting from resource maldistribution relative to SDOH is a potential explanation for observed disparities. With researchers challenged to elucidate mechanistic drivers of inequity, this avenue deserves investigation. Our overarching hypothesis is that a disproportionate number of vulnerable children, as measured by SDOH, have low geographic access to care. Preliminary analyses in Massachusetts revealed that 88.3% of the pediatric population reside within a 60-minute drive of hospitals that admit children. Wealth indices (100 is the U.S. average) were significantly lower in areas more than 60 minutes from a hospital (mean difference, 48; 95% CI, 19-77, P = 0.004). Massachusetts is rich in health resources so observed disparities justify the study of geographic access in the United States and quality critical care resource allocation across other SDOH.

To meet this need we will perform cross-sectional analyses of pediatric healthcare distribution using sophisticated geospatial approaches that incorporate SES, diversity, and urbanism. First, we will quantify children’s geographic access to hospitals defined by 30-, 60-, and 120-minute driving radii (Aim 1). Next, we will characterize SDOH of families living increasing distance (less geographic access) from hospitals (Aim 2). Finally, we will evaluate geographic access according to SDOH stratified by hospital features, critical service availability, and quality indicators (Aim 3).

This research will deliver a novel framework to evaluate geographic distribution of pediatric health infrastructure according to SDOH, providing insights into geographic access as a contributor to inequity and improved hospital-level risk adjustment, with public health implications to analyze current service allocation and inform expansion.

Topic: The role of ARG-1 in Microglia During Efferocytosis After Neonatal Brain Hypoxia-Ischemia 
 
 Abstract: Hypoxic-ischemic brain injury (HI) remains the major cause of long-term disabilities in children because therapies are limited to therapeutic hypothermia, which provides only partial neuroprotection. A critical determinant of neuronal survival is neuroinflammation and, most importantly, biological processes that help to ameliorate it. In pursuit of new pathways that may serve as new therapies by minimizing the initial inflammatory response, this proposal focuses on the relatively underexplored arginase (ARG-1) pathway in microglia/macrophages (mi/ma). ARG-1 is a key regulatory enzyme of inflammatory and tissue repair pathways in the body that become activated after HI, such as macrophage polarization, oxidant/nitrosative stress, apoptosis, clearance of dead cells (efferocytosis), and tissue repair. While recent studies associate increased ARG-1 expression with better outcomes in various neuropathologies, and ARG-1 has become widely used as a major marker of pro-repair microglia (mi/ma), the exact role of ARG-1 expressed by ARG-1+mi/ma in neuroprotection remains unknown. We are the first to describe the spatiotemporal changes in ARG-1 activity and expression during neurodevelopment and after HI. After HI, the subset of ARG-1+mi/ma accumulate in the injured hemisphere within 4 hours of injury, where they engulf dead and dying neurons, suggesting the involvement of ARG-1+mi/ma in efferocytosis. We also showed that ARG-1+mi/ma remain at the injury site for a long time; however, HI suppresses ARG-1 expression at 8 days, possibly worsening the outcome. 

Our proposal is built on the strong scientific premise that multiple regulatory molecules of efferocytosis upregulate ARG-1, possibly leading to synthesis of polyamines necessary for building a cytoskeleton for phagocytosis, thereby enhancing clearance of dead cells. This is how efferocytosis prevents stimulation of proinflammatory cytokines and contributes to the resolution of inflammation. In the brain, the role of ARG-1+mi/ma in the regulation of efferocytosis has not been explored. Our work will precisely elucidate the extent that brain efferocytosis depends on ARG-1 (aim 1) and whether inducing the ARG-1 pathway will accelerate efferocytosis and limit the inflammatory environment (aim 2), thereby improving histologic and neurologic outcomes (aim 3). The hypothesis to be tested is that ARG-1 is pivotal for regulation of efferocytosis functions of ARG-1+mi/ma, contributing to neuroprotection.

Topic: Move to Music Video Intervention: A Music and Video Guided Exercise Intervention for ICU Survivors

Abstract: Each year, more than 5.7 million people are admitted to intensive care units (ICUs). Because of inactivity during their ICU stay and following discharge, ICU survivors experience more profound and persistent physical impairments compared with other hospitalized patients. To address this problem, we have developed an innovative and engaging music-guided exercise intervention called Move to Music (M2M), which targets inactivity as a reversible risk factor to promote better patient outcomes. Our preliminary M2M study provides promising findings for improving physical strength and subsequent overall functioning; however, in response to feedback from M2M participants, we propose adding a video component to create an M2M video intervention (M2M-V) to further promote ICU survivors’ motivation and ability to self-manage exercise. 

The M2M-V intervention uses rhythmic music and verbal cues to guide targeted upper and lower extremity exercises, while the video provides ongoing guidance and feedback. This low-cost, tailored, and easily implemented intervention has not been tested among ICU survivors. Our specific aim is to determine the preliminary efficacy of the M2M-V intervention on physical outcomes by randomly assigning ICU survivors to two groups (M2M-V and M2M). We anticipate that ICU survivors who receive the M2M-V intervention will demonstrate improved physical health, physical activity, and handgrip strength, as well as higher adherence to their exercise program compared with those assigned to M2M. Findings from this preliminary study will provide important data to support a larger clinical trial designed to assess long-term rehabilitation and recovery for ICU survivors. Our premise is that a tailored, self-managed music and video guided exercise intervention (M2M-V) will reduce physical inactivity and improve physical outcomes among ICU survivors. The proposal is directly aligned with SCCM’s research priority areas to advance and improve patient experience and outcomes for ICU survivors.

Topic: Using Video Games to Reduce Diagnostic Errors in Acute Respiratory Failure

Abstract: Each year, two million Americans are hospitalized with acute respiratory failure, and one out of five will not survive their hospitalizations. Early diagnosis and treatment can prevent death. Yet, because several different conditions can cause acute respiratory failure, accurate diagnosis is difficult. As a result, diagnostic errors remain a critical, yet potentially avoidable, problem.
 
This proposal seeks to address two key knowledge gaps. First, the current structure of medical training requires direct one-on-one learning from expert physicians, which is time-consuming, unstructured, and limited by the availability of experts. Second, improvement in diagnostic ability requires a controlled and repetitive training environment followed by immediate feedback, which is often impossible to achieve in routine practice.
 
To address these problems, we propose to use video game technology to reduce diagnostic errors through two pathways: 1) widely disseminating the mental models used by physicians to make diagnoses, and 2) using an enjoyable yet realistic virtual training environment to hone diagnostic skills.
 
Our aims are to: 1) identify the most relevant clinical characteristics used by physicians to diagnose the cause of acute respiratory failure, and 2) develop a video game to reduce diagnostic errors in acute respiratory failure.
 
This proposal is directly aligned with SCCM’s research priority areas to incorporate cognitive psychology, systems engineering, social science, and simulations into critical care education and training. The findings from this study will form the foundation for future R-series proposals to pilot and conduct a multicenter randomized trial of a video game to reduce diagnostic errors in acute respiratory failure.

Topic: Nano-Scale Drug Carriers Targeted to Alveolar Marginated Neutrophils for the Treatment of ARDS

Abstract: Acute respiratory distress syndrome (ARDS) is an acute inflammation of the alveoli (air sacs) of the lungs that afflicts 190,000 Americans each year and has a mortality rate of 40%. There are no FDA-approved drugs for ARDS due to three pharmacologic challenges. First, the patients have multisystem organ failure and therefore tolerate off-target drug side effects poorly. Second, the alveoli are covered with viscous liquid, preventing inhaled drug delivery. Third, ARDS has many mechanisms, so targeting a single molecular pathway is unlikely to work.
 
To overcome these challenges, we have created a nanotechnology to deliver unprecedented amounts of multiple drugs to inflamed alveoli at very high concentrations, thus lowering off-target side effects. Our technology, called D20-tagged liposomes (DLs), consists of 100-nanometer-diameter lipid spheres that are loaded with small-molecule drugs and are covalently coated with our newly discovered D20 tag. On IV injection, DLs massively accumulate in the alveolar marginated neutrophils, which are markedly increased in number in human ARDS and animal models of acute lung injury.
 
In this proposal, our aims are to further translational development of DLs in two ways: 1) assess the therapeutic efficacy of DL-loaded drugs in two ARDS-like mouse models, and 2) test DLs in ex vivo human lungs. Pursuing these two aims will provide fundamental insights into mechanisms of drug delivery and potentially create a new therapy for ARDS.

Topic: PTSD in ICU Family Caregivers: Trajectories, Risk, and Association With Patient Health Outcomes

Abstract: Emotional distress is common among family caregivers of patients admitted to the intensive care unit (ICU), with nearly two-thirds of caregivers affected by posttraumatic stress disorder (PTSD). PTSD is associated with negative outcomes including reduced physical health, unemployment, and suicide attempts. Furthermore, research in non-ICU populations has shown that heightened caregiver emotional distress is associated with worse patient health outcomes. Interventions to reduce ICU family caregiver PTSD have been met with limited success, which may indicate an incomplete understanding of the underlying mechanisms. I am proposing a prospective cohort study that will provide a comprehensive understanding of ICU family caregiver PTSD. The specific aims are to: 1) define six-month PTSD trajectories for ICU family caregivers and identify patient and caregiver characteristics that predict trajectory membership, 2) identify stressors and preferences for emotional support among caregivers with significant PTSD symptoms, and 3) measure the association between caregiver PTSD trajectory and patient health outcomes.

Topic: ReACT: Recovery Analytics in Hypoxic-Ischemic Coma Treatment

Abstract: More than 500,000 cardiac arrests occur yearly in the United States. The majority of patients with cardiac arrest who survive to admission in the intensive care unit do not regain consciousness by the time of formal prognostication, and over half of them will have life-sustaining therapies withdrawn due to resumed poor neurologic prognosis. No available monitoring method provides quantifiable and real-time feedback from the neural networks’ dynamics associated with neurologic recovery after hypoxic-ischemic brain injury, limiting identification of patients for whom intensive care support might lead to improved outcomes. We propose to ask whether quantitative electroencephalography (qEEG) can improve the accuracy of early outcome prediction in hypoxic-ischemic brain injury compared to standard prognostication methods. Our preliminary work indicates that changes on qEEG signals trends such as EEG spectra, epileptiform patterns, and frontal functional connectivity predict functional outcome with good performance as early as 24 hours after cardiac arrest despite the presence of sedation and hypothermia. We hypothesize that machine-learning techniques applied to continuous qEEG data will: 1) enhance multimodal prediction of long-term functional recovery from coma and 2) enable identification of individualized longitudinal recovery trajectories. The proposed study will take advantage of an already available clinical and EEG database with data from more than 1,100 adult comatose cardiac arrest subjects who had continuous EEG monitoring and targeted temperature management (six-month functional outcomes available). We aim to determine the added benefit of qEEG and EEG functional network connectivity to standard prognostication approaches with clinical examination, visual EEG review, somatosensory evoked potentials, and brain imaging (Aim 1). We will utilize state-of-the-art signal processing techniques and machine-learning methods to identify which qEEG signatures will have best performance, predicting long-term neurologic outcome at specific time points during the coma recovery process. We plan to employ similarity modeling to identify personalized qEEG recovery trajectories for early identification of patients with potential for recovery (Aim 2). The individualized neuromonitoring system we envision has the potential to facilitate data-driven decisions at the point of care and also provide insights into the mechanisms associated with coma recovery.

Topic: Exploring Changes in Peritoneal Macrophage Composition and Function During Sepsis 

Abstract: Sepsis occurs when an infection leads to a systemic inflammatory response that is harmful to the host. Immunologic dysregulation and organ damage are central features of this disease. The mortality rate from severe sepsis remains quite high (30%-50% before hospital discharge). Additionally, many patients who survive the acute phase of sepsis go on to develop a persistent inflammation, immunosuppression, and catabolism syndrome (post-intensive care syndrome [PICS]). Tissue-resident macrophages are early sentinels of infection and exert both beneficial and detrimental functions during sepsis. As phagocytes, they ingest and kill bacteria. Macrophages also express pattern recognition receptors (PRRs), such as toll-like receptors. Activation of PRRs by bacterial ligands and host danger signals induce the production of proinflammatory cytokines, such as interleukin-6. While these inflammatory mediators play an important role in host defense, during sepsis their levels become excessive, and the resulting inflammation can damage host tissues and lead to organ failure. This proposed study will explore the presence and function of monocyte and macrophage populations in the mouse peritoneum after sepsis is induced via cecal ligation and puncture. We will identify differences between mice predicted to live and those predicted to die. We will also identify differences in mice that exhibit signs of PICS versus those that return to homeostasis after sepsis.

Topic: The Psychological Impact of Inter-ICU Transfers

Abstract: Patients with ventilator dependent respiratory failure (VDRF) are among the most seriously ill ICU patients and thus theoretically should benefit from treatment in centers with greater expertise necessitating transfer between ICUs and inter-ICU transfer is common. While intended to benefit patients, inter-ICU transfer may impact patient's family who are removed from their local support systems and may experience substantial travel burdens to be near their family member. It is widely recognized that family of ICU survivors experience depression, post-traumatic stress and anxiety at rates substantially higher than that of the US population but the influence that an inter-ICU transfer has on psychological outcomes in families is entirely unknown. Thus, our objective was to utilize a mixed methods approach to gather insights into the psychological impact of inter-ICU transfer on families. The lack of clarity and paucity of knowledge about family experiences during inter-ICU transfer are important knowledge gaps that this study will help address.

Topic: Influence of Free Heme as a Red Blood Cell DAMP in Sepsis (RBC-DAMPS)

Abstract: Sepsis phenotype is an emergent property of invasive infection and host response that leads to either resolution or to significant morbidity and mortality; frequently from development of secondary infection during a period of immunoparalysis. Interestingly, at least ½ of critically ill patients in the US with sepsis receive a RBC transfusion during their ICU stay. Mounting evidence from models of infection and from humans with sepsis indicate that red blood cell (RBC) transfusion is associated with altered immunity and worsened outcome, though the specific mechanism for this observation is unknown. All transfusion, to a degree, leads to intravascular hemolysis. In prior work with a canine sepsis model, we have shown that plasma hemoglobin and its metabolites, in synergy with infection, worsen multi-organ failure and increase mortality. To examine this intersection of transfusion-associated immune modulation, we will focus upon a Hb metabolite in plasma, cell-free heme (CFH), which upregulates innate immune response by acting as a damage associated molecular pattern (DAMP) molecule via TLR4 activation. With transfusion, lysed RBSs may directly influence host innate immune signaling by priming TLR-4. Thus, in sepsis after RBC transfusion, we hypothesize that circulating heme induces immunoparalysis via repetitive TLR-4 activation and that this phenomenon is dependent upon timing and quantity of circulating heme. This interaction may be critical in globally understanding whether heme uptake worsens immunoparalysis in sepsis. Thus, to further refine this hypothesis, we will study the transfusion of mouse specific RBCs and evaluate timing and dose response of heme on survival in a murine cecal ligation model of sepsis (Aim 1). Furthermore, we will serially assay septic mice to define heme processing (Aim 2) during evolution of disease and conduct mechanistic studies on murine monocytes to elucidate the impact of plasma heme upon innate immune phenotype in the setting of active infection over time (Aim 3). This work will help define the impact and explore consequences of plasma CFH metabolism and the evolution of monocyte phenotype during murine sepsis through heme-TLR4 interaction, and to identify specific mechanistic therapeutic targets for future intervention into translational models.

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. 

Topic: ERole 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.

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.

Topic: Coagulopathy Following Cardiac Arrest

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.