Discovery, the Critical Care Research Network Programs

Vitamin C, Corticosteroids and Thiamine in Sepsis Study VICTAS
Jonathan Sevransky, MD, MHS

Sepsis is a clinical syndrome characterized by life-threatening organ dysfunction, caused by a dysregulated host response to infection.1. The treatment of sepsis currently consists of expedient supportive care and control of infection.2. Recently, a combination of inexpensive medications has been asserted to effectively combat the dysregulated metabolism that accompanies sepsis. These medications include Vitamin C, Thiamine (also known as Vitamin B1), and hydrocortisone.. The assertion is based on the before-after data reported by a single hospital. The response to this trial, which received widespread interest of the public ,has been mixed, with some clinicians suggesting that the results are “too good to be true” to “why not give the combination of medications to all sepsis patients?” The most general opinion reflects clinical equipoise: genuine uncertainty in the expert medical community over whether the medication combination treatment will be beneficial, with reciprocal uncertainty as to whether the medication combination will be wasteful or even harmful.

We propose to evaluate this potential treatment in a randomized placebo controlled , multicenter trial. This trial will require 40-60 sites and will have as a primary outcome measure the number of days of vasopressor and ventilator free days.

Early after TBI Study: Opposing Sympathetic Drive Early after Traumatic Brain Injury-Phase 3 OSD-3
Bellal Joseph, MD, FACS

Severe TBI is defined by a Glasgow Coma Scale (GCS) ≤ 8. This sets a host-adaptive neuroendocrine, immune-metabolic, and inflammatory response that is integrated by an increased sympathetic drive and exaggerated catecholamine surge. This unopposed sympathetic drive triggers a secondary brain insult that occurs hours to days after the primary TBI and manifests as systemic and intracranial hypertensions, abnormal heart rate variability, agitation, cerebral edema and cerebral hypo-perfusion to collectively cause the poor neuropsychological outcome. Opposing the sympathetic drive through neutralization of the catecholamine actions in TBI is therefore, a viable option for neuroprotection against a secondary brain insult. However, there is no clinical evidence from a prospective randomized trial demonstrating the safety and effectiveness of opposing the sympathetic drive after TBI.

Methods/Design: OSD after TBI Study is a two-arm, single-blind; block randomized, controlled, phase III, multi-center trial of the efficacy of early opposing the sympathetic drive as neuroprotection strategy in TBI subjects with a GCS ≤ 8. One half of the qualified subjects will be enrolled via EFIC or proxy consent and block randomized to the opposed sympathetic drive experimental arm. This will receive intravenous propranolol every 6h at an adjustable dose to achieve a targeted heart rate <100. Propranolol will be held for hypotension (systolic <100) or bradycardia (heart rate <60 beats per minute). The maximum daily dose for the treatment of hypertension of 640 mg will not be exceeded in this study. Subjects randomized to the unopposed sympathetic drive control arm will receive the standard of care treatment and will not receive propranolol or other β-adrenoceptor antagonist or α2-agonist. If a subject randomized to the unopposed sympathetic drive arm develops hypertension and increased heart rate, this subject will be treated according to the standard of care by the trauma team caring for the subject. End-point measurements include plasma catecholamine and metabolites levels, serum levels of neuronal injury-specific biomarkers, heart rate variability, arrhythmia occurrence, infections rate, medication use, agitation measures, coma-free days, and ventilator-free days, length of ICU and hospital stays, and mortality. Neuropsychological outcomes in the domains of reasoning, concentration, problems solving, and memory together with the Glasgow Outcome Scale-Extended (GOS-E) will be performed at hospital discharge and at 3 and 12 months after the injury.
The specific aims are to demonstrate that early administration of propranolol after severe TBI:
  • Decreases the plasma levels of catecholamine (epinephrine, norepinephrine, and dopamine) and their break down products (vanillylmandelic acid, metanephrine, and normetanephrine) measured at day 7.
  • Decreases serum level of neuronal injury-specific biomarkers [S100-B, NSE, myelin basic protein (MBP), ubiquitin C-terminal hydrolase (UCLH1), tau protein and Glial fibrillary acidic protein (GFAP)] measured at day 7.
  • Decreases heart rate variability, agitation, occurrence of arrhythmia, and infection as assessed daily.
  • Decreases days on ventilation, length of intensive care unit and hospital stay times, and in-hospital mortality as assessed daily.
  • Improves neuropsychological outcome in the domains of reasoning, concentration, problems solving, and memory as measured at hospital discharge and at 3 and 12 months after the injury.
  • Improves the neurologic outcome measured by the Glasgow Outcome Scale-Extended (GOS-E) 3 and 12 months after the injury.

Understanding the implications of left ventricular global longitudinal strain in septic cardiomyopathy
Samuel Brown, MD

Septic cardiomyopathy is common and serious. Global longitudinal strain of the left ventricle is a promising measure of ventricular function. Strain has been well established in coronary artery disease, oncocardiology, and healthy populations. Norms and thresholds for abnormal are reasonably well established in these populations. What thresholds are relevant among patients with sepsis are unknown, however. Knowing the range of normal would aid attempts to use global longitudinal strain diagnostically in sepsis. In addition, global longitudinal strain should be validated against post-septic outcomes to better understand the longer-term implications of septic cardiomyopathy.

This research pursues two related aims in two multicenter cohorts. The aims are: 1) Establish norms for global longitudinal strain among septic patients; 2) Determine whether abnormal GLS during sepsis is associated with GLS at 3 months.

Monitoring EEG in Comatose ICU Patients: A point prevalence observational study of intensive care unit experiences MECIP
Manuel M. Buitrago Blanco, MD, PhD

Non-convulsive seizures detected by continuous electroencephalography (cEEG) occur in about 30% of patients in coma. cEEG is also indicated for aiding in management and prognosis of critically ill patients with brain injury. Societal guidelines recommend the use of cEEG monitoring in this population to better aid in their management, yet implementation remains challenging.

This research proposal consists of an observational study to learn about the use of continuous electroencephalography for the evaluation and treatment of patients in coma in intensive care units (ICUs) across the United States. The goal is to assess for current practice, quality, barriers to implementation and opportunities for improvement, in the use of cEEG for evaluation and treatment of patients in coma.
The study is a cross-sectional point prevalence observational detailed study of users, equipment, readers, patient categories, duration of EEG among ICUs whether they are specialty or general ICUs. One hundred institutions will be recruited through an outreach effort via the Neurocritical Care Research Network (NCRN) and the Critical Care Research Network (CCRN). With the endorsement of the NCRN, participation of its forty seven institutional members is anticipated. We expect to enroll additional institutions academic and nonacademic via the CCRN.
By conducting MCIP, we expect to identify areas of top priority to improve the delivery of standard of care in coma patients admitted to critical care units by identifying the main barriers to implementation of cEEG. The direct impact of this study will translate into better delivery of care and improved ability to execute collaborative inter-institutional research endeavors in the future.
Our specific aims are: 1) To determine clinical practices to the patient in coma in intensive care units in the United States. We hypothesize that there is underutilization of cEEG monitoring in coma in most centers, independent of unit type; 2) To identify effects on predefined outcomes such as mortality, length of stay, and adverse effects of cEEG monitoring of coma patients. We hypothesize that utilization of goal-directed cEEG monitoring reduces mortality; 3) To define specific barriers to practical implementation of cEEG in the coma patient once the indication for testing has been recognized by intensive care specialists. We hypothesize that the two main barriers are equipment unavailability and lack of neurology EEG readers.

WorldwidE AssessmeNt of Separation of pAtients From ventilatry assistancE WEAN SAFE
Phillippe R. Bauer, MD, PhD

Successful weaning of patients from invasive mechanical ventilation represents a crucial step in the recovery process following severe respiratory failure, and is a key clinical challenge for ICU clinicians. Many of the serious complications of IMV are directly related to the duration of ventilation. Failure to successfully separate patients from IMV contributes directly to poorer patient outcomes: including longer duration of ventilation, longer length of stay in the ICU and in the hospital, and higher patient mortality. Patients spend a considerable amount of time in being liberated from invasive mechanical ventilation. The systematic utilization of approaches to reduce the duration of ventilation are therefore of fundamental importance.

Despite the importance of the weaning period, this process is not rigorously defined, with wide variations in definitions and practices. In addition, the specific impact of weaning difficulties on patient outcomes is still poorly understood. While guidelines do exist on the classification of weaning, a key recent study has shown that these are not applicable to all patients. Moreover different practices exist in regard to weaning procedures and some confusion exists even in what should be considered the beginning of weaning process. This is an important problem, because general recommendations regarding the entire weaning process may encompass completely different causes and consequences of its prolongation and therefore may be totally inappropriate for individual patients.
The WEAN SAFE study will aim to address key issues relating to weaning from invasive MV. WEAN SAFE will have a structure similar to LUNG SAFE, in that a large set of patients receiving invasive MV will be enrolled, without setting “weaning” as an inclusion criterion, but rather attempting to identify the weaning process “retrospectively.”
WEAN SAFE aims to describe, in a large population of ICU patients the current procedures for weaning, the applicability of existing classification systems to ‘real world;’ weaning from IMV, to describe centers/management/patient’s characteristics associated to duration of weaning. It will answer the following questions:
  • What is the frequency of delayed weaning from invasive mechanical ventilation?
  • What are the current approaches taken to wean patients from invasive mechanical ventilation? What are the factors that are used to determine when patients are in the weaning phase?
  • What are the barriers to effective weaning from invasive MV?
  • What factors (patient, institutional, medical practice) contribute to failed attempts to wean from invasive mechanical ventilation?
  • What is the impact of sedation management on weaning from invasive MV?
  • What is the impact of premorbid conditions and of frailty on weaning from invasive MV?
  • What is the utility of existing classifications for weaning from invasive MV?
  • What is the impact of early versus delayed and/or failed weaning from invasive MV?
  • What regional or geo-economic differences exist regarding weaning from invasive MV?
  • What is the therapeutic resource use in patients with delayed weaning from IMV?

Metabolomic analysis of lactate clearance in traumatically brain injured patients
Thomas C. Glenn, PhD

Elevated blood concentrations of both lactate and lactate clearance rates have been used, with varying success, to predict outcome following trauma, sepsis, and traumatic brain injury (TBI) (Glenn 2003, Nguyen, 2016, Jones, 2010). What complicates the picture is that lactate, which was once thought to be a waste product of metabolism, has now been shown to be taken up by the brain and used as a fuel (Glenn 2003, Glenn 2015). Furthermore, while showing that lactate is an important gluconeogenic substrate following TBI, we have also shown that other compounds such as amino acids will increase during lactate infusion (Glenn, 2014 Wolahan, 2017). This research will occur at two UC level 1 trauma centers, and be a prospective observational study of blood metabolites. Venous samples will be collected 2 times a day for 3 days. The primary endpoints will be lactate concentrations over time. Secondary endpoints will be metabolomics analyses of blood samples and CSF, discharge outcome, GCS at time of blood draw, and microdialysis and CSF glucose and lactate. This study will be the most extensive study of blood metabolites performed to date in critical care patients.

Our aims are to: 1) Determine the time course of lactate blood clearance in TBI patients; 2) Determine a targeted metabolomic profile of blood following traumatic injury; 3) Determine if modeling/multivariate analysis of targeted blood metabolites leads to a better prognostic model of outcome compared to glucose and lactate blood levels alone.

VOLUME-CHASERS: Observation of Variation in Fluids Administered and Characterization of Vasopressor Requirements in Shock
JT Tina Chen, MD
While fluid resuscitation is a mainstay of treatment for most cases of shock, excessive volume resuscitation is associated with worse clinical outcomes.  There are many studies that have shown that dynamic hemodynamic measurements can predict fluid responsiveness, but little is known as to their association with important clinical outcomes. The overall goal of VOLUME-CHASER is to conduct a multicenter, observational cohort study across a broad range of hospitals, including patients in the emergency department, ICU, and non-ICU areas, to determine the variability in shock resuscitation and modalities used to determine the amount of fluid and vasopressor administered.  We will explore the possible outcome differences associated with this variability in practice.

Titration of Inspired Oxygen During Mechanical Ventilation Using Electronic Alerts via Electronic Health Records: A Multicenter Study
Sonal R. Pannu, MD, MS
Hyperoxia, defined as fraction of inspired oxygen (FIO2) of greater than 0.5, can be injurious, augments ventilator-associated lung injury, and is associated with higher mortality. Liberal oxygenation practices are also associated with increased mortality in subsets of critically ill patients with post-cardiac arrest, stroke, and traumatic brain injury. FIO2 is titrated via oxygen saturations (SpO2); however, there is often delay in reducing FIO2 despite adequate SpO2. Processes of ventilator weaning and liberation may be delayed with inadequate titration. Hyperoxia prevails in most ICU settings due to poor awareness of the adverse effects of even mild hyperoxia and fear that even mild or short duration of hypoxia could be life-threatening. Therefore, there is a critical need to institute measures to improve practice of FIO2 titration in a conservative range to maintain optimal oxygen saturation. 

The plan is to conduct a step-wedge, clustered, randomized implementation by sequential adoption every three months in participating ICUs with concurrent controls available until all sites adopt the protocol. 

The aims of the study are to: 

  1. Reduce the duration of hyperoxia in mechanically ventilated critically ill patients 
  2. Demonstrate improved ICU outcomes of increased ventilator-free days and shorter ICU lengths of stay 
  3. Study providers for burden of electronic alerts and learning effect of alerting process 

Structure, Process, and Utilization of Intermediate Care in the United States
David N. Hager, MD, PhD
Intensive care resources are limited, while the number of patients needing intensive care is increasing. It was previously recognized that, among patients admitted to intensive care units (ICUs), many do not require intensive care but are admitted for close monitoring. Intermediate care units (IMCUs), also known as high-dependency units, step-down units, or progressive care units, were created to accommodate patients whose needs do not require intensive care but surpass the care and monitoring feasible on a general ward. Patients may be transitioned to an IMCU after being stabilized in an ICU or having worsened on a general ward or may be directly admitted from the emergency department or post-anesthesia care unit. 

Over the last 20 years, billing for intermediate care and the prevalence of IMCUs have increased. However, the optimal staffing structure, physical layout, and admission guidelines for these units are not well-defined. This is complicated by regional needs, institutional missions, clinical expertise, and physical resources. This marked heterogeneity of IMCUs and the characteristics of the patients they serve has resulted in limited generalizability of IMCU patient outcomes and cost-effectiveness studies to date. A better understanding of IMCU organizational structure paired with patient outcomes would greatly inform the use of this level of care in the future. 

This will be a study of variability in the structure and use of IMCUs in different regions and centers. We will survey centers to characterize the current structure of intermediate care in the United States.

Severe ARDS: Generating Evidence SAGE
Pauline K. Park, MD, FCCM
Approximately one-quarter of patients with acute respiratory distress syndrome (ARDS) develop severe hypoxemia (PaO2/FiO2 < 100).  In large series, severe hypoxemia has been associated with high observed mortality rates, approximating 40-50%. The severity of hypoxia in the majority of these patients is established at initial presentation, suggesting an opportunity for early intervention. Development of strategies to reduce mortality is hampered by the difficulty of conducting randomized trials in this population. 

While a number of interventions in ARDS have been shown in randomized, controlled trials to lead to improved outcomes, studies to date indicate that the use of these evidence-based practices is highly variable and inconsistent.  At the same time, treatment modalities that are unproven remain commonly used in the management of ARDS. 

The SAGE study was conducted to evaluate current US practice in management of severe ARDS, both to inform practicing clinicians and to form the basis for future research. 

Objective:  An assessment of early management of severe ARDS, including ventilator management and use of rescue therapy. 

Specific Aims: 

  • Describe US management practices and variation in use of ventilator strategies and rescue modalities in patients with severe ARDS. 
  • Determine prospectively the factors in early severe ARDS associated with survival or need for adjuvant therapy. 
  • Evaluate characteristics, management, and survival in patients admitted to SAGE centers compared to patients transferred to SAGE centers from other sites. 
  • Determine the variability in the use of tidal volume and PEEP and its association with subsequent mortality among patients with severe ARDS on ECMO.

Design:  Multicenter, prospective, observational cohort study conducted through participating sites between October 2016 – April 2017 

Inclusion criteria: 
  • Age > 18 years 
  • Patients with acute respiratory failure in the ICU requiring invasive mechanical ventilation 
  • Presence of severe ARDS 

Registry for Acute CarE – A Pilot Study RACE
Kianoush Kashani, MD, MS, FASN, FCCP
Intensive care units (ICUs) generate vast amounts of data that could be used to enhance value-based care for critically ill patients. United States Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) are national registries for end-stage renal disease and transplant patients, respectively. They have contributed significantly toward improving outcomes in these populations. Variations in processes of care are prevalent across ICUs at different centers and are associated with variations in outcomes. With increasing emphasis on value-based care, a comprehensive real-time registry that encompasses the domains relevant to the measurement of processes of care and their associated key ICU outcomes is the need of the hour. We are proposing a pilot project to build a cloud-based Registry for Acute CarE (RACE), which will provide data to generate metrics for standards of care for critically ill patients and will also permit the use of critical care-specific data by participating institutions for research and internal quality control. The goal is to ultimately expand the registry to a national scale.

Programs for Emergency Preparedness PREP
J. Perren Cobb, BA, MD, FCCM
The appropriate treatment of critically ill or injured patients can vary from minute to minute. Thus, timely access to reliable data is one of the foundations of contemporary intensive care. It follows that optimal responses during public health emergencies, for both clinicians and decision-makers, would benefit from comprehensive, real-time event reporting. This should include physiologic patient data that are needed to provide immediate insight into the impact of the event on critical healthcare resources and to identify groups at high risk for morbidity and mortality. The Program for Emergency Preparedness (PREP) has as its goal to significantly enhance the national capability to rapidly glean crucial information regarding the clinical course of acute illness and injury and guide clinical resource requirements during emergent events through the following six aims: 

  • Development of a national network of acute and critical care research organizations of academic and community hospitals for adults and children, across the care continuum 
  • A rapid communication network with quarterly queries to assess national health system stress 
  • Infrastructure for prospective trails for national public health emergencies, such as influenza and anthrax 
  • A national data coordinating center 
  • Human subjects research review with local and national IRBs (i.e., PHERRB) 
  • Coordination with international organizations and clinical trials groups 
Working with the federal agencies of the Office of the Assistant Secretary for Preparedness and Response, the Food and Drug Administration, the Biomedical Advanced Research and Development Authority, the Centers for Disease Control and Prevention, the National Institutes of Health, leading professional organizations, and the Homeland Security Information Network, PREP is developing mechanisms for rapid data collection, analysis, and dissemination of findings during public health emergencies. Pre-event work on protocols, data collection processes, rapid analysis techniques, and means to quickly disseminate findings to stakeholders are all crucial to making clinical science networks effective at enhancing the response. PREP will leverage existing infrastructure to both strengthen pre-event operational science capabilities and provide timely data and situational awareness across the emergency care continuum during public health emergencies. Critical illness and injury professional organizations will use this rapid dissemination plan to inform their membership, in aggregate representing over 150,000 front-line clinicians, thereby saving lives and minimizing suffering based on the timely accurate guidance gleaned from operational science. 

Prevention Of Organ Failure PROOF
Michelle Ng Gong, MD
The PReventions Of Organ Failure (PROOF) program is composed of critical care researchers, represented by a multidisciplinary group of critical care specialists from anesthesia, emergency medicine, internal medicine, pulmonary, surgery, and trauma, who are interested in the prevention of injuries and diseases and their progression in the critically ill population. 

Projects Conducted Under PROOF: 

  • Lung Injury Prediction Study 
  • Lung Injury Prevention Study-Aspirin (LIPS-A) 
  • Accurate Prediction of Prolonged Ventilation (APPROVE) and Prevention Of Organ Failure CHECKlist (PROOFCHECK) 

Practices Surrounding the Identification, Prevention, and Treatment of Delirium in the ICU
Amy L. Dzierba, PharmD, BCPS, FCCM
This investigation aims to describe the practices of detection, prevention, and treatment of delirium in adult ICU patients across institutions and to compare the perceived and actual activities surrounding detection, prevention, and treatment activities in a snapshot. This study will provide ICU clinicians, hospital administrators, and researchers with information on discrepancies between actual patient care and recently published evidence-based guideline recommendations.

Oral Midodrine Hydrochloride in Early Sepsis: Randomized, Double-Blind, and Placebo-Controlled Feasibility Study
Rahul Kashyap, MBBS
The aim of this patient-centered study is to conduct a feasibility clinical trial on oral midodrine in early sepsis and to seek alternatives to minimize the burden of an ICU stay in these patients. 

Sepsis is the second leading cause of death in medical intensive care units, carrying a mortality rate of between 25% and 30%. Cardiovascular compromise in sepsis manifests as hypotension due to arterial vasodilation between 25% and 30%. Cardiovascular compromise in sepsis manifests as hypotension due to arterial vasodilation. Hypotension can persist despite initial resuscitation, prompting additional fluid boluses and subsequent central venous catheterization for the infusion of intravenous vasopressor agents. Both excess fluid boluses and central venous catheterization may expose patients to risk, harms, and discomfort. 

Midodrine is an oral vasopressor agent approved for treating orthostatic hypotension. Preliminary data during the past several years suggest a markedly increased off-label use as a vasopressor-sparing agent in critically ill patients. However, no randomized trials have been conducted to evaluate the safety and efficacy of this practice. 

The central hypothesis is that administering oral midodrine to septic patients who have received initial fluid resuscitation and appropriate antimicrobial treatment will mitigate systemic hypotension and decrease the need for additional fluid and vasopressor use. The proposed multicenter pilot trial is necessary to test the feasibility of enrollment, appropriate population, timing, effect size to determine the need, and sample size for subsequent phase II pragmatic clinical trial. 

Recovery Analytics in Hypoxic-Ischemic Coma Treatment (ReACT)
Edilberto Amorim, MD
Over 500,000 cardiac arrests happen yearly in the United States. Most cardiac arrest patients who survive to hospital admission will not have regained consciousness at the time of formal prognostication, and over half of them will have life-sustaining therapies withdrawn due to brain injury. No available monitoring method provides quantifiable and real-time feedback from the neural networks’ dynamics associated with neurologic recovery after hypoxic-ischemic coma. We propose to ask whether quantitative electroencephalography (qEEG) can improve accuracy of outcome prediction in hypoxic-ischemic coma compared to current prognostication practices. Our preliminary work indicates that long-term continuous qEEG trends strongly predict functional outcome despite presence of sedation and hypothermia. We hypothesize that machine-learning techniques employing qEEG data will a) have high accuracy predicting long-term functional recovery; b) account for the effects of temperature and sedation on EEG; and c) enhance prognostication predictions made with neurologic examination, visual EEG review, somatosensory evoked potentials, and imaging tests alone. 

This prospective study will involve adult comatose cardiac arrest subjects who had continuous EEG monitoring and targeted temperature management. We propose to: 1) test the ability of qEEG features to prospectively predict long-term functional outcome in hypoxic-ischemic brain injury based on training clinical and qEEG data from a large retrospective cohort of cardiac arrest subjects; 2) determine the effects of targeted temperature management and sedation on qEEG; and 3) identify whether continuous qEEG trends improve long-term functional outcome predictions compared to standard prognostication practices. We anticipate that 100 patients will be evaluated prospectively. 

The individualized neuromonitoring system we envision has the potential to facilitate data-driven decisions at the point of care and provide insights into the mechanisms associated with neurologic recovery after severe brain injury. The overarching goal of the research program we propose is to establish a network of investigators focused on patient-oriented research in hypoxic-ischemic coma and to provide the infrastructure needed to carry out interventional clinical trials that aim to improve outcomes for cardiac arrest patients. 

Inhaled Versus Early Systemic Steroids for Treatment of Pneumonia (INVESST Pneumonia) INVESST
Emir Festic, MD, MS, FCCM
Inhaled Versus Early Systemic Steroids for Treatment of Pneumonia (INVESST Pneumonia) will be a multicenter, double-blind, placebo-controlled, three-arm randomized trial to compare the efficacy of early treatment with an inhaled corticosteroid combined with a beta-agonists versus systemic corticosteroids versus usual care for prevention of acute respiratory failure (ARF) requiring mechanical ventilation and, second, to reduce hospital length of stay in patients with severe pneumonia. 

The three aims are to: 

1. Test the efficacy of early treatment with an inhaled corticosteroid (budesonide, 0.5 mg) combined with a beta-agonist (formoterol, 20 µg) or systemic steroid (IV methylprednisolone, 0.5 mg/kg) versus usual care for the prevention of ARF 

2. Compare the efficacy and side effect profiles of inhaled delivery of a corticosteroid combined with a beta-agonist versus systemic steroids in regard to hospital length of stay, duration of need for supplemental oxygen, hyperglycemia, and arrhythmias 

3. Identify biologic pathways associated with progression to ARF in patients with pneumonia and explore the effect of systemic versus inhaled delivery of corticosteroids on peripheral markers of inflammation (IL-6 and CRP), inflammasome activation (IL-18), and markers of endothelial (Ang-2) and epithelial (RAGE) lung injury. 

High-Flow Oxygen Versus Positive Pressure Ventilation in the Emergency Department Program USCIIT-HOPE
Jarrod M. Mosier, MD, FCCM
The management of acute hypoxemic respiratory failure (AHRF) in the emergency department (ED) is difficult because of resource and logistical challenges. This is particularly true in patients with, or at risk for, acute lung injury. Many clinicians prefer treating these patients with noninvasive positive pressure ventilation (NIPPV) with the goals of preventing the need for deep sedation and invasive mechanical ventilation. More recently, a newer and potentially more efficacious therapy has been introduced: high-flow nasal cannula (HFNC) with a heated, humidified circuit and adjustable fraction of inspired oxygen with flows between 40 and 60 liters per minute. Recent studies have shown that HFNC might be superior for patients with AHRF in the intensive care unit. However, the utility of starting this therapy earlier in the disease course—in the ED—is unknown. 

Although the mechanistic basis for any superiority of HFNC over NIPPV is unclear, presumably HFNC reduces lung injury by maintaining a lower transpulmonary pressure gradient and more lung-protective tidal volumes than NIPPV in spontaneously breathing patients with airspace disease. Thus, earlier initiation of this therapy in the ED would provide a greater benefit. 

The overall goal of our research is to design a prospective multicenter randomized controlled trial to compare the rate of intubation at 72 hours for HFNC and NIPPV in adult ED patients with AHRF. The three specific aims are to: 

1. Determine the failure rates (rate of intubation) of each therapy to adequately power a multicenter trial 

2. Compare rates of intubation in ED patients with AHRF treated with either HFNC or NIPPV 

3. Assess lung injury and inflammation in these patients before, during, and after treatment with either FHNC or NIPPV 

Feasibility and Impact of Structured Telemedicine-Focused Strategy for End-of-Life Discussion During ICU Phase of Critical Illness
Sanjay Subramanian, MD
Acquiring an understanding of patient care goals in the context of a serious illness is an essential element of high-quality care, allowing clinicians to align the care provided with what is most important to the patient and family. Evidence indicates an increase in moral distress for critical care clinicians delivering futile care. Early discussions about goals of care are associated with better quality of life, reduced use of nonbeneficial medical care near death, enhanced goal-consistent care, positive family outcomes, reduced costs, and reduced clinician emotional exhaustion. 

We aim to study the feasibility and impact of using a structured telemedicine strategy to initiate discussion and implement a plan for goals of care in the first 24 to 48 hours of septic shock after admission to the ICU.

Effect of Pharmacist Participation in Acute Ischemic Stroke on Door-to-Needle Time to Recombinant Tissue Plasminogen Activator and Patient Outcomes
Megan A. Rech, PharmD, MS, BCPS, BCCCP
This is a multicenter, retrospective cohort study of patients who received recombinant tissue plasminogen activator (rtPA) for acute ischemic stroke (AIS) in either the emergency department or a different area of the hospital. Patients who had a pharmacist at the bedside will be compared to those who did not have a pharmacist on their multidisciplinary stroke team. Patients will be grouped according to pharmacist coverage at study sites. The specific aim of this study is to determine whether pharmacist presence at the bedside during AIS reduces door-to-needle (DTN) times in a nationally represented sample. 

Additionally, the relationship between inclusion of a pharmacist in patients’ bedside care and the proportion of patients in each group that met a DTN time goal of < 60 minutes and < 45 minutes will be explored. 

Finally, the impact of a pharmacist on the long-term outcomes of a 90-day National Institutes of Health Stroke Scale and modified Rankin Scale will be assessed. A linear regression analysis will be performed to assess factors that influence DTN time. If a pharmacist at the bedside is found to positively impact patient outcomes, this study could lead to improved emergency treatment for AIS patients and guideline recommendations for the inclusion of a pharmacist on the multidisciplinary stroke team.

Early Psychological Support for the Critically Ill
Lioudmila V. Karnatovskaia, MD
Millions of people are admitted to intensive care units (ICUs) in the United States every year. Most of them survive, but survival does not often mean the end of their struggles; post-illness challenges may persist on multiple levels. These challenges often include ravaging physical debility whereby the body is unable to function at pre-illness levels and the loss of the ability to think clearly and to function at work or at home. Additionally, feelings of depression, episodes of anxiety, and flashbacks of hallucinations and other memories of the ICU plague patients after critical illness. All these scars of surviving a critical illness are collectively known as post-intensive care syndrome (PICS). 

Early physical therapy has been shown to reduce physical debility in critical illness survivors; however, there is no available psychological intervention that can be implemented for patients while still in the ICU. The objective of this study is to test an intervention to prevent formation of psychocognitive morbidity in the ICU and improve health-related quality of life (HRQOL). This single-center pilot study will explore feasibility and preliminary efficacy of Early Psychological Support for the Critically Ill (EPSCI), providing data for the design of a subsequent multicenter trial.

Data Utilization of Admitting ICU Staff During Transfer of Critically Ill Patients from Outside Hospitals: A Multi-Institutional Survey Study
Kelly M. Pennington, MD
Inter-hospital transfers of critically ill patients is common practice; however, little data exist regarding the information accepting providers deem necessary to initially triage and treat critically ill transfers. Failure to clearly communicate critical information at times of transition, such as transfer of care, significantly increases the risk of patient harm. A potential solution to this problem is to develop a standardized handoff tool consisting of high-yield data points. In an attempt to objectify data and improve care across the continuum from the transferring to the accepting facility, we are identifying decision-making cues that will help us develop a formal hand-off tool.

Critical Illness Outcomes Study CIOS
Jonathan E. Sevransky, MD, FCCM
Variations in both structure and process are known to affect clinical outcomes in intensive care units (ICUs). With both increasing demand and increasing costs of adult critical care, it is important to understand how to best reduce variations in care. The Critical Illness Outcomes Study (CIOS) was designed to characterize the organizational structure, processes of care, use of protocols, and outcomes of ICUs, and to determine which of these structural and process-of-care factors might be associated with outcomes such as inpatient mortality. 

Of the 94 U.S. ICUs we approached, 69 are participating in the study: 25 (36%) are medical; 24 (35%), surgical; and 20 (29%), mixed. We surveyed the 69 ICUs about their organization, size, volume, staffing, processes of care, and use of protocols, and investigated the relationship of structure and process to ICU mortality. 

We collected patient demographic and treatment information one day each week until at least 100 patients were enrolled in each participating ICU. We have completed enrollment, with more than 6,400 patients, and are currently validating the data collected. CIOS is planning a second study to better determine which factors might be associated with high-performing ICUs.

Checklist for Early Recognition and Treatment of Acute Illness and Injury CERTAIN
Rahul Kashyap, MBBS
The Checklist for Early Recognition and Treatment of Acute Illness and iNjury (CERTAIN) is designed to standardize the approach to the evaluation and treatment of acutely decompensating patients. The design and content was informed by the survey of clinicians from diverse international settings. Available in electronic (laptop/mobile) and paper formats, CERTAIN provides evidence-based diagnostic checklists, clinical decision support, educational modules on performing critical procedures, and the ability to time and document real-time interventions.

A Multi-Centre Observational Study on the Relationship Between the Quality of Brain Resuscitation, Consciousness, Neurological, Functional and Cognitive Outcomes Following Cardiac Arrest (AWAReness during Resuscitation [AWARE II]) AWARE II
Sam Parnia, MD
Neuropsychological deficits after cardiac arrest resuscitation include memory impairment, depression, and posttraumatic stress disorder. As long-term neurologic disorders and disorders of consciousness likely relate to quality of brain resuscitation during CPR, an understanding of the relationship between the quality of brain resuscitation, neurologic status, and consciousness is an important step. By limiting ischemia during resuscitation, higher cerebral oxygenation leads to improved cortical function during CPR and is associated with improved survival as well as favorable neurologic, functional, and neuropsychological outcomes. Mental and cognitive activity and awareness during CPR may reflect verifiable events and are associated with the quality of brain resuscitation. 

Our goals are to a) determine the relationship between the quality of brain resuscitation during cardiac arrest with survival and neurologic, neurocognitive, and functional outcomes; b) evaluate the qualitative nature of patients’ experiences and cognitive activity during cardiac arrest and; c) assess the relationship between the quality of brain resuscitation, consciousness awareness, and mental activity during CPR.

A Multicenter Study to Evaluate Predictive Factors for Multidrug-Resistant Healthcare-Associated Pneumonia in Critically Ill Patients (DEFINE) DEFINE
Ishaq Lat, PharmD, FCCM
Pneumonia is a leading cause of death in the United States and is associated with significant costs to the healthcare system. Increasing rates of multidrug-resistant (MDR) pathogens challenge critical care clinicians to provide effective antimicrobial therapy while preserving the armamentarium of effective therapies. Literature describing the incidence and epidemiology of MDR pneumonia in the United States is limited. We conducted this study across 35 U.S. sites to elucidate the incidence of MDR pneumonia in the critical care setting.

Antipsychotic Use in the ICU and on Transitions of Care
John Marshall, BCPS, PharmD, BCCCP

An Integrated Electronic Health Record and Online Patient-Reported Outcomes Approach for Characterizing Post-Intensive Care Syndrome: A Cross-Sectional and Nested Parallel Cohort Study
Neha S. Dangayach, MD
Post-intensive care syndrome (PICS), characterized by unintended cognitive, functional, and mental health disturbances, has emerged as an important public health problem for intensive care unit (ICU) survivors and their families. With an increase in the aging population, the number of older, critically ill patients also continues to grow. More and more ICU survivors will likely have underlying dementia, prior stroke, traumatic brain injury, or other neurologic comorbidities making them neurologically vulnerable. 

Our goals are to a) better characterize risk factors for PICS in neurologically vulnerable patients compared to non-neurologically vulnerable patients using data captured in electronic health records as part of routine clinical workflow; b) understand limitations in diagnosing PICS in these patients by assessing whether we can measure various domains of PICS adequately using measurement tools that have been validated in non-neurologically vulnerable patients; and c) based on these risk factors, determine whether we can develop and validate a PICS prediction tool for both neurologically vulnerable and non-neurologically vulnerable patients. 

This will be a cross-sectional study with a nested parallel cohort design, with patients categorized as neurologically vulnerable or non-neurologically vulnerable based on the presence or absence of any known structural neurologic injury. We will use a multicenter approach with 16 recruiting sites.