Applicants to our Fellowship program often question the value of research. It is time consuming. It is not why I went to medical school. It will not directly affect my practice. These observations are legitimate, especially, early in a career when the value of research is difficult to see. However, a well designed and constructed clinical research enterprise is essential to the production of a well rounded surgeon.
Three concepts, in evolution, are going to define the landscape for the practice of clinical medicine in the foreseeable future:
- Patient Centered Medicine
- Personalized Medicine
- Information Technology
In 2001, the Institute of Medicine challenged the American health care system to become more patient- and family-centered, a model that widens our focus to embrace the needs of the patient as a whole. No longer is survival or hospital length of stay a sufficient benchmark. We must develop new benchmarks which incorporate life after acute care: return to function, and quality of life. Patient centered care places a premium on patient education, self-efficacy, family involvement, and emotional support.
In 2004 the National Institutes of Health made the development of personalized medicine a cornerstone of its funding priorities. In its most simple form, personalized medicine aims to discover how an individual's genetic, molecular and environmental context predicts the risk of disease and the response to therapy.
Today, we sit astride the first ripple of the information tsunami. Soon clinical information will overwhelm the physician's ability to process it. Detailed standardized medical records will be instantly available; medications will be tailored to the patient's genome; patient follow up will be internet based; and patient education will employ distance learning technology.
Our goal IS NOT to make every student, resident, or fellow, a career research professional.
It IS our goal to:
- Expose you to those foundational concepts upon which your successful practice will depend.
- Give you strategic exposure to research, not tactical intimacy.
- Expose you to study design so you can read the literature critically.
- Expose you to clinical informatics so you can identify robust decision support tools.
- Expose you to personalized medicine and its underlying science.
And finally, our goal is to expose you to patient centered care, so you appreciate the art of medicine. To achieve these goals we have created the Surgical Critical Care Research Platform.
The intensive care unit is a hostile research environment, filled with uncertainty, uncontrollable elements and regulatory challenges. All of these challenges create opportunity.
Over the past decade we have assembled a platform which permits productive research in the ICU; specifically, acute care surgery patients. The research component of the platform is comprised of 4 Cores: Human Subjects, Informatics, Biomarkers and Genetics. Our long-term vision is to create a platform for translational research using trauma an acute-care surgery as a model for critical care. Our long term goal is pathway discovery, designed to illuminate unappreciated biologic pathways controlling the metabolic response to injury and illness.
It is useful to think of the research enterprise as a portfolio of synergistic businesses. Each business has its strengths and weaknesses but as a well-balanced portfolio they are more efficient and cost-effective then each business line in isolation.
Our research portfolio contains 3 types of research products designed to fulfill our research mission: To Improve patient care, to advance basic science and to train new investigators. Figure 1 depicts the overall research structure for Vanderbilt's trauma/critical care program.
There are 3 products: Clinical trials, investigator initiated research and government funded research. Each of these products complements the 4 cores: Human subjects, informatics, genetics and biomarkers.
Clinical trials, also called contract research, medical research or research studies, determine safety and efficacy of new drugs or treatment modalities. These studies are most often multi-institutional, global trials sponsored by pharmaceutical corporations.
Strengths of the clinical trials product are: the trials are of short duration, provide educational value and if properly priced, offset expenses. Their weaknesses include the fact that they are often very labor-intensive, volatile (terminated with little notice at the discretion of the drug company) and therefore high risk.
Clinical trials, in our patient care center, are managed by our Human Subjects Core under the direction of Judith M. Jenkins RN, MSN. Each clinical trial has a division faculty member designated as site Principal Investigator (PI) and has multiple Sub-investigators. Junior faculty, interested in trial design and execution, are encouraged to become PIs.
Since its inception 14 years ago, our Human Subjects Core has successfully conducted 46 clinical trials, managed 5 federal grants, procured over 10,000 biologic samples (including 7,000 genetics samples), contributed to numerous abstracts and manuscripts, supervised six data repositories, and ensured regulatory compliance for all research endeavors of the division.. Research-experienced critical care nurses provide coverage 24 hours a day, 7 days a week. These nurses screen patients, obtain informed consent, procure specimens and foster the clinical research culture across the Surgical Critical Care platform.
Involvement in clinical trials provides practical experience within the Fellowship structure that allows the Fellow exposure to study design, implementation, IRB regulations, and subject protections. A well designed well executed clinical trials program provides significant revenue enhancement for the division. Therefore it is useful skill for the Fellow's career development.
Investigator sponsored research is unique in that it is funded internally by the division. This is where the junior investigator gets their feet wet. Each first year Fellow is given the opportunity to be mentored, contribute to a research project for presentation at a national meeting and co-author a peer-reviewed manuscript.
Investigator sponsored research product has two goals:
- To improve the patient experience.
- Provide preliminary data for a government funded grant
Research to improve the patient experience covers a broad-spectrum of opportunities:
- Improvement in health care delivery, efficiency and performance.
- Quality improvement and systems research.
- Provision of patient and family centered care. Dr. Morris is recognized nationally for his work in health care delivery, efficiency and performance. Dr. May's research interest is in quality improvement and outcomes research. And Dr. Miller is a leader in the provision of family centered care.
All government funded initiatives require preliminary data. However, that preliminary data is often clinical in nature and results from a single clinician asking a single, often simple, clinical question:
Why is the ventilator associated pneumonia rate higher in trauma centers than in other intensive care units? That question prompts numerous potential hypothesizes:
- Pre-hospital failure of airway control.
- Immunosuppression secondary to magnitude of injury.
- Genetic predisposition
To answer these questions preliminary data must be generated. Such data may refine the definition of the disease (May), characterize resistance patterns (McNew) or predisposing factors (Miller) or demonstrate basic science associations (Norris). Over time, the accumulation a preliminary data allows the construction of a basic science hypothesis, the generation of a government funded grant or the creation of a new clinical trial.
The investigator initiated research product is supported by the Informatics Core, under the direction of Patrick Norris PhD. Our Informatics Core capitalizes on Vanderbilt's world-class clinical informatics infrastructure, including electronic physician-order, laboratory, microbiology, pharmacy and radiology systems, to provide data on all patients.
Over the past decade, the informatics core has made seminal contributions to over a hundred investigator initiated abstracts and manuscripts.
In addition to data stored in the EMR, the Trauma Center maintains specific data bases to support investigator initiated research. These include: the trauma registry (TRACS), the Signal Interpretation and Monitoring (SIMON) initiative, SICU and Trauma repositories.
TRACS data has been maintained on VUMC patients admitted for trauma since 1990; over 54,000 admissions to date. More than 350 parameters are retrospectively captured following discharge, including demographics, injuries, comorbidities, operative procedures, hospital disposition, complications, costs, resource utilization and lengths of stay at various levels of care.
SIMON is a continuous physiological data management system, developed collaboratively with VUMC and the School of Engineering. SIMON automatically captures vital signs and physiologic waveforms from all trauma ICU beds, including: heart rate, invasive and non-invasive blood pressures, intracranial and cerebral perfusion pressures, arterial and venous oxygen saturations, temperature, pulmonary and central venous pressures, cardiac index, and end diastolic volume index and ventilator parameters.
SIMON is the first system in the country to routinely archive such data over an entire ICU, and to routinely report the first of a new generation of vital signs, heart rate variability (HRV), to clinicians daily. Since December 2000, data has been collected on over 7,000 patients, representing more than 700,000 hours of continuous monitoring and over 50 billion data points.
Figure 3 describes the process by which the informatics core selects constituent information from core data sources, and links in together in a deidentified IRB approved research database for complex statistical analysis.
Our long-term vision is to foster hypothesis-based and translational research around the human metabolic/physiologic response to injury and/or critical illness. The purpose is three-fold: to improve understanding of biologic processes after trauma or critical illness; to foster translational research, bringing the bench to the bedside; and, to encourage interaction and communication within the Institution and throughout the trauma community.
Our Genetics and Computation Core is supported by NIH and DOD funding. We postulate that the routine identification of the stress genotype, coupled with covariates of the stress environment (shock, injury severity, comorbidities) and identification of the stress phenotype, will allow the introduction of strategies that personalize therapy and improve outcome. Our conceptual framework is:
Stress Genotype + Stress Environment = Stress Phenotype
Classically, phenotype is defined as observable characteristics (demographic, anatomic and behavioral) which result from the expression of an individual's genotype. We believe that host factors, in general, and genetic factors, in particular, are under-appreciated components of injury outcome. The population contains genetic variations (polymorphisms) which, under normal circumstances, are masked. They are not pathologic and have no impact on an organism's ability to function in non-stress states. In the stress state, such as multisystem trauma, these polymorphisms are exposed and result in differing outcomes among patients. We call this concept 'the stress genotype'.
In conjunction with the Division of Trauma Orthopedics, we have funding to look at the problem of heterotopic ossification, a complication which has close to a 60% penetration rate in military casualties with high velocity blast injury. Using the paradigm outlined above the equation become simple:
H.O. Genotype + High Velocity Fracture = Risk for Heterotopic Ossification
Over the past decade, advances in genetic technology have been applied to many disciplines in medicine. In trauma, the process is difficult because the disease is common and the phenotype, and its interaction with the stress environment, is profoundly complex. We hypothesize that a few critical pathways largely determine the host response following trauma. Variation in the genetic composition of these critical pathways (the stress genotype) affects their function, alters the stress response and can dramatically affect patient outcome (stress phenotype).
The stress environment is highly variable; introducing numerous confounders to the genetic signal. These confounders are both patient-based (age, injury characteristics, concomitant injuries and co-morbidities, and differences in therapy - pharmacologic and surgical) and system-based (quality of care and clinical variation inherent to the practice of individual physicians). Practice variability in our Trauma Center is obviated by a care delivery structure that aggregates trauma patients in the hands of a small number of physicians practicing under standardized evidence-based protocols.
To ensure the integrity of the genetic signal, one must confront the challenges of simultaneously measuring the confounders of the stress environment and the stress phenotype. The solution requires a robust information management system capable of dense data collection on individual patients and the aggregation of this data to populations of patients. Our existing research Core infrastructure was developed to achieve just this goal.