Cognitive Impairment in Trauma Patients Without Closed Head Injury

Personnel

William Todd Obremskey, MD, MPH	Orthopaedic Trauma	Principal Investigator
Wes Ely, MD MPH	General Internal Medicine	Co-Investigator
Frank Schuler, MD, PhD	Orthopaedic Trauma	Co-Investigator
Robin Edwards Driver, RN	Orthopaedic Trauma	Study Coordinator
Erin Roman, RN	Orthopaedic Trauma	Research Nurse
Mary Alice Nading	Orthopaedic Trauma	Research Assistant
Frank E Harrell Jr, PhD	Biostatistics
Theresa Scott, MS	Biostatistics

E-mail addresses:william.obremskey@Vanderbilt.Edu,f.harrell@vanderbilt.edu,theresa.scott@vanderbilt.edu

Purpose

Systemic Inflammatory Response Syndrome (SIRS) in multiple trauma is recognized as a systemic illness involving marked inflammatory and coagulopathic disturbances leading to dysfunction of many organ systems - including in almost all cases the central nervous system (CNS). Dysfunction of the CNS is also particularly likely to be further exacerbated by iatrogenic factors such as the use of psychoactive drugs or impaired metabolism of the myriad of medications administered to multiple trauma patients. Understanding the etiology of CNS dysfunction and interactions between the CNS and other dysfunctional organs could improve the overall approach to multiple trauma patients. However, in contrast to routinely monitored forms of organ dysfunction (i.e., pulmonary, cardiac, hepatic, renal, and hematologic systems), the CNS has not traditionally been monitored or studied to a great extent. Acute cognitive dysfunction is extremely common in multiple trauma patients due to factors such as age, critical illness, pathophysiologic effects of the illness, and medical management The relationship between acute cognitive dysfunction and long-term cognitive deficits in multiple trauma survivors has not been studied to date, and little is known about the risk factors leading to either condition.

Specific Aims

In a prospective cohort of patients with multiple trauma (ISS >18), we will conduct studies:

1. To determine whether the severity and duration of specific injuries, treatment or interventions in multiple trauma patients are predictors of long-term cognitive impairment in a retrospective cohort.

Background

According to the National Research Council, for many people in good physical condition who succumb to an acute illness, cognitive decline is the main threat to their ability to recover and enjoy their favorite activities and for those whose physical activities are already limited, cognitive decline is a major additional threat to quality of life. We know that multiple trauma patients are at great risk for multiple organ dysfunction syndrome (MODS), and that the brain is one of the most frequent organs involved in this process. Furthermore, both the lay public and health care professionals are becoming increasingly concerned not only with survival, but also with the quality of patients' lives, which is determined in large measure by their neuropsychological outcomes. Angus et al documented that at 6 months following Acute Lung Injury (ALI), the proportion of patients complaining of psychiatric, cognitive, and neurologic symptoms were 57%, 32%, and 44%, respectively. In a recent study published in the New England Journal of Medicine regarding treatment preferences in seriously ill patients, 9 out of 10 patients declared that they would rather die than survive and be cognitively impaired. As the medical community strives to improve the outcomes of patients with multiple trauma, it is imperative that we better understand the epidemiology and risk factors of cognitive dysfunction in multiple trauma patients.

Definitions of Cognitive Impairment

To understand this proposal, it is necessary to define key terms. Long-term cognitive impairment will refer to abnormalities documented through neuropsychological testing at 6-month and 12 month follow-up, which involve cognitive domains that are required for daily functioning such as language, mental processing speed, memory, executive function, and visuo-construction abilities. To assess and adjust for possible baseline cognitive deficits (i.e., mild dementia), we have experience using well-validated and widely accepted dementia screening instruments completed by surrogates that quantify the presence of dementia . While we will be excluding patients with known baseline dementia, subclinical cognitive impairment prior to entry would be a confounder and these test results will be used to adjust for this possibility using multivariable analysis. The neuropsychological tests and quality of life instruments will be in 6-month and 12 month follow-up patients.

Long-Term Cognitive Impairment

Cognitive deficits in patients with pulmonary disorders like COPD and obstructive sleep apnea with concomitant hypoxemia are well documented. Neuropsychological impairments due to hypoxemia include impaired memory, executive dysfunction, visual-spatial deficits and global cognitive decline. The high prevalence of long-term cognitive impairment following critical illness, ALI, and infections has recently been recognized. Dr. Ramona Hopkins assessed neuropsychological outcomes in two patients with Hantavirus Pulmonary Syndrome. The two patients experienced severe hypoxemia and neuropsychological impairment at hospital discharge and at one year. Based on these data, she prospectively assessed cognitive function in a larger group of ALI survivors, who had impaired memory, attention, concentration, and decreased mental processing speed. At the time of hospital discharge, 100% of the patients experienced cognitive impairment, and at one-year follow-up, 78% had at least one of the following: impaired memory, attention, concentration and/or mental processing speed. In this cohort, pulse oximetry was measured for a total of 31665 hours, and data without a good pulse waveform was excluded. The patients' mean saturations were below 90% for 122-144 hours per patient, below 85% for 13-18 hours, and below 80% for 1-3 hours. These data were surprising to many intensivists at Dr. Hopkin?s institution, suggesting that patients were hypoxemic for an unrecognized period of time even in a meticulously monitored ICU setting. The degree of hypoxemia correlated significantly with neurocognitive sequelae (r2 0.25 to 0.45, all P<0.01) . In a case-control investigation of 33 ALI patients versus 24 ICU survivors without ALI, it was observed that ALI patients had more profound neuropsychological deficits at 1 year follow-up than did the non-ALI controls. These deficits were noted in domains of attention, visual processing, psychomotor speed, and executive function (all P<0.05), and were partly explained by the degree of hypoxemia. Attention and memory impairments are commonly associated with infectious diseases , which are the leading cause of ALI. Induced cytokine activation in healthy male volunteers by intravenous injection of Salmonella abortus equi endotoxin, resulted in increased anxiety, depressed mood, and impaired memory that correlated with cytokine secretion.

The duration of cognitive deficits following a variety of causes of critical illness has been surprising. For example, it has been shown that neuropsychological sequelae following coronary artery bypass graft surgery have an important effect on outcomes up to 5 years later. In another cohort of ICU survivors, up to 25% had deficits at 6 years following their ICU stay. Lastly, the societal implications of an enlarging population of ALI survivors with cognitive impairment could be tremendous. Recent data from the Cardiovascular Health Study showed that even mild cognitive impairment leads to serious adverse neuropsychiatric consequences. Another publication, using multivariable analysis in over 1800 patients, found that a 3 point decrease on MMSE was associated with a $6,000 yearly increase in the cost of an individual's overall healthcare expenditures, which may under-represent the decrement experienced by many ALI survivors. Generally speaking, the economic consequences of long-term cognitive impairment are strikingly high. It is estimated that the annual per-patient societal cost burden ranges from $15,022 for mild cognitive impairment to $34,515 for more severe forms. The cost of informal caregiving alone for patients with dementia has been estimated to exceed $18 billion annually.

In contrast to the body of knowledge regarding the etiology of neuropsychological outcomes of patients following coronary artery bypass grafting, which have been studied for 15 years and linked to factors specific to the surgical and anesthetic management, we do not have robust data in the multiple trauma population. Therefore, in this cohort of patients, we will study risk factors such as age, baseline co-morbidity scores, baseline cognitive status, ISS, shock, the degree and duration of hypoxemia, and iatrogenic factors such as sedative and analgesic drugs. In a recent report from Surviving Intensive Care 2002 Roundtable Conference held in Brussels, the need for future investigations in neurocognitive abnormalities among survivors of ALI and sepsis received the strongest recommendation from the international panel of experts. This investigation will evaluate long term cognitive function at 6 or 12 months post injury in miltiple trauma patients and assess risk factors during their hospitalization in order to understand the relationships and predictive features between the major proposed risk factors (see Research Design and Methods) and patients? cognitive outcomes.

Inclusion Criteria

• Injury severity Score Greater than 18.
• No closed head injury evident on CT scan.
• Informed consent
• Greater than 18 years old
• Patient admitted to trauma intensive care unit
• English competent
• Patient enrolled in Trauma Registry

Exclusion criteria

• Closed head injury
• Less than 18 years old
• Unable to obtain consent
• Follow-up is unreliable

Data Collected

1. Demographics: age, sex, address, contact information
2. Injury Severity Score
3. AIS Head
4. AIS Extremity
5. AIS pelvis
6. AIS - abdomen
7. AIS Chest
8. ARDS: pAO2/FIO2 <200
9. ALI: pAO2/FIO2 <300
10. Ventilation days
11. Long bone fractures
12. Long bone fracture with IMN
13. Transfusions
14. Education level
15. Smoking
16. Substance abuse History
17. Income level
18. Pre-injury employment status: labor/non-labor
19. SF-36
20. Pre-injury: Surrogate cognitive function
21. Outcome testing

Cognitive Instruments

1. Modified Mini Mental State Exam: a brief test of global mental status
2. Rey Complex Figure (copy and 30 minute delay): a test of visual construction and visual memory that requires a subject to copy a complex figure and to recreate it from memory
3. Rey Auditory Verbal Learning Test (RVALT): a test of multiple aspects of memory with immediate, delay, and recognition components that requires a subject to recite word lists
4. Trails A: a test of attention that requires a subject to connect (draw a line between) a series of numbers on a page as quickly as possible.
5. Trails B: a test of executive functioning that requires a subject to connect (draw a line between) a series numbers and letters in a specified sequence as rapidly as possible.
6. Digit Span: a test of attention, concentration, and working memory that requires a subject to recite a progressive greater number of digits (forwards/backwards).
7. Digit Symbol: a test of information processing speed in which a subject is required to copy appropriate symbols in a series of empty numbered boxes using a answer key.
8. FAS: a test of language (verbal fluency) and executive functioning comprised of 3 trials in which a subject generates a many words as possible beginning with the letters F, A, and S.
9. AMNART: a test that provides a gross estimate of premorbid intellectual functioning in which a subject reads and attempts to pronounce a series of progressively more difficult words.
10. IQCODE or MBDRS: surrogate measures of premorbid cognitive impairment which can reliably detect the presence of pre-existing dementia. The IQCODE will be used routinely except in those cases where an informant who has known the subject for at least 10 years (a requirement of the test) is available. In these cases, the MBDRS will be used.

Emotional Instruments

1. Beck Depression Inventory: a brief depression screening tool.
2. Beck Anxiety Inventory: a brief anxiety screening tool.
3. PTSS-10: a brief screening tool that detects probable. The IES (Impact of Events Scale) has been used so this may be a better choice.)
4. Clinician Administered PTSD Scale (CAPS): A comprehensive clinician administered interview in which a subject is evaluated for a formal diagnosis of PTSD. THIS WILL BE USED ONLY WHEN A PATIENT SCORES IN THE CLINICAL RANGE ON THE PTSS-10.
5. CAGE: A brief alcoholism screening tool

Functional Instruments

1. Functional Activities Questionnaire (FAQ): a brief surrogate measure of independent activities of daily living (IADL) which assesses higher order functions such as cooking, money management, map reading, etc.
2. Activities of Daily Living (ADL): a brief measure of basic functional abilities such as bathing and transferring.
3. SF-36 Health Survey: a measure of quality of life that assesses domains of both emotional health and physical health.
4. Employment Questionnaire: a brief questionnaire that assesses employment history and current employment status.
5. Awareness Questionnaire: a brief questionnaire with identical versions for both the patient and surrogate in which they rate the patient?s functional abilities across multiple domains and skill areas.

Total administration time for this battery is approximately 75 minutes. An identical battery is currently being used in the ABC Trial, an RCT currently being conducted by Vanderbilt investigators at St. Thomas Hospital. It has been widely accepted by patients and families and has been well tolerated.

Data Management

A patient database will be constructed and maintained by the coordinator. Data will only be entered by coordinator and/or assistant for reasons of consistency and confidentiality. Signed consents, source documents, case report forms, patient completed questionnaires and follow-up information will be kept in file cabinet in coordinator's study office. This will limit access of information to research staff only and will ensure patient confidentiality. A phone and fax will be readily available in coordinator's office to place and receive patient related phone calls. This will also help to ensure patient confidentiality.

Each participant will be assigned a Study ID# at time of enrollment, by the PI or coordinator. The study ID numbers will begin with 1001 for the first patient enrolled and randomized and increment sequentially for each participant enrolled within any one center. This ID# will be the patient's identifier for the duration of the study and will ensure confidentiality for study participants. The Principal Investigator, Study Coordinator, Research Nurse and Research Assistant will have access to study ID numbers and patient data.

Data and Safety Monitoring

This is a retrospective observational study and no adverse events or safety concerns will be applicable. Principal Investigator and Coordinator will continuously monitor to ensure site compliance with study protocol and all patient data gathered is accurate. Compliance will be identified primarily by completed case report forms and proof documents. We will ensure frequent communication between research staff through research meetings, e-mail, memos, newsletters, and/or telephone.