Effects of day-of-injury alcohol intoxication on neuropsychological outcome in the acute recovery period following traumatic brain injury

Archives of Clinical Neuropsychology 23 (2008) 809–822

Effects of day-of-injury alcohol intoxication on neuropsychological outcome in the acute recovery period following traumatic brain injury夽 Rael T. Lange a,∗ , Grant L. Iverson a , Michael D. Franzen b a

British Columbia Mental Health and Addiction Services & University of British Columbia, Canada b Allegheny General Hospital, Canada Accepted 21 July 2008

Abstract Some researchers have found that day-of-injury alcohol intoxication is associated with worse outcome following traumatic brain injury (TBI). The purpose of this study is to examine the effects of day-of-injury intoxication on the acute neuropsychological outcome from TBI. Participants were 36 patients with TBI (18 sober, 18 intoxicated) matched on injury severity characteristics and demographic variables. A larger group of 146 patients (112 sober, 36 intoxicated) with TBI was also selected for analyses; not matched on injury severity or demographic variables. Patients had no history of pre-injury alcoholism and were assessed within 10 days post-injury on 13 cognitive measures. Unexpectedly, patients who were sober at the time of injury performed lower on many of the cognitive measures compared to those who were intoxicated. In contrast to the research literature, these results suggest that individuals who were intoxicated at the time of injury performed similarly, and in some cases, better than those who were sober at the time of injury. Crown Copyright © 2008 Published by Elsevier Ltd on behalf of National Academy of Neuropsychology. All rights reserved. Keywords: Ethanol; Head injury; Cognition; Neurocognitive; Acute outcome; Risk factors

1. Introduction Individuals who sustain a traumatic brain injury (TBI) are frequently intoxicated with alcohol at the time of injury (Brismar, Engstrom, & Rydberg, 1983; Edna, 1982; Kaplan & Corrigan, 1992; Sparadeo, Strauss, & Barth, 1990). The prevalence of positive blood alcohol levels (BAL) in hospital patients presenting to the Emergency Department (ED) with head trauma ranges from 33% to 72% (e.g., Corrigan, 1995; Dikmen, Machamer, Donovan, Winn, & Temkin, 1995; Gurney et al., 1992; Kreutzer, Doherty, Harris, & Zasler, 1990; Rimel & Jane, 1983; Solomon & Malloy, 1992; Sparadeo & Gill, 1989; Sparadeo et al., 1990), with 37–53% having BALs that exceed the legal limit for intoxication (Gurney et al., 1992; Kraus, Morgenstern, Fife, Conroy, & Nourjah, 1989; Rimel, Giordani, Barth, & Jane, 1982). Day-of-injury alcohol intoxication has significant implications for the diagnosis, management, treatment, and recovery 夽

A portion of these data were presented at the annual conference of the Research Society on Alcoholism, July 2007, Chicago, Illinois, USA. Corresponding author at: BC Mental Health and Addiction Services, Suite 201, 601 West Broadway, Vancouver, BC V5Z 4CZ, Canada. Tel.: +1 604 707 6374; fax: +1 604 707 6399. E-mail address: [email protected] (R.T. Lange). ∗

0887-6177/$ – see front matter. Crown Copyright © 2008 Published by Elsevier Ltd on behalf of National Academy of Neuropsychology. All rights reserved.

doi:10.1016/j.acn.2008.07.004

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from TBI. Patients who present to the ED with a positive BAL are more difficult to manage and treat, have a slower acute recovery (Barker et al., 1999; Brismar et al., 1983; Cunningham, Maio, Hill, & Zink, 2002; Gururaj, 2004; Kaplan & Corrigan, 1992; Kraus et al., 1989; Wilde et al., 2004), and consequently place an increased economic burden on the health care system. The effects of day-of-injury alcohol intoxication on the neuropsychological and neuropathological outcome from TBI have received modest attention in the research literature. Researchers have reported that patients who are intoxicated at the time of TBI have worse cognitive recovery (Bombardier & Thurber, 1998; Kelly, Johnson, Knoller, Drubach, & Winslow, 1997; Sparadeo & Gill, 1989; Tate, Freed, Bombardier, Harter, & Brinkman, 1999; Wilde et al., 2004) and greater atrophic changes in the brain (Barker et al., 1999; Wilde et al., 2004) compared to those who are sober. Specifically, individuals who are intoxicated at the time of injury (a) have worse global cognitive and neurobehavioral status at discharge as measured by the Rancho Los Amigos Scale (Sparadeo & Gill, 1989), (b) show greater trauma induced degenerative changes post-injury as indicated by higher ventricle-to-brain ratio and lower whole brain volume (i.e., grey and white matter) (Barker et al., 1999; Wilde et al., 2004), and (c) perform more poorly on measures of verbal ability, visuospatial ability, immediate and delayed memory, processing speed skills, and executive functioning (Bombardier & Thurber, 1998; Kelly, Johnson, et al., 1997; Tate et al., 1999; Wilde et al., 2004). Although some studies have reported findings that are inconsistent with this premise (Barker et al., 1999; Bigler et al., 1996; Lange, Iverson, & Franzen, 2007b; Vickery et al., 2008), the majority of the research literature in this area provides support for the presence of a deleterious interaction between day-of-injury alcohol intoxication and outcome from TBI. It has been suggested that worse outcome following day-of-injury alcohol intoxication may be the result of an increased magnitude of brain injury resulting from a variety of negative responses in the brain not present in a person who is sober at the time of injury. Negative responses include, but are not limited to, hemodynamic and respiratory depression, altered homeostasis due to increased blood clotting time, blood–brain barrier impairment, and/or increased risk for developing hematomas (Alexander, Kerr, Yonas, & Marion, 2004; Altura & Altura, 1999; Altura, Memon, Altura, & Cracco, 1995; Barker et al., 1999; Kelly, 1995; Mautes et al., 2001; Sparadeo & Gill, 1989; Wilde et al., 2004; Woolf, Cox, Kelly, McDonald, & Hamill, 1990; Zink & Feustel, 1995; Zink et al., 2001). However, researchers have reported a significant relationship between day-of-injury alcohol intoxication and premorbid history of alcohol abuse in TBI samples (Dikmen et al., 1995; Kreutzer et al., 1996; Sparadeo & Gill, 1989), with up to 75% of patients who are intoxicated at the time of injury having a positive history of pre-injury chronic alcoholism (Bombardier, 1995). Regardless of BAL at the time of injury, prevalence rates of chronic alcoholism in all TBI patients range from 25% to 79% (Bogner, Corrigan, Mysiw, Clinchot, & Fugate, 2001; Corrigan, 1995; Corrigan, Bogner, Mysiw, Clinchot, & Fugate, 2001; Kolakowsky-Hayner et al., 1999; Kreutzer et al., 1990; Rimel et al., 1982; Sparadeo & Gill, 1989; Tobis, Puri, & Sheridan, 1982). As such, worse outcome may simply reflect the effects of pre-injury alcohol abuse that is very common in this patient population (e.g., Barker et al., 1999; Bogner et al., 2001; Corrigan et al., 2001; Fein, Fletcher, & Di Sclafani, 1998; Kolakowsky-Hayner et al., 1999; Paraherakis, Charney, & Gill, 2001; Parsons, 1998; Pfefferbaum & Sullivan, 2002; Pfefferbaum et al., 2000). The influence of pre-injury alcohol abuse on poor outcome following intoxicated TBI cannot be underestimated. Researchers attempting to differentiate the contribution of day-of-injury alcohol intoxication from pre-injury chronic alcohol abuse have found mixed results. Some studies have clearly supported the influence of alcohol intoxication at the time of injury as more influential in determining neuropsychological and neuropathological outcome than pre-injury alcohol abuse history (Brooks et al., 1989; Tate et al., 1999), other studies have found pre-injury alcohol abuse to be more influential than day-of-injury intoxication (Lange et al., 2007b), or have reported that day-ofinjury intoxication and pre-injury alcohol abuse are equally important (Wilde et al., 2004) or non-contributory factors (Vickery et al., 2008). Although these studies do not provide us with clear answers regarding the competing influence of these two alcohol variables on outcome from TBI, this research highlights the methodological importance of controlling for the effects of pre-injury alcohol consumption in research examining the effects of day-of-injury alcohol intoxication. The purpose of this study is to examine the effects of day-of-injury alcohol intoxication on the acute neuropsychological outcome (i.e., within the first 10 days post-injury) from TBI in a sample of patients with no pre-injury alcohol abuse. It is hypothesized that patients who are intoxicated at the time of injury will have worse neuropsychological outcome compared to those who were sober at the time of injury.

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2. Method 2.1. Participant pool and selection procedure Participants were selected from an archival database of 2160 patients seen as part of the Allegheny General Hospital (AGH) trauma service clinical pathway in Pittsburgh, Pennsylvania, for a known or suspected TBI. These patients presented to the trauma service during the period of 1991–1994 and 2002–2003. The basic clinical pathway for any person with known or suspected brain injury, irrespective of severity, involved a Glasgow Coma Scale (GCS) rating obtained on admission to the trauma centre (by emergency department personnel), head X-ray, CT scan of the brain, and an assessment of post-traumatic amnesia with the Galveston Orientation and Amnesia Test (Levin, O’Donnell, & Grossman, 1979). Only those patients with a definite TBI were of interest, defined by the following criteria: (a) evidence of skull fracture on X-ray, (b) evidence of trauma-related brain abnormality (e.g., edema, hematoma, or contusion) on CT-scan, and/or (c) a Glasgow Coma Scale score of eight or less. Of the sample, 667 patients (42.4%) were classified as sustaining a definite TBI. Patients were further selected for inclusion if they had a blood alcohol level (BAL) measured as part of a toxicology screen on admission (n = 524; 78.6%). Toxicology screening at the time of admission is fairly routinely undertaken by the trauma service; however, some patients do not receive a toxicology screen (n = 143, 21.4%; e.g., not ordered or refusal). Alcohol intoxication was defined as a BAL of 100 mg/dl or higher, consistent with the extant research literature. Of the patients who received a toxicology screen, the prevalence of (a) any detectable alcohol (i.e., BAL > 0) at the time of injury was 53.4% (n = 280), (b) intoxication (i.e., BAL ≥ 100 mg/dl) at the time of injury was 49.2% (n = 258), and (c) sobriety at the time of injury (i.e., BAL = 0 mg/dl) was 50.8% (n = 266). Patients were only selected if their BAL at the time of admission was 0 mg/dl or ≥100 mg/dl (n = 480, 91.6%). Patients with BAL between 1 mg/dl and 99 mg/dl were excluded in order to create two distinct BAL groups. Patients were further selected for inclusion if they had available information regarding their pre-injury alcohol use (n = 360, 75.0%). Pre-injury alcohol use was determined by a chart review and patient interview by the neuropsychologist on duty at the time evaluation. Patients with a significant history of pre-injury alcohol use were targeted for exclusion. Pre-injury alcohol abuse was classified as present when (a) the patient’s medical records indicated a history of abuse or treatment, or heaving drinking [i.e., more than 5–6 drinks a few times per week] and (b) if the patient reported, during interview, a history of abuse or treatment, or heavy drinking. Patients classified as having a significant pre-injury alcohol abuse history represent a relatively mixed group of individuals whose pre-injury alcohol abuse varied from mild to severe. Detailed information relating to duration, frequency, and degree of pre-injury alcohol abuse was not coded and entered into the database, and is not available. Nonetheless, representative patients in this category who were excluded were those patients (a) with a current addiction problem at the time of injury, (b) who participated in a rehabilitation treatment program several years prior to injury, (c) who participated in a rehabilitation treatment program just prior to injury, (d) had a history of addiction in the past, (e) who reported to consume 5–6 alcoholic drinks a few times a week, and/or (f) who reported to consume more than 5 drinks per day. Of the 360 patients with available information, 50.8% (n = 183) had a positive pre-injury alcohol abuse history and 49.2% (n = 177) had a negative pre-injury alcohol abuse history. All patients presenting to the trauma service with a known or suspected traumatic brain injury were referred to the neuropsychology service for consultation. A brief neuropsychological battery was administered to document the patient’s cognitive status in terms of attention, memory, language, and executive functions. In order to control for the effects of testing time post-injury, only those patients who were tested within 10 days of injury were selected for inclusion (n = 148, 86.4%; TBI Sober, n = 112; TBI Intoxicated, n = 36 [BAL: M = 158.4 mg/dl, S.D. = 41.5, range = 100–268 mg/dl; participants with BAL > 200 mg/dl = 4]). In many cases however, all measures were not routinely administered due to time constraints and/or other factors (such as orthopedic injuries). Only those patients who had been administered the entire battery of tests were included (n = 95, 62.1%). Of this group, 25.3% of patients (n = 24) were intoxicated (i.e., BAL ≥ 100 mg/dl) at the time of injury, and 74.7% of patients (n = 71) were sober at the time of injury (i.e., BAL = 0 mg/dl). Through sorting and visual inspection, an attempt was made to match the 24 patients who were intoxicated at the time of injury with a patient who was sober. Patients were matched based on (a) injury severity classification [e.g., complicated mild TBI, mild TBI with skull fracture, moderate TBI, and severe TBI], (b) ethnicity, (c) days post-injury [±2 days], (d) age [±5 years], and (e) education [±2 years]. Patients who could not be matched on all five criteria

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Table 1 Demographic and injury severity characteristics TBI Sober

Age (in years) Education (in years) GCS score Days tested post-injury

TBI Intoxicated

M

S.D.

M

S.D.

26.8 12.4 11.5 5.0

8.8 1.7 4.8 2.6

27.6 12.6 11.3 3.6

9.4 1.5 5.2 2.6

TBI Sober N Gender Male Female

TBI Intoxicated %

N

%

12 6

66.7 33.3

12 6

66.7 33.3

6 6 6

33.3 33.3 33.3

6 6 6

33.3 33.3 33.3

LOC Positive Negative Equivocal

12 2 4

66.7 11.1 22.2

10 3 5

55.6 16.7 27.8

Mechanism of injury MVA/MCA Falls Pedestrian struck MV Object/blow/assault Other

12 2 2 0 2

66.7 11.1 11.1 – 11.1

9 1 2 2 4

50.0 5.6 11.1 11.1 22.2

CT scan Normal Abnormalities Missing

5 12 1

27.8 66.7 5.5

5 12 1

27.8 66.7 5.5

Data collection period 1991–1993 2002–2003

17 1

94.4 5.6

15 3

83.3 16.7

Injury severity MTBI with skull Fx Complicated MTBI Severe TBI

Note: n = 36 (TBI Sober, n = 18; TBI Intoxicated, n = 18); CT = computed tomography; GCS = Glasgow Coma Scale; LOC = loss of consciousness; MTBI = mild traumatic brain injury; TBI = traumatic brain injury; MVA = motor vehicle accident; MCA = motor cycle accident; MV = motor vehicle.

were not included. Of the 24 patients who were intoxicated at the time of injury, 18 patients were matched successfully to 18 patients who were sober. All other patients were excluded from the final sample. The results, as seen in Table 1, were two closely matched groups on demographic and injury severity variables. 2.2. Participant description The participants in the final sample were 36 patients (i.e., 18 sober [0 mg/dl]; 18 intoxicated [≥100 mg/dl; M = 151.6, S.D. = 33.1, range = 100–248 mg/dl] with definite TBI and no history of alcohol abuse or other substances. More than half of the patients (61.1%) were assessed within 4 days after presenting to the trauma service, with all patients assessed within 10 days. The average age and education of the sample was 27.2 years (S.D. = 9.0) and 12.5 years (S.D. = 1.6), respectively. There were no significant differences between TBI-sober versus TBI-intoxicated groups in the number of days tested post-injury (p = .308), age (p = .755), or education (p = .558). Sex of the sample was predominantly male (66.7%). Mechanism of injury was predominantly motor vehicle accident with no seatbelt (41.7%), followed by motor vehicle accident with seatbelt (11.1%), and pedestrian struck by a motor vehicle (11.1%). The breakdown of injury

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Table 2 Descriptive statistics, ANOVA results, and effect sizes by group Measures

Logical Memory I Logical Memory II LM % Savings Visual Rep I Visual Rep II VR % Savings Digit Span: Forward Digit Span: Backward Trails A Trails B COWAT: CFL WCST-64 Categories WCST-64 PE

TBI Sober

TBI Intoxicated

M

S.D.

M

S.D.

21.0 12.8 56.3 31.8 24.7 75.8 8.0 4.7 32.7 97.1 29.7 2.4 16.4

6.0 8.8 34.1 6.5 10.9 32.4 1.8 1.8 18.7 57.9 9.5 1.4 11.7

24.5 19.1 76.0 34.6 31.9 91.4 8.9 5.7 27.0 61.4 35.3 3.7 8.8

6.7 7.7 19.6 4.6 6.9 12.5 1.8 2.4 7.7 21.0 13.1 1.2 4.4

p

d

Effect size

.109 .028 .041 .148 .023 .066 .151 .197 .242 .019 .158 .009 .015

0.55 0.77 0.73 0.50 0.82 0.69 0.50 0.44 0.43 0.91 0.50 0.92 0.94

Medium Large Medium-Large Medium Large Medium-Large Medium Small-Medium Small-Medium Large Medium Large Large

Note: n = 36 (TBI Sober, n = 18; TBI Intoxicated, n = 18). Cohen’s (1988) effect size (d): small (.20), medium (.50), large (.80). LM = Logical Memory; Visual Rep/VR = Visual Reproduction; COWAT = Controlled Oral Word Association Test, CFL Letters; WCST-64 = Wisconsin Card Sort Test-64; PE = Perseverative Errors.

severity for the sample was 33.3% for mild TBI with skull fracture [i.e., GCS score = 13 to 15 with a skull fracture on X-ray, but no intracranial CT abnormality], 33.3% for complicated mild TBI [i.e., GCS score = 13 to 15 and abnormal day-of-injury CT], and 33.3% for severe TBI [i.e., GCS score < 9 and abnormal day-of-injury CT (e.g., presence of cerebral contusion, swelling, or intracranial hematoma]. The breakdown regarding loss of consciousness was 61.1% positive, 13.9% negative, 5.6% equivocal, and 19.4% unknown. Ethnicity of the sample was predominantly Caucasian (94.6%). There were an identical number of patients between groups for gender, ethnicity, and injury severity categories. There were no significant differences in the proportion of patients in each group for mechanism of injury (p = .277) or loss of consciousness (p = .300). Given that the trauma patients were seen in the first few weeks post-injury, as part of the trauma clinical pathway, it is unlikely that they had major incentives to malinger at the time of evaluation. However, effort was not formally assessed. 2.3. Measures The cognitive measures were the Trail Making Test [TMT] (Reitan, 1992): Part A and Part B; Controlled Oral Word Association Test [COWAT] (Benton, Hamsher, & Sivan, 1994): Total letters CFL; Wisconsin Card Sorting Test-64 Card Version [WCST-64] (Kongs, Thompson, Iverson, & Heaton, 2000): Total Categories and Perseverative Errors; and selected subtests from the Wechsler Memory Scale-Revised [WMS-R] (Wechsler, 1987): Digit Span Forward and Backward, Logical Memory I and II, Visual Reproduction I and II. Savings scores for the Visual Reproduction and Logical Memory subtests were also included in the analyses. Savings scores represent a ratio (presented as a percentage) of the amount of information recalled after a delay relative to the initial acquisition of information. This is calculated by dividing the delayed recall score by the immediate recall score and multiplying this product by 100 (e.g. [Logical Memory II/Logical Memory I] × 100). These measures were selected based on the available data in the AGH Trauma database. These measures were originally selected by the AGH clinicians to provide a brief evaluation of neuropsychological functioning as soon as practical following injury. Raw scores were used in the analysis unless otherwise stated. A total of 13 cognitive measures were considered in all. 3. Results A series of one-way ANOVAs were conducted using the 13 cognitive measures as dependent variables and day-ofinjury alcohol intoxication status as the independent variable (i.e., TBI-Sober & Intoxicated). The use of MANOVA was precluded by the relatively small sample size and large number of dependent variables. Descriptive statistics, ANOVA results, and effect sizes (Cohen, 1988) for the 13 cognitive measures by group are presented in Table 2.

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There were significant main effects on six of the 13 cognitive measures (range: p = .009 to p = .041). Overall, patients who were sober at the time of injury performed worse on tasks of delayed verbal memory (Logical Memory II and LM % Savings), delayed visual memory (Visual Reproduction II), and executive functioning (Trails B, WCST-64 Categories, and WCST-64 Perseverative Errors) compared to those who were intoxicated at the time of injury. For all comparisons, the effect sizes were large, ranging from d = 0.73 to d = 0.94. Medium effect sizes were found on four additional cognitive measures (d = .50 to .55), although not statistically significant likely due to small sample size (p = .109 to .158). For these measures, patients who were sober at the time of injury again performed worse on tasks of immediate verbal memory (Logical Memory I), immediate visual memory (Visual Reproduction I), immediate attention span (Digit Span forward), and verbal fluency (COWAT: CFL). Additional analyses were undertaken based on the clinical interpretation of these measures. Raw scores were converted to percentile scores using the following published norms: (a) WMS-R manual for Logical Memory I and II, Digit Span Forward and Backward, and Visual Reproduction I and II (Wechsler, 1987), (b) normative tables by Prifitera and Ledbetter (1992) for Logical Memory and Visual Reproduction savings scores (Spreen & Strauss, 1998), (c) WCST-64 manual for Total Categories and Perseverative Errors (Kongs et al., 2000), (d) TMT Part A and B completion time normative data by Heaton and colleagues (Heaton, Miller, Taylor, & Grant, 2004), and (e) COWAT normative data for the letters CFL by Ruff and colleagues (Ruff, Light, Parker, & Levin, 1996). The percentages of patients with scores less than the 10th percentile and 16th percentile on each of the 13 cognitive measures by group are presented in Table 3. Chi-square analysis was used to compare the proportion of low scores on each measure between groups. In some analyses, the expected frequencies of cells were less than five and Fishers Exact Test statistics were interpreted. Cutoff scores at the 1st percentile, 10th percentile, and 16th percentile are often used by clinicians to infer “degrees” of cognitive impairment. However, a cutoff score at the 1st percentile was not included in these analyses due to the low prevalence of scores in this range. Overall, there was a greater number of low scores in the TBI-sober group compared to the TBI-intoxicated group. Using the 10th percentile cutoff score, the prevalence of low scores on the 13 individual cognitive measures in the Sober-TBI group ranged from 5.6% (Digit Span Forward) to 50.0% (LM % Savings), with 11 of the 13 measures having a prevalence rate greater than 22.1%. For the TBI-Intoxicated group, the prevalence of scores falling below the 10th percentile on the 13 cognitive measures ranged from 5.6% (e.g., Digit Span Forward, Trails A) to 16.7% (LM % Savings), with 10 of the 13 measures having a prevalence rate less than 11.2%. Chi-square analyses revealed significant differences in the proportion of low scores between groups on three of the 13 measures (all p < .05; LM % Savings, VR % Savings, WCST-64 Categories). However, the small sample size likely masked other differences between groups. Using the 16th percentile cutoff score, the prevalence of low scores on the 13 cognitive measures in the Sober-TBI group ranged from 27.8% (e.g., Trails A, Visual Reproduction I and II) to 50.0% (e.g., LM % Savings, WCST-64 Table 3 Prevalence of low scores on each cognitive measure by group Measures

TBI Sober (<10th)

TBI Intoxicated (<10th)

TBI Sober (<16th)

TBI Intoxicated (<16th)

Logical Memory I Logical Memory II LM % Savings Visual Reproduction I Visual Reproduction II VR % Savings Digit Span: Forward Digit Span: Backward Trails A Trails B COWAT: CFL WCST-64 Categories WCST-64 PE

27.8 33.3 50.0a 22.2 22.2 38.9a 5.6 33.3 16.7 27.8 27.8 44.4b 27.8

11.1 11.1 16.7a 5.6 11.1 11.1a 5.6 16.7 5.6 5.6 16.7 5.6b 5.6

33.3 50.0a 50.0 27.8 27.8 38.9 22.2 44.4 27.8 38.9 33.3 50.0a 50.0

11.1 11.1a 22.2 5.6 16.7 16.7 11.1 38.9 16.7 22.2 22.2 16.7a 22.2

Note: n = 36 (TBI Sober, n = 18, TBI Intoxicated, n = 18). Fisher’s Exact Test; a p < .05; b p < .01, LM = Logical Memory; VR = Visual Reproduction; COWAT = Controlled Oral Word Association Test, CFL Letters; WCST-64 = Wisconsin Card Sort Test-64; PE = Perseverative Errors. Fisher’s Exact Test was used for the majority of comparisons with the exception of LM % Savings and the following measures using the 16th percentile criterion: LM II, VR % Savings, Digit Span Backward, Trails B, COWAT-CFL, and the WCST-64.

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Categories), with 10 of the 13 measures having a prevalence rate of greater than 33.2%. For the TBI-Intoxicated group, the prevalence of low scores on the 13 cognitive measures ranged from 5.6% (e.g., Visual Reproduction I) to 38.9% (Digit Span Backwards), with 12 of the 13 measures having a prevalence rate of less than 22.3%. Chi-square analyses revealed significant differences in the proportion of low scores between groups on two measures (all p > .05, Logical Memory II, WCST-64 Categories). 3.1. Additional analyses Given that the results of this study were in the opposite direction of the expected hypothesis, a second set of analyses was also undertaken using a larger sample of patients. This sample included those patients that were selected prior to exclusion due to the failure to complete all neuropsychological test measures, and prior to the application of the matching procedure. In sum, the patients included in the larger sample had (a) sustained a definite TBI, (b) had a BAL of 0 mg/dl or ≥100 mg/dl, (c) had a confirmed absence of a history of pre-injury alcohol abuse, and (d) were tested within 10 days of injury (n = 148; TBI Sober, n = 112; TBI Intoxicated, n = 36 [BAL: M = 158.4, S.D. = 41.5, range = 100–268]). Demographic and injury severity characteristics of this sample are presented in Table 4. Of this group, 37.9% had not completed the entire neuropsychological test battery due to time constraints and/or other factors (such as orthopedic injuries). More than half of the patients (61.5%) were assessed within 6 days after presenting to the trauma service. There were no significant differences between TBI-sober versus TBI-intoxicated groups in the number of days tested post-injury (p = .221), GCS score (p = .100), education (p = .451), gender (.731), or injury severity classification (p = .480). However, a significant difference was found on age (p = .001). To explore the effect of day-of-injury alcohol intoxication in this sample, a series of one-way ANOVAs were conducted using the 13 cognitive measures as dependent variables, and day-of-injury alcohol intoxication status as the independent variable (i.e., TBI-Sober & TBI-Intoxicated). Prior to the analyses, the relationship between potential confounding variables on neuropsychological test performance was examined. A series of regression analyses using the 13 dependent variables and the following four potential confounding variables were evaluated: (a) age [in years], (b) education [in years], (c) injury severity [GCS score], and (d) days tested post-injury. Any variable found to be a significant predictor of neuropsychological test performance was included as a covariate in the ANOVA. Descriptive statistics, ANOVA results, and effect sizes (Cohen, 1988) for the 13 cognitive measures by group are presented in Table 5. There were significant main effects on three of the 13 cognitive measures (range: p = .015 to p = .042). Overall, patients who were sober at the time of injury performed worse on tasks of immediate and delayed visual memory Table 4 Demographic and injury severity characteristics TBI Sober

Age (in years) Education (in years) GCS score Days tested post-injury

TBI Intoxicated

p

M

S.D.

M

S.D.

37.1 12.1 12.2 5.8

17.2 2.5 4.3 3.5

26.7 12.4 10.7 4.9

8.5 1.2 5.1 3.4

TBI Sober

TBI Intoxicated

.001 .451 .100 .221 p

N

%

N

%

Gender Male Female

72 40

76.6 23.4

22 14

74.1 25.9

.731

Injury severity MTBI with skull Fx Complicated MTBI Moderate TBI Severe TBI

29 45 15 23

25.9 40.2 13.4 20.5

8 12 4 12

22.2 33.3 11.1 33.3

.480

Note: n = 148 (TBI Sober, n = 36; TBI Intoxicated, n = 112). GCS = Glasgow Coma Scale; MTBI = mild traumatic brain injury; TBI = traumatic brain injury.

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Table 5 Descriptive statistics, ANOVA and ANCOVA results, and effect sizes by group Measures

Logical Memory I Logical Memory II LM % Savings Visual Rep I Visual Rep II VR % Savings Digit Span-Forward Digit Span-Backward Trails A Trails B COWAT-CFL WCST-64 Categories WCST-64 PE

TBI Sober

TBI Intoxicated

M

S.D.

M

S.D.

20.5 14.6 66.0 28.4 22.0 77.2 7.8 5.2 40.3 109.0 30.0 2.9 13.1

7.5 8.9 30.5 8.3 10.7 36.8 2.1 2.2 20.5 60.5 12.0 1.6 11.0

20.7 15.3 67.8 34.0 28.8 82.5 8.1 5.8 30.3 75.2 31.8 3.3 10.2

7.9 9.4 30.8 5.4 9.6 21.0 2.2 2.3 10.8 38.0 11.6 1.5 5.6

p

d

Effect size

.909 .592 .794 .042 .028 .290 .557 .447 .172 .015 .300 .478 .169

.03 .06 .06 .74 .65 .16 .12 .27 .55 .62 .16 .27 .30

Very small Very small Very small Medium-Large Medium-Large Small Small Small Medium Medium-Large Small Small Small-Medium

Note: Total possible sample: n = 148 (TBI Sober, n = 36; TBI Intoxicated, n = 112). Actual sample sizes by measure are as follows (TBI Sober/TBI Intoxicated): Logical Memory I and II, and LM % Savings (88/27), Visual Rep I (90/28), Visual Rep II & VR % Savings (89/28), Digit Span-Forward (99/33), Digit Span-Backward (98/33), COWAT-CFL (100/35), Trails A (97/31), Trails B (92/30), WCST-64 PE & WCST Categories (86/30). Cohen’s (1988) effect size (d): small (.20), medium (.50), large (.80). LM = Logical Memory; Visual Rep/VR = Visual Reproduction; COWAT = Controlled Oral Word Association Test, CFL Letters; WCST-64 = Wisconsin Card Sort Test-64; PE = Perseverative Errors. Use of covariates in ANOVA: (a) Age = Visual Rep I, Visual Rep II, Digit Span-Backward, Trails A, WCST-64 Categories; (b) Education = Visual Rep I, Trails A; (c) Days tested Post-injury = Logical Memory II, Trails A, COWAT-CFL; (d) GCS score = Logical Memory II, VR % Savings, COWAT-CFL.

(Visual Reproduction I and II), and executive functioning (Trails B) compared to those who were intoxicated at the time of injury. For all comparisons, the effect sizes were medium-large, ranging from d = 0.62 to d = 0.74. A medium effect size was found on one additional cognitive measure (Trails A, d = .55), although not statistically significant (p = .172). For this measure, patients who were sober at the time of injury again performed worse compared to their intoxicated counterparts. Analyses were again undertaken based on the clinical interpretation of these measures. Raw scores were converted to percentile ranks using published norms. Chi-square analysis was used to compare the proportion of impaired scores on each measure between groups. Overall, there was a higher percentage of low scores in the TBI-sober group compared to the TBI-intoxicated group. Using the 10th percentile cutoff score, the prevalence of low scores on the 13 individual cognitive measures in the Sober-TBI group ranged from 10.2% (Digit Span Forward) to 41.2% (COWAT: CFL), with 11 of the 13 measures having a prevalence rate greater than 26%. For the TBI-Intoxicated group, the prevalence of scores falling below the 10th percentile on the 13 cognitive measures ranged from 7.1% (Visual Reproduction I) to 35.7% (Logical Memory II), with 10 of the 13 measures having a prevalence rate less than 26%. Chi-square analyses revealed significant differences in the proportion of low scores between groups on only two of the 13 measures (both p < .05; Visual Reproduction I and Trails A). Using the 16th percentile cutoff score, the prevalence of low scores on the 13 cognitive measures in the Sober-TBI group ranged from 16.3% (Digit Span Forward) to 48.5% (COWAT: CFL), with only five of the 13 measures having a prevalence rate of less than 41%. For the TBI-Intoxicated group, the prevalence of low scores on the 13 cognitive measures ranged from 17.9% (Visual Reproduction I) to 40.7% (LM % Savings), with all 13 measures having a prevalence rate of less than 41%. Chi-square analyses revealed significant differences in the proportion of low scores between groups on only one measure (p < .05, Trails A). 4. Discussion The purpose of this study was to examine the effects of day-of-injury alcohol intoxication on the acute neuropsychological outcome (i.e., within the first 10 days post-injury) from TBI in a sample of patients with no pre-injury alcohol abuse. Two different patient groups were examined: (a) a sample of 36 patients carefully matched on injury

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severity and demographic variables, and (b) a larger sample of 148 patients not matched on these variables. Based on the research literature, it was hypothesized that patients who were intoxicated at the time of injury would have worse neuropsychological outcome compared to those who were sober. In contrast to the research literature (Bombardier & Thurber, 1998; Brooks et al., 1989; Kelly, Johnson, et al., 1997; Tate et al., 1999; Wilde et al., 2004), the results from the matched sample suggests that individuals who were intoxicated at the time injury actually had better neuropsychological outcome in the acute stage of recovery from TBI. In sum, on average, patients who were intoxicated at the time of injury had higher scores on the neuropsychological measures, and had fewer scores that fell in the impaired range compared to patients who were sober at the time of injury. In the unmatched sample, these effects were not as prominent, with fewer differences noted between the two groups. Nonetheless, the results from the larger sample were also inconsistent with the research literature in which individuals who were intoxicated at the time injury either had comparable or better neuropsychological outcome compared to their sober counterparts. It is difficult to explain why these results are inconsistent with the extant research literature suggesting that alcohol intoxication at the time of injury results in worse neuropsychological outcome following TBI (Bombardier & Thurber, 1998; Brooks et al., 1989; Kelly, Johnson, et al., 1997; Tate et al., 1999; Wilde et al., 2004). There are five main reasons that may account for these discrepancies. First, previous studies have focused on outcome from TBI ranging from 2 to 3 months post-injury (Barker et al., 1999; Bombardier & Thurber, 1998; Kelly, Johnson, et al., 1997; Tate et al., 1999) to more than 1.5–7 years post-injury (Bigler et al., 1996; Brooks et al., 1989; Wilde et al., 2004). It is possible that the negative effects of day-of-injury alcohol intoxication may not manifest during the first 10 days of recovery, and the differences noted between groups is the result of other unknown factors. While it does not make biological sense to suggest that any potential negative neurophysiological effects of acute alcohol intoxication at the time of injury would have a delayed onset following injury, it is possible that the mid- to long-term recovery trajectory of patients who are sober at the time of injury may be superior and this benefit is not apparent until later in the recovery trajectory. Although this is considered an unlikely explanation, future research in this area using a longitudinal research design would help clarify this issue further. Second, it is possible that the sample selection procedures used in this study may have influenced our findings regarding the neuropsychological effects of TBI and concurrent day-of-injury alcohol intoxication. This is particularly relevant for the matched sample. The goal of the sample selection procedure for the matched sample was to carefully and systematically control for the effects of a variety of factors that are known to influence cognitive test performance following TBI (e.g., pre-injury alcohol history, injury severity classification, ethnicity, days tested post-injury, age, gender, and education). From an initial sample of 2160 patients, 36 patients were included in this study, carefully matched on these variables. Patients that could not be matched on these variables were not included. Statistical comparisons between groups revealed no differences on all relevant demographic variables and injury-related variables. Given the rigorous sample selection procedure employed here, it would be difficult to obtain a more closely matched sample using this population. However, one potential source of bias that may have occurred in the selection of the matched sample relates to the exclusion of patients who did not complete the entire battery of neuropsychological tests. It is possible that the most severely affected patients were unable to complete all tests and were thus not included in the matched sample. When a larger unmatched sample was used that consisted of patients that did not complete the entire battery of tests, the effects of day-of-injury alcohol intoxication was less prominent in this study. When these two groups are compared, the most notable difference between the matched and unmatched sample was the larger percentage of impaired scores in the TBI Intoxicated group from the larger unmatched sample (Table 6) compared to the TBI Intoxicated group in the matched sample (Table 3). It is possible that our selection of patients who had only completed all neuropsychological tests in the matched group resulted in a bias towards selection of a higher functioning TBI Intoxicated group. Nonetheless, even when this is taken into consideration, the results from the larger sample are still inconsistent with past research. Third, it is possible that the influence of pre-injury alcohol abuse on post-injury neuropsychological status is more substantial than the effects of day-of-injury alcohol intoxication and previous studies that have not controlled for preinjury alcohol factors have drawn erroneous conclusions (Bombardier & Thurber, 1998; Kelly, Johnson, et al., 1997). Many studies in this area suffer from a myriad of methodological limitations that preclude us from understanding the effects of day-of-injury alcohol on cognitive outcome following TBI. The most significant problem is the failure to adequately measure and control for the effects of pre-injury alcoholism. Other significant problems include not using BAL to define patients who are “intoxicated”, and not assessing patients within the same post-injury time period. However, in support of the day-of-injury alcohol hypothesis, Tate and colleagues (Tate et al., 1999) have provided

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Table 6 Prevalence of low scores on each cognitive measure by group Measures

TBI Sober (<10th)

TBI Intoxicated (<10th)

TBI Sober (<16th)

TBI Intoxicated (<16th)

Logical Memory I Logical Memory II LM % Savings Visual Reproduction I Visual Reproduction II VR % Savings Digit Span: Forward Digit Span: Backward Trails A Trails B COWAT: CFL WCST-64 Categories WCST-64 PE

26.1 27.3 33.0 27.2a 28.6 32.6 10.2 30.9 40.6a 37.0 41.2 31.4 22.1

33.3 35.7 29.6 7.1a 21.4 25.0 18.2 15.2 16.1a 20.0 25.7 16.1 13.3

34.1 43.2 44.3 33.7 41.8 42.7 16.3 41.2 47.9a 44.6 48.5 38.4 30.2

33.3 35.7 40.7 17.9 28.6 35.7 21.2 33.3 22.6a 30.0 34.3 29.0 23.3

Note: Total possible sample: n = 148 (TBI Sober, n = 36; TBI Intoxicated, n = 112). Actual sample sizes by measure are as follows (TBI Sober/TBI Intoxicated): Logical Memory I and II, and LM % Savings (88/27), Visual Rep I (90/28), Visual Rep II & VR % Savings (89/28), Digit SpanForward (99/33), Digit Span-Backward (98/33), COWAT-CFL (100/35), Trails A (97/31), Trails B (92/30), WCST-64 PE & WCST Categories (86/30). Chi-square test; a p < .05; LM = Logical Memory; VR = Visual Reproduction; COWAT = Controlled Oral Word Association Test, CFL Letters; WCST-64 = Wisconsin Card Sort Test-64; PE = Perseverative Errors.

one of the most well-controlled studies in this area to date, by examining the influence of blood alcohol level on post-acute neuropsychological outcome (tested 2.3 months [S.D. = 2.2] post-injury), in a sample of 67 patients with mild to severe TBI. Using standard least squares regression analyses, Tate and colleagues concluded that BAL at hospital admission predicted poorer performance on several neuropsychological measures (e.g., delayed recall for prose material, verbal memory, planning, organization, and visuospatial ability) and “accounted for a significant, unique portion of the variance in these cognitive measures beyond that of variables known to moderate recovery from TBI, including age, [education], TBI severity, and history of alcohol abuse” (p. 776). The results of the current study are inconsistent with the results of Tate and colleagues. Methodologically, the current study differs to the work by Tate and colleagues in which the effects of pre-injury alcohol abuse were controlled via exclusion of such patients, rather than by using statistical methods. Statistically controlling for pre-injury alcohol consumption is a common and well-accepted statistical procedure. However, given the known influence of chronic alcohol abuse on neuropsychological status, it may be possible that controlling for this variable by statistical means may not be as effective as we would anticipate. Fourth, it is possible that the GCS scores in the intoxicated patients are artificially suppressed by BAL, leading them to appear more severely impaired than they really are. As such, when patients are matched based on GCS scores, the intoxicated group may actually have less severe injuries than their matched sober counterparts and as a result will actually do better on cognitive testing. Although it is a common clinical perception that alcohol intoxication systematically lowers GCS ratings, the research findings in this area do not support such a relationship. Although some researchers have concluded that GCS scores are lowered by alcohol intoxication and thus fail to provide an accurate evaluation of brain injury severity (Alexander et al., 2004; Brickley & Shepherd, 1995; Chatham-Showalter et al., 1996; Galbraith, Murray, Patel, & Knill-Jones, 1976; Jagger, Fife, Vernberg, & Jane, 1984; Kelly, Johnson, et al., 1997; Shih et al., 2003; Smith-Seemiller, Lovell, & Smith, 1996), a comparable number of studies have found that there are no effects of BAL on GCS (Albrecht-Anoschenko, Uhl, Gilsbach, Kreitschmann-Andermahr, & Rohde, 2005; Barker et al., 1999; Christensen, Janson, & Seago, 2001; Hall, Riley, & Swann, 2005; Nath, Beastal, & Teasdale, 1986; Pories et al., 1992; Sperry et al., 2006; Stuke, Diaz-Arrastia, Gentilello, & Shafi, 2007). The mixed findings in these studies are largely the result of the lack of control for the influence of brain injury severity. Brain injury obviously depresses GCS scores. Therefore, if brain injury severity is not statistically or methodologically controlled for, differences in GCS scores due to alcohol intoxication are likely to be confounded by the influence of brain injury severity in a given sample. In one of the most well-controlled studies in this area to date, Sperry and colleagues (Sperry et al., 2006) examined the influence of BAL on GCS scores in a sample of 1075 patients with TBI of all severities. Injury severity was classified using the Abbreviated Injury Scale (AIS) for brain injuries (AIS range = 3 to 5). When GCS scores were evaluated separately in each injury severity subgroup, there were no differences in GCS scores between the intoxicated and non-intoxicated groups, with the exception of those patients with the most severe injuries (AIS score = 5) where

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GCS in the intoxicated group was 1.4 points lower than in the non-intoxicated group. In a recent study by our own research group using the same database as used in the current study (Lange, Iverson, & Franzen, 2007a), we found that there was no significant relationship between BAL and GCS scores for the majority of patients, with the exception of those patients who had BALs greater than 200 mg/dl and who had an abnormal day-of-injury CT scan. Given that the present study includes only one patient with an abnormal CT scans and a BAL > 200 mg/dl (and whose GCS score was 15), we are confident that the current results are not biased by the effects of BAL on GCS scores. Fifth, and most controversial of all, it might be possible that day-of-injury alcohol intoxication may have a neuroprotective role in determining neuropsychological outcome following TBI. Some animal research has found that small to moderate doses of alcohol (e.g., 1–2.5 g/kg) may have a neuroprotective effect on the brain at the time of injury by preservation of cognitive abilities (Is et al., 2005; Janis, Hoane, Conde, Fulop, & Stein, 1998; Kelly, Lee, Pinanong, & Hovda, 1997; Tureci et al., 2004); although not all animal research in this area has supported this conclusion (Biros, Kukielka, Sutton, Rockswold, & Bergman, 1999; Zink & Feustel, 1995). In animals, it is thought that day-of-injury alcohol intoxication may have a neuroprotective effect due to the inhibition of NMDA RECEPTOR-mediated excitotoxicity (Cebere & Liljequist, 2003; Chandler, Sumners, & Crews, 1993; Danysz, Dyr, Jankowska, Glazewski, & Kostowski, 1992; Takadera, Suzuki, & Mohri, 1990). In humans, some studies have suggested that moderate doses of alcohol (e.g., <230 mg/dl) on the day of severe TBI is associated with reduced mortality (Blondell, Looney, Krieg, & Spain, 2002; Tien et al., 2006; Ward, Flynn, Miller, & Blaisdell, 1982). However, there is currently no available research that has suggested that alcohol may have a neuroprotective effect on cognitive deficits following TBI. Although the results of this study did support a global positive effect of alcohol intoxication on neuropsychological status in the first 10 days post-injury, we were not able to explore the relationship between dose of alcohol at the time of injury and neuropsychological outcome. In this study, only a handful of patients had a BAL that was greater than 200 mg/dl and the effects of moderate versus heavy alcohol consumption was not able to be examined appropriately. As such, the BAL in the majority of patients in our study could be classified as a moderate dose of alcohol consistent with the neuroprotective hypothesis. This study is not without its limitations and the results of must be interpreted with these in mind. First, this study addresses short-term outcome only (first 10 days post-injury) and does not address medium- or long-term outcome. The stability of this finding throughout the recovery trajectory is not known. Second, this study did not examine the effects of day-of-injury alcohol intoxication in a sample of patients with a history of pre-injury alcohol abuse. The generalizability of these findings in that patient population is unknown. Third, this study included a small sample size of patients who were intoxicated at the time of injury and the generalizability of these results to all patients with TBI is limited. There are many practical limitations in obtaining an adequate sample size of patients in this category. Patients who are intoxicated at the time of injury and have no concurrent pre-injury alcohol abuse represent a low-prevalence group. However, this group is of most interest to study in an effort to understand the role of day-ofinjury alcohol intoxication on cognition. Fourth, the available information regarding CT scan results was limited to a simple dichotomous variable, indicating the presence or absence of day-of-injury intracranial abnormality. Information pertaining to the type or severity of such intracranial abnormality was not available. Despite these limitations, the methodological strengths of this study should not be overlooked. These strengths include (a) the use of day-of-injury BAL to categorize intoxication groups, (b) the comparison of neuropsychological test performance in patients who were assessed within the same time period post-injury [within 10 days], (c) rigorous control for the effects of pre-injury chronic alcoholism via exclusion of such patients, and (d) carefully matched samples on demographic and injury-related variables designed to reduce the effects of variables known to effect TBI. Carefully controlled, prospective, systematic research is needed to assess the relative effects of day-of-injury alcohol intoxication on short-, medium- and long-term outcome following TBI.

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