Functional Changes after Recombinant Human Growth Hormone Replacement in Patients with Chronic Traumatic Brain Injury and Abnormal Growth Hormone Secretion.

We explored the effects of recombinant human growth hormone (rhGH) replacement on physical and cognitive functioning in subjects with a moderate-to-severe traumatic brain injury (TBI) with abnormal growth hormone (GH) secretion. Fifteen individuals who sustained a TBI at least 12 months prior to study enrollment were identified as having abnormal GH secretion by glucagon stimulation testing (maximum GH response less than 8 ng/mL). Peak cardiorespiratory capacity, body composition, and muscle force testing were assessed at baseline and one year after rhGH replacement. Additionally, standardized neuropsychological tests that assess memory, processing speed, and cognitive flexibility, as well as self-report inventories related to depression and fatigue, were administered at baseline and 1 year after rhGH replacement. Comparison tests were performed with proper post hoc analyses. All analyses were carried out at α < 0.05. Peak O2 consumption, peak oxygen pulse (estimate of cardiac stroke volume), and peak ventilation all significantly increased (p < 0.05). Maximal isometric and isokinetic force production were not altered. Skeletal muscle fatigue did not change but the perceptual rating of fatigue was reduced by ∼25% (p = 0.06). Cognitive performance did not change significantly over time, whereas self-reported symptoms related to depression and fatigue significantly improved. The observed changes suggest that rhGH replacement has a positive impact on cardiorespiratory fitness and a positive impact on perceptual fatigue in survivors of TBI with altered GH secretion.

Blunted IL-6 and IL-10 response to maximal aerobic exercise in patients with traumatic brain injury.

INTRODUCTION: In healthy individuals, strenuous exercise typically results in a transient increase in the inflammatory cytokine, interleukin-6 (IL-6). This increase in IL-6 is reported to have pleiotropic effects including increased glucose uptake, increased fat oxidation, and anti-inflammatory actions. PURPOSE: The purpose of this study was to determine if patients with a traumatic brain injury (TBI) have a differential cytokine response to exercise compared to healthy control subjects (CON). METHODS: Eight patients with a TBI and eight age- and sex-matched controls completed an exercise test to volitional exhaustion. Metabolic data were collected continuously, and blood was collected at baseline, immediately post-exercise, and every 10 min for an hour post-exercise. Serum was analyzed for IL-6, tumor necrosis factor-alpha, interleukin-10 (IL-10), and cortisol. RESULTS: Peak oxygen consumption (CON 33 ± 2 ml kg(-1) min(-1); TBI 29 ± 2 ml kg(-1) min(-1)) and respiratory exchange ratio during exercise were equivalent between groups. There were no baseline differences between groups for cytokine or cortisol concentrations. Exercise did not increase IL-6 in TBI, whereas IL-6 was elevated from baseline in CON at 0, 40, and 50 min post-exercise (p < 0.05). IL-10 and cortisol increased from baseline in CON at 40 min post-exercise (p < 0.05). CONCLUSIONS: These data indicate that patients recovering from TBI have blunted IL-6, IL-10, and cortisol responses following a peak exercise test compared to non-TBI controls. This lack of an exercise response may represent impaired hypothalamic-pituitary-adrenal axis function.

Neuropsychological and physiological correlates of fatigue following traumatic brain injury.

BACKGROUND: Fatigue is a common and debilitating phenomenon experienced by individuals with traumatic brain injury (TBI) that can negatively influence rate and extent of functional recovery by reducing participation in brain injury rehabilitation services and increasing maladaptive lifestyle practices. The underlying mechanisms of TBI-related fatigue are not entirely understood and focused research on symptom reduction or prevention is limited. REVIEW: The current review of the literature suggests that the aetiology of TBI-related fatigue can be viewed as a multifactorial and complex model impacting physiological systems (i.e. endocrine, skeletal muscle and cardiorespiratory) that can be directly or indirectly influenced by neuropsychological correlates including cognitive and psychological impairment. Distinguishing central from peripheral fatigue is helpful in this regard. Potential therapeutic strategies and pharmacological agents to help alleviate fatigue in this patient population are discussed.

Ventilatory anaerobic thresholds of individuals recovering from traumatic brain injury compared with noninjured controls.

OBJECTIVE: The purpose of this study was to compare the peak aerobic capacities and ventilatory anaerobic thresholds (VAT) of individuals with a traumatic brain injury (TBI) to age- and gender-matched controls. METHODS: Nineteen participants that previously suffered a mild to moderate TBI and 19 apparently healthy controls volunteered as subjects. Traumatic brain injury and healthy controls were matched for age and gender and were similar in weight and body mass index. Volunteers performed a maximal graded treadmill test to volitional failure where oxygen consumption ((Equation is included in full-text article.)O2), carbon dioxide production ((Equation is included in full-text article.)CO2, ventilation ((Equation is included in full-text article.)E, and heart rate were measured continuously. From metabolic and ventilatory data, VAT was measured using a previously described method. VAT and peak exercise responses of participants with a TBI were compared with healthy controls. RESULTS: The (Equation is included in full-text article.)O2, and (Equation is included in full-text article.)CO2 at VAT and peak exercise were lower for TBI compared with healthy controls. (Equation is included in full-text article.)E was also lower for TBI at VAT and peak exercise. Heart rate was lower for TBI at VAT; however, TBI had similar heart rate to healthy controls at peak exercise. CONCLUSIONS: The VAT and peak exercise capacities of participants with a TBI were below the metabolic demands of many routine daily activities. The data suggest that therapeutic interventions for individuals with a TBI should include targeted exercise prescriptions to improve cardiorespiratory fitness.

Responsiveness and validity of the six-minute walk test in individuals with traumatic brain injury.

BACKGROUND: A simple test of aerobic fitness for patients with traumatic brain injury (TBI) that is valid, reliable, and responsive to change is needed to provide clinicians a functional measure of cardiorespiratory capacity. OBJECTIVE: The purpose of this study was to examine the validity and responsiveness to change of the Six-Minute Walk Test (6MWT) in individuals with TBI. DESIGN: A cohort, pretest-posttest, comparison study was conducted. METHODS: Twenty-one patients performed the 6MWT upon admission to and prior to discharge from a postacute rehabilitation facility. Heart rate and distance traveled were recorded. A physiologic cost index (PCI) (beats per meter) was calculated based on steady-state heart rate. At discharge, all participants were able to perform a graded treadmill exercise test to exhaustion during which peak oxygen consumption (Vo(2)) was measured. RESULTS: Between admission and discharge, mean total distance increased from 342.6 m (SD=127.0) to 408.9 m (SD=124.2), and work increased from 27,185 kg·m (SD=10,528) to 34,114 kg·m (SD=12,057). The effect size indexes were 1.10 and 1.12 for distance and work, respectively. Correlations (r) between the discharge peak Vo(2) and the discharge 6MWT distance, PCI, and work were .58, -.61, and .47, respectively. LIMITATIONS: Stratification by gait speed may have improved responsiveness, especially for the slow ambulators. CONCLUSIONS: All measures correlated well with peak Vo(2), establishing an acceptable level of criterion-related (concurrent) validity. The addition of heart rate and calculating the PCI was only slightly better at predicting peak Vo(2), albeit nonsignificant, than a simple measure of total distance. The 6MWT provides a good estimate of peak aerobic capacity, and some measures are more responsive to change than others in patients recovering from TBI.

What are critical outcome measures for patients receiving pituitary replacement following brain injury?

There are scant prospective studies defining improvements in critical outcome measures with hormone replacement in hypopituitarism secondary to brain injury. We review the tests of cognition and physical function and summarize their use for subjects that are deficient in anterior hormone production during anterior pituitary hormone replacement in brain injury and propose these as the minimal tests that are feasible for a physician to perform in a clinical setting. We summarize the studies conducted to assess outcome measures after brain injury and also report preliminary findings for improvements in cognition and physical function in subjects with brain injury and GH deficiency.

Serum IGF-1 concentrations in a sample of patients with traumatic brain injury as a diagnostic marker of growth hormone secretory response to glucagon stimulation testing.

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in adults is established through growth hormone (GH) stimulation testing, which is often complex, expensive, time-consuming and may be associated with adverse side effects. The decision to perform GH provocative testing is influenced by clinical findings, medical history and biochemical evidence. We report in this study our experience using the glucagon stimulation test (GST) in assessing GHD in adult patients with traumatic brain injury (TBI) as it relates to baseline serum insulin-like growth factor-1 (IGF-1) concentrations. DESIGN: A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal IGF-1 cut-off for diagnosis of GHD at different potential diagnostic GST cut-off values (<3, <5, & <10 µg/l). PATIENTS: One hundred and thirty-eight patients (98 men and 40 women) with a documented history of moderate to severe TBI were assessed for GHD using serum IGF-1 concentrations and the GST. MEASUREMENTS: IGF-1 values were compared with peak GH values obtained following the GST. RESULTS: An IGF-1 cut-off value of 175 µg/l minimized the misclassification of GHD patients and GH-sufficient patients and provided a sensitivity of 83% and specificity of 40%, as well as a negative predictive power of 90% considering a criterion for peak GH response of <3 µg/l. CONCLUSIONS: Our current findings are consistent with previous work assessing peak GH response using the insulin tolerance test (ITT) in a non-TBI sample, suggesting that diagnostic accuracy may be optimized if the GST is used when obtained serum IGF-1 concentrations are below 175 µg/l. While the decision to perform provocative testing to assess GHD in adult patients should be based on the clinician's clinical impression, the findings from this retrospective study can provide useful clinical information and serve as a guide.

Effect of growth hormone replacement therapy on cognition after traumatic brain injury.

Traumatic brain injury (TBI) is a major public health issue, and yet medical science has little to offer for the persistent symptoms that prevent many of these individuals from fully re-entering society. Post-traumatic hypopituitarism, and specifically growth hormone deficiency (GHD), has been found in a large percentage of individuals with chronic moderate to severe TBI. Presently, there are no published treatment studies of hormone replacement in this population. In this study, 83 subjects with chronic TBI were screened for hypopituitarism. Forty-two subjects were found to have either GHD or GH insufficiency (GHI), of which 23 agreed to be randomized to either a year of GH replacement or placebo. All subjects completed the study with no untoward side effects from treatment. A battery of neuropsychological tests and functional measures were administered before and after treatment. Improvement was seen on the following tests: Dominant Hand Finger Tapping Test, Wechsler Adult Intelligence Scale III-Information Processing Speed Index, California Verbal Learning Test II, and the Wisconsin Card Sorting Test (executive functioning). The findings of this pilot study provide preliminary evidence suggesting that some of the cognitive impairments observed in persons who are GHD/GHI after TBI may be partially reversible with appropriate GH replacement therapy.

Endurance training and cardiorespiratory conditioning after traumatic brain injury.

OBJECTIVE: To examine the importance of cardiorespiratory conditioning after traumatic brain injury (TBI) and provide recommendations for patients recovering from TBI. METHOD: Review of literature assessing the effectiveness of endurance training programs. MAIN OUTCOMES AND RESULTS: A sedentary lifestyle and lack of endurance are common characteristics of individuals with TBI who have a reduction in peak aerobic capacity of 25% to 30% compared with healthy sedentary persons. Increased physical activity and exercise training improves cardiorespiratory fitness in many populations with physical and cognitive impairments. Therefore, increasing the endurance and cardiorespiratory fitness of persons with TBI would seem to have important health implications. However, review of the TBI literature reveals that there have been few well-designed, well-controlled studies of physiologic and psychological adaptations of fitness training. Also lacking are long-term follow-up studies of persons with TBI. CONCLUSIONS: Assessing endurance capacity and cardiorespiratory fitness early in the TBI rehabilitation process merits consideration as a standard of care by professional rehabilitation societies. Also, providing effective, safe, and accessible training modalities would seem to be an important consideration for persons with TBI, given the mobility impairments many possess. Long-term follow-up studies are needed to assess the effectiveness of cardiorespiratory training programs on overall morbidity and mortality.

Effect of recombinant growth hormone replacement in a growth hormone deficient subject recovering from mild traumatic brain injury: A case report.

OBJECTIVE: To assess the effects of growth hormone (GH) replacement in an individual who sustained mild traumatic brain injury (mTBI) as an adult and was found to have GH deficiency by glucagon stimulation testing. PARTICIPANT: A 43-year old woman who sustained a mild TBI at age 37 years. She was 6.8 years post-injury when she began supplementation. INTERVENTION: Recombinant human GH (rhGH) subcutaneously per day for 1 year. MAIN OUTCOME MEASURES: Single fibre muscle function was evaluated from muscle biopsies. Body composition, muscle strength and peak aerobic capacity were also measured. In addition, neuropsychological tests of memory, processing speed and motor dexterity and speed, as well as a self-report depression inventory were administered. All assessments were performed at baseline and after 6 and 12 months of rhGH replacement therapy. RESULTS: Single muscle fibre changes were greatest at 6 months. Body composition showed continuous improvement. Muscle strength improved for knee extension. Peak oxygen consumption increased at 6 months and total work and ventilatory equivalents continued to improve at 12 months. Significant improvements in neuropsychological test performance were not found, with the exception of performance on a test of motor dexterity and speed. CONCLUSION: rhGH replacement in a subject with GH deficiency after mild TBI improves muscle force production, body composition and aerobic capacity. Reliable improvements on tests of cognition were not found in this subject.

Relationships between the Quality of Life Questionnaire (QLQ) and the SF-36 among young adults burned as children.

OBJECTIVE: To examine the relationship between two measures that can be used to examine quality life among pediatric burn survivors. DESIGN: Prospective, correlational study. SETTING: Acute and rehabilitation pediatric burn care facility. PARTICIPANTS: Eighty young adult survivors of pediatric burns, who were 18-28 years of age, with burns of 30% or greater, and were at least 2 years after burn. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The SF-36 and the Quality of Life Questionnaire (QLQ) were used to assess participant's self-reported general health and long-term adjustment. RESULTS: Significant correlations (p< or =0.001) were found between the total quality of life score of the QLQ and the mental component scale of the SF-36. However, no significant correlations were found between the total quality of life score of the QLQ and the SF-36 physical component scale. CONCLUSIONS: Approximately 100,000 children are treated for burns annually, with a high percentage surviving, creating a challenge for health care professionals who need to prepare burn survivors with their psychosocial and physical well-being as adults. This study found that the SF-36 and QLQ are measuring somewhat different aspects of psychosocial and physical adjustment. It is recommended that both tools could be useful to the burn practitioner in assessing quality of life.

Aerobic capacity and growth hormone deficiency after traumatic brain injury.

CONTEXT: GH deficiency occurs in approximately 20% of all individuals who suffer from a moderate to severe traumatic brain injury. OBJECTIVE: This study determined whether GH deficiency secondary to traumatic brain injury had an effect on aerobic capacity. DESIGN: Subjects were screened for GH deficiency by the glucagon stimulation test and performed a maximal treadmill exercise test. SETTING: Patients were studied in the postacute recovery phase after traumatic brain injury. PARTICIPANTS: Thirty-five individuals were studied. Groups were formed as follows: normal GH axis, greater than 8 ng/ml response (n = 12); insufficient, GH 3-8 ng/ml response (n = 11); and deficient, less than 3 ng/ml response (n = 12). INTERVENTION: There was no intervention. MAIN OUTCOME MEASURE: Aerobic capacity was assessed by measuring expired gases during a graded treadmill exercise test. One-way and two-way ANOVAs were carried out on all peak and submaximal cardiorespiratory variables, respectively. Appropriate post hoc comparisons followed as necessary. RESULTS: Significantly higher peak oxygen consumption was found in traumatic brain injury subjects with GH normal vs. GH insufficient and deficient [26.4 +/- 6.9, 20.8 +/- 4.6, and 19.7 +/- 5.0, respectively (P < 0.05)]. Submaximal oxygen consumption was significantly higher in the GH normal group. All other variables were statistically similar. CONCLUSIONS: This study shows that individuals with traumatic brain injury with normal GH secretion have below normal aerobic capacity and those patients who have GH insufficiency/deficiency are further deconditioned. Studies of GH replacement in these subjects should be conducted to assess whether GH therapy can improve cardiorespiratory fitness and prevent secondary disability.

Cardiorespiratory capacity after weight-supported treadmill training in patients with traumatic brain injury.

BACKGROUND AND PURPOSE: The primary goal of body-weight-supported treadmill training (BWSTT) has been to improve the temporal and spatial characteristics of unsupported overground walking; however, little attention has been given to cardiorespiratory adaptations. The purpose of this case report is to describe the effects of BWSTT on cardiorespiratory fitness in 2 patients recovering from severe traumatic brain injury (TBI). CASE DESCRIPTION: Both patients were involved in motor vehicle accidents and were studied after admission to a postacute residential treatment program. Patient 1 was a 25-year-old man (initial Glasgow Coma Scale [GCS] score=3) who began observation and treatment 3 months after the injury. Patient 2 was an 18-year-old woman (initial GCS=6) who began observation and treatment 1 year after the injury. OUTCOMES: Each patient received 2 to 3 sessions of BWSTT per week. Aerobic capacity was measured while they ambulated on a treadmill without body-weight support before and after BWSTT. Both patients' submaximal and peak responses improved. For patient 1 and patient 2, total treadmill work performed increased 134% and 53%, respectively. Peak oxygen uptake increased 24% for patient 1 and 16% for patient 2. Estimated cardiac stroke volume (oxygen pulse) increased 32% and 26% for patient 1 and patient 2, respectively. DISCUSSION: The observations made on these 2 patients suggest that BWSTT has the potential to favorably change cardiorespiratory capacity after TBI.

Aerobic capacity after traumatic brain injury: comparison with a nondisabled cohort.

OBJECTIVE: To compare aerobic capacity of people recovering from traumatic brain injury (TBI) with an age- and sex-matched group of nondisabled sedentary people. DESIGN: Descriptive comparative study of peak and submaximal physiologic responses. SETTING: Residential postacute treatment center. PARTICIPANTS: Convenience sample of 13 people with TBI and 13 age- and sex-matched nondisabled subjects. All subjects could walk 5.3 kph (3.3 mph), follow 2-step commands, and comply with testing using the gas collection apparatus. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Subjects performed a graded maximal treadmill test during which heart rate, minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production, and respiratory exchange ratio (RER) were measured every minute until exhaustion. Ventilatory equivalents for oxygen (VE/VO2) and oxygen pulse were calculated. RESULTS: Subjects recovering from TBI had significantly lower peak responses for heart rate, VO2, VE, and oxygen pulse TBI (P<.01). Peak RER and VE/VO2 were similar. There were significant differences in submaximal responses for VE/VO2 and oxygen pulse. CONCLUSIONS: Patients with TBI were significantly more deconditioned than a comparable group of sedentary people without disability. Participation in cardiorespiratory fitness programs after TBI should be encouraged to prevent secondary disability.

Reliability of graded exercise testing after traumatic brain injury: submaximal and peak responses.

OBJECTIVE: To assess the reliability of the submaximal and peak responses to a treadmill graded exercise test in individuals recovering from traumatic brain injury. DESIGN: A total of 15 individuals (11 men, 4 women; 28.5 +/- 9.2 yrs) with moderate to severe traumatic brain injury admitted into a postacute residential treatment center 10 +/- 7 mos after injury performed two treadmill graded exercise tests separated by 4-8 days. Heart rate, oxygen consumption (in milliliters per minute per kilogram), minute ventilation (in liters per minute), and respiratory exchange ratio (carbon dioxide output/oxygen consumption) were continuously monitored at 1-min intervals. Submaximal and peak values were analyzed for absolute level of agreement using the intraclass correlation coefficient. RESULTS: The submaximal intraclass correlation coefficient values for all variables between minutes 3 and 7 ranged from 0.80 to 0.93. Submaximal intraclass correlation coefficients before and in the subsequent minutes were less than optimal for heart rate and minute ventilation. Lower intensity workloads elicited slightly better agreement than higher intensity workloads. The peak response intraclass correlation coefficients ranged from 0.77 (heart rate) to 0.92 (oxygen consumption). CONCLUSION: Despite the presence of other co-morbidities, subjects recovering from traumatic brain injury provided consistent individual responses, allowing for reliable assessments of cardiorespiratory conditioning programs. Assessments of ambulatory efficiency, endurance, and aerobic fitness adaptations as a result of treatment for persons with traumatic brain injury should include analyses of submaximal responses to graded exercise.

Reliability of a timed walk test in persons with acquired brain injury.

OBJECTIVE: The purpose of this study was to assess the reliability of a 6-min walk test in individuals with acquired brain injury. DESIGN: A total of 23 clients (14 men, 9 women) participated. All participants were clients in a postacute residential rehabilitation facility. The time from injury averaged 12 mo (range, 7-38 mo). Subjects were instructed to walk around a rectangular track as many times as possible during a period of 6 min. The test was performed twice, separated by 1-10 days. Heart rate was monitored continuously throughout the test, and distance traveled was recorded in meters after completion. A physiologic cost index (beats per meter) was calculated. Intraclass correlation coefficients were calculated for distance traveled, heart rate responses, and physiologic cost index. RESULTS: The mean distance walked was 403 +/- 105 m (trial 1) and 417 +/- 106 m (trial 2). The intraclass correlation coefficient for distance was 0.94. The mean steady-state heart rate was 118 +/- 21 beats/min (trial 1) and 117 +/- 20 beats/min (trial 2), and the intraclass correlation coefficient was 0.65. The mean physiologic cost index was 0.52 +/- 0.19 beats/m (trial 1) and 0.55 +/- 0.22 beats/m (trial 2), and the intraclass correlation coefficient was 0.89. CONCLUSIONS: Distance traveled and the physiologic cost index demonstrated excellent reliability, whereas heart rate responses for individual minutes demonstrated only fair reliability. The individuals studied were very consistent in their efforts, despite a combination of physical and cognitive impairments. The results suggest that the 6-min walk test can be used reliably in the assessment of functional ambulation in persons with acquired brain injury.