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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0368
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 7 2581-2587
Copyright © 2008 by The Endocrine Society

Aerobic Capacity and Growth Hormone Deficiency after Traumatic Brain Injury

Kurt A. Mossberg, Brent E. Masel, Charles R. Gilkison and Randall J. Urban

Department of Physical Therapy (K.A.M.) and Medicine (C.R.G., R.J.U.), University of Texas Medical Branch, Galveston, Texas 77555; and Transitional Learning Center (B.E.M.), Galveston, Texas 77550

Address all correspondence and requests for reprints to: Kurt A. Mossberg, P.T., Ph.D., Department of Physical Therapy, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1144. E-mail: kmossber{at}utmb.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
New cases of traumatic brain injury in the United States are estimated to be at 1.5 million each year. Annually it is estimated that 70,000–90,000 patients with traumatic brain injury lose significant functioning as a result. There are approximately 5.4 million people living with the effects of traumatic brain injury in the United States (about 2% of the U.S. population) (1). The majority of these individuals are young adults, but a greater number of older adults are suffering traumatic brain injury as the population ages. Many of these cases are a result of motor vehicle accidents, falls, and violence.

Pituitary dysfunction as a result of traumatic brain injury has been extensively documented with approximately 30–40% of patients showing a deficiency of one or more anterior pituitary hormones (2, 3, 4, 5). GH deficiency is the most common hormone deficiency (6), and it is estimated to affect approximately 20% of individuals with traumatic brain injury (7). Others have suggested that the prevalence of GH deficiency may be as high as 33–50% (8).

Traumatic brain injury results in a constellation of signs and symptoms as a result of diffuse axonal injury and/or focal damage (9). Among the myriad of impairments that patients with traumatic brain injury experience, one of the most common, regardless of severity of injury and time of recovery, is fatigue (10). Fatigue is also a common complaint of patients diagnosed with GH deficiency (8). Contributors to fatigue or the lack of endurance include both mental and physical factors (11), and both the patient with traumatic brain injury and the patient with GH deficiency present with one or more of these characteristics. From a psychological and behavioral standpoint, both patient groups have impaired concentration, motivation, and desire to complete the task at hand. Physically both groups of patients have reduced muscle endurance and strength and impaired cardiovascular function that contribute to fatigue.

A well-established method of assessing one’s physical endurance and fatigue resistance is the measure of aerobic capacity during a graded exercise test. It evaluates the cardiovascular, pulmonary, and muscular systems and reflects oxygen delivery by the cardiovascular system, oxygen-diffusing capacity of the lungs, and the ultimate utilization of oxygen by the active skeletal muscles. It is well established that patients with GH deficiency have reduced aerobic capacity, altered body composition, reduced strength, and decreased cognitive and psychological fitness, compared with healthy controls (12, 13). In addition, patients recovering from traumatic brain injury, without GH deficiency are known to have reduced aerobic capacity, compared with healthy controls (14). Kelly et al. (15) reported on the combined effects of traumatic brain injury and GH deficiency on quality of life and neurobehavioral function. The effects of traumatic brain injury in combination with GH deficiency on aerobic capacity have not been investigated. Therefore, the purpose of this study was to determine whether GH deficiency secondary to traumatic brain injury had an effect on aerobic capacity in patients in the postacute recovery phase after traumatic brain injury. In doing so, we compared patients with deficient GH (<3 ng/ml), patients with insufficient GH (3–8 ng/ml), and patients with normal GH (>8 ng/ml). We hypothesized that the greater the GH deficiency, the greater the deficiency in peak aerobic capacity.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

A total of 35 individuals in the postacute phase of recovery participated. Inclusion criteria were 18–60 yr of age, no overt cardiovascular disease, able to follow two-step commands, and the capacity to ambulate on a treadmill without manual assistance. Most patients suffered moderate to severe injuries (Glasgow Coma Scale score 3–12); five patients had mild injuries (Glasgow Coma Scale 13–15). Approximately 70% of the injuries were the result of vehicular accidents; other causes were falls and assaults. Written consent was obtained from either the patient or guardian. All study procedures were approved by institutional review boards at a local university and a postacute treatment center specializing in traumatic brain injury rehabilitation.

Methods

A standard glucagon stimulation test (GST) was used to assess GH secretion. Glucagon (1 mg) was administered im with blood sampling for GH occurring at 0, 90, 120, 150, and 180 min (16, 17). GH was measured by RIA kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). Groups were formed as follows: sufficient GH (GHS), response greater than 8 ng/ml (n = 12); insufficient GH (GHI), response between 3 and 8 ng/ml (n = 11); deficient GH (GHD), response less than 3 ng/ml (n = 12).

Subjects included in the GH groups above were also screened for dysfunction of their cortisol (ACTH stimulation test), thyroid (free T4 and TSH), and reproduction axis (normal menstruation in a female and total testosterone in a male). Two subjects in the sufficient group were found to be hypothyroid. All other subjects were in the normal ranges with respect to cortisol, thyroid, and reproductive axes.

Each subject had their resting and exercise heart rate (HR) monitored by electrocardiography (Cardio Perfect Inc., Atlanta, GA). Minute ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2) during rest and exercise were determined by an automated metabolic cart (Medical Graphics Corp., St. Paul, MN). The metabolic cart was calibrated before each test, using gases of known concentration. The pneumotach was calibrated with a 3-liter syringe. Gas exchange data were averaged over the last 20 sec of each minute and used as submaximal and peak values.

Aerobic capacity was measured while ambulating on a treadmill. Speed was held constant throughout the test, and greater workloads were brought about by 2% increases in incline every minute until exhaustion. This testing protocol was a modification of the Balke stress test (18) and has been used previously in patients with traumatic brain injury (19, 20), and both submaximal and peak responses have been shown to be reliable in this population (21). Whereas speed was constant for a given subject, it was not the same for all subjects. Because of the variability in gait impairments, treadmill speed was set just below the maximum speed at which the subject could walk safely. The primary goal of testing was to encourage the patient to give a maximal effort. Objective indicators of maximal aerobic capacity included: 1) reaching 85–90% of age-predicted maximum HR, 2) a plateau in VO2 with an increase in workload, and 3) a respiratory exchange ratio equal to or greater than 1.15 (22). The test was stopped if the subject’s safety became compromised or if the subject requested to stop. No manual assistance was provided.

Data analyses

Oxygen pulse was calculated by dividing oxygen uptake (milliliters per minute) by HR (beats per minute) and gave an estimate of cardiac stroke volume (milliliters O2 per beat) (23). Ventilatory equivalents for oxygen (VE per VO2) and carbon dioxide (VE per VCO2) were also calculated. One-way ANOVAs were performed on all peak cardiorespiratory variables. Newman-Keuls post hoc comparison was performed when a significant F ratio was identified. Repeated-measures two-way ANOVAs were performed on all submaximal variables followed by one-way ANOVAs and Newman-Keuls post hoc comparisons as necessary. Submaximal data were analyzed only through minute 6 of the test because many subjects started to reach their peak levels of exertion after this time point. Pearson’s correlation coefficient was calculated to examine relationships between variables. All analyses were carried out at an {alpha}-level of 0.05. Graphical data are presented as means ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Details of the patient characteristics are shown in Table 1Go. There were no differences in either the age at which subjects were injured or the age at which the subjects were tested (recovery time). Each of the three groups were significantly different with respect to their maximum serum GH concentration in response to glucagon (maxGH) (P < 0.02). IGF-I levels were different only between GHS and GHD groups (P < 0.02) (GHS 221 ± 92, GHI 175 ± 56, GHD 132 ± 60). No differences were found in height or weight, but when body mass index was calculated, there was a significant difference between the GHD group and the other two groups (P < 0.01).


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  		TABLE 1. Subject characteristics (GHS, n = 12; GHI, n = 11; GHD, n = 12)

 
Table 2Go lists the peak physiological responses for the three groups of subjects. Significantly higher peak oxygen consumption was observed in subjects with traumatic brain injury who had normal GH axis vs. those with insufficient or deficient response to the GST (P < 0.05; see Fig. 1Go). The level of anaerobic effort was similar based on the similarities in peak respiratory exchange ratios (Table 2Go). Whereas there was a tendency for heart rate, oxygen pulse, and minute ventilation to be higher in the normal GH group, there were no statistically significant differences noted. Submaximal oxygen uptake was significantly higher beginning at minute 2 of the exercise for those patients with traumatic brain injury who had normal GH levels (P < 0.05; Fig. 2Go). None of the other submaximal variables differed significantly, although there was a tendency for oxygen pulse to be higher in the GHS group, particularly when compared with the GHI group (data not shown).


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  		TABLE 2. Peak physiological responses (GHS, n = 12; GHI, n = 11; GHD, n = 12)

 

Figure 1
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  		FIG. 1. Peak oxygen consumption during graded treadmill exercise testing. Values are mean ± SE. *, P < 0.05.

 

Figure 2
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  		FIG. 2. Submaximal oxygen consumption during graded treadmill exercise testing. Values are mean ± SE. *, P < 0.05.

 
Figures 3Go and 4Go show the relationship between maxGH and peak oxygen consumption and body mass index, respectively. There was a significant positive relationship between maxGH and peak VO2 (r = 0.41, P = 0.02) and a significant negative relationship between maxGH and body mass index (r = –0.52, P = 0.002). We also assessed the relationship between maximal safe treadmill speed and oxygen consumption and found a significant positive relationship (r = 0.64, P = 0.001). We found no relationship between gait speed and maxGH (r = 0.21, P = 0.23). maxGH was not correlated to age at injury, time of recovery, or any other variables.


Figure 3
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  		FIG. 3. The relationship between peak oxygen consumption and maxGH in response to glucagon stimulation (r = 0.41, P = 0.02; 95% confidence interval).

 

Figure 4
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  		FIG. 4. The relationship between body mass index and maxGH in response to glucagon stimulation (r = –0.52, P = 0.002; 95% confidence interval).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Patients in postacute recovery from traumatic brain injury that are GH insufficient/deficient have significant reductions in aerobic and endurance capacity, compared with patients with traumatic brain injury who have a normal GH axis. We believe this is the first study to examine the combined effects of traumatic brain injury and GH deficiency on aerobic capacity and cardiorespiratory fitness. Our study shows that subjects with traumatic brain injury and severe GH deficiency (GH response to GST of < 3 ng/ml) have a significantly reduced aerobic capacity. Moreover, we also show that subjects with a GH response between 3 and 8 ng/ml in response to the GST have a similar reduction in aerobic capacity. The GH response to stimulation testing results in a window of response that is frequently termed the gray zone with the question arising whether this is a significant departure from the normal response of the GH axis and whether this moderate response is clinically significant. Our results indicate that for subjects with traumatic brain injury and a maxGH response between 3 and 8 ng/ml to the GST, there is a significant reduction in their aerobic capacity, compared with traumatic brain injury subjects that have a response of 8 ng/ml or greater. These data are supportive of the need to replace traumatic brain injury subjects within this range of GH response to the GST with recombinant human GH (rhGH). Surprisingly, the patients in the GH insufficient group (3–8 ng/ml) had slightly lower estimated cardiac stroke volumes (oxygen pulse) and peak ventilatory capacities.

We have recently shown that individuals with traumatic brain injury in the postacute recovery phase have peak aerobic capacity levels that were 76% of an age and gender-matched comparison group of healthy sedentary individuals (14). The patients in the current study were tested using the same graded exercise protocol as reported previously. This sample of traumatic brain injury patients with normal GH levels had peak responses very similar to those previously reported (14). In a study by Thomas et al. (24), patients with GH deficiency had peak VO2 values of 19.3 ml/kg·min, which compare favorably with the patients in the current study with traumatic brain injury and GH levels of 8 ng/ml or less. However, we tested patients while ambulating on a treadmill, and the patients in the study by Thomas et al. were tested on the cycle ergometer. One should be cautious when making such comparisons because of the differences in O2 uptake between exercise testing protocols (25, 26, 27, 28).

It is well known that many patients recovering from traumatic brain injury have cognitive and behavioral impairments that can impact their ability to attend to a task and perform maximally. In addition, GH deficiency is known to cause behavioral and cognitive impairments. Consequently, one could argue that patients with traumatic brain injury, and especially those with GH deficiency, lack the motivation to reach a peak O2 uptake. Close examination of the time course of O2 uptake with increasing workload and our data on the similarities in respiratory exchange ratios across the three groups suggest, however, that all groups achieved equal levels of intensity. This is reinforced by previous findings (14) that compared healthy sedentary individuals with persons with traumatic brain injury and found similar respiratory exchange ratios but significantly different peak VO2 levels.

Differences noted between groups (Table 2Go) for HR and oxygen pulse (estimated cardiac stroke volume), although not significant, are consistent with the negative effects of GH deficiency on cardiovascular status (29, 30). Similarly, we found decreased pulmonary minute ventilation, which agrees with other studies of lung function in patients with adult-onset GH deficiency (31). In addition, we found modest but significant correlations of maxGH to body mass index and peak O2 uptake (Figs. 3Go and 4Go). These data are consistent with what is currently known about changes in body composition and aerobic capacity.

We also examined the relationship between the maximal safe speed of treadmill ambulation and peak O2 uptake and maxGH. Patients with low maxGH tended to ambulate at slower speeds and patients who ambulated at faster speeds had higher peak VO2. There was a strong tendency for the GHS group to ambulate faster (Table 2Go), even though there was no statistical differences in gait speed between groups (P = 0.124) due to the large variability within groups. Surprisingly, the GHI group (3–8 ng/ml) had the slowest speed of ambulation. This difference, although statistically nonsignificant, is considered clinically significant. Whether this was a function of GH or some other factor is unknown. A better understanding of these differences and similarities could come from future studies that match better for physical function, i.e. gait speed. It is possible that those individuals with GH deficiency or insufficiency were less active and more sedentary than those patients with a normal GH axis.

GH replacement therapy has received considerable attention in childhood and adult-onset GH deficiency (13, 32). Previously it has been shown that patients with adult onset GH deficiency who received rhGH therapy demonstrated improved aerobic performance, decreased feelings of fatigue, and improved activity of daily living performance (33). More recently it has been shown that patients with adult onset GH deficiency who received rhGH replacement therapy and exercise training demonstrated improvements in aerobic capacity with exercise or rhGH alone, but there was no additive effect when the two treatments were combined (24). We have presented a case report of a patient many years after traumatic brain injury who received GH replacement therapy without an exercise intervention and found increases in aerobic capacity (34). Our case study results indicate that rhGH administration in patients with traumatic brain injury found to be GH insufficient/deficient by GST could result in an improvement in cardiorespiratory capacity and prevent secondary disability. A randomized placebo-controlled trial is currently being carried out by our group on a large sample of patients with traumatic brain injury and GH insufficiency/deficiency.

Our first priority was to make our sample groups as homogeneous as possible with regard to age at injury, severity of injury, and time of recovery. Subjects were not matched by gait speed (evident from the above discussion). Speed of treadmill ambulation and severity of injury determined by Glasgow Coma Scale score were not correlated (r = 0.04, P = 0.86). In addition, we did not have a history of GH axis status between the time of injury and the time of testing because it is known that this can fluctuate during the recovery period (35). We did find a weak but insignificant correlation between maxGH and time of recovery (r = 0.31, P = 0.08), but again no difference in recovery time between groups was found (P = 0.77). We also did not have access to each patient’s prior rehabilitation history. Greater intensity and longer duration therapy interventions could have impacted the gait speed and cardiorespiratory status of the subjects. The possibility exists that the rehabilitation outcome was influenced by the status of the GH axis. In addition, it would have been helpful to have histories of prior activity levels outside a rehabilitation setting, both before and after the injury.

Fatigue is multifactorial, having both physical and mental components. It has been described as: 1) weariness on the part of the subject, 2) reduced interest in performing a task, and 3) demonstrable physiological signs and symptoms (11). Individuals recovering from traumatic brain injury have a diminished tolerance for continuous physical activity, and indeed, fatigue is one of the most commonly reported complaints among individuals living with traumatic brain injury (36). It is estimated that the prevalence of fatigue in samples from the general population range from 10 to 28% (37, 38). However, the prevalence of fatigue in community-dwelling individuals with traumatic brain injury has been estimated to range from 50 to 80% (39). Interestingly, the prevalence of fatigue in the traumatic brain injury population does not significantly change over time. Olver et al. (40) surveyed community-dwelling individuals with a traumatic brain injury and found that at 2 yr after injury, 68% reported issues with fatigue. At 5 yr after injury, 73% of the same group reported issues with fatigue. The further reduction in aerobic capacity in the sample of patients with GH deficiency reinforces the need to adequately screen individuals recovering from traumatic brain injury for hypopituitarism, particularly GH deficiency (8). Whether chronic fatigue is a result of hypopituitarism or simply a reduction in aerobic capacity requires further study. Data were presented many years ago that strongly suggested peak aerobic capacity was related to employment productivity after traumatic brain injury (41). Recently it has been suggested that pituitary function is predictive of outcome after traumatic brain injury (42). Despite the facts that fatigue in traumatic brain injury poses a significant barrier to the resumption of normal function, its etiology has not been adequately studied. Proper screening of all patients with traumatic brain injury should be done and periodic follow-ups should be a routine part of the medical management to optimize rehabilitation outcomes and quality of life in these individuals (43).

Conclusions

This is a first step in the examination of aerobic capacity as a result of GH insufficiency/deficiency secondary to traumatic brain injury and certainly a first step in the identification of an etiology in the multifactorial issue of fatigue after a traumatic brain injury. Aerobic capacity was significantly compromised in subjects with traumatic brain injury and GH insufficiency/deficiency. The decrease in cardiorespiratory endurance could partially explain the ever-present fatigue that many patients experience many years after traumatic brain injury and the combination of traumatic brain injury and GH insufficiency/deficiency compounds the problem. If rhGH replacement therapy is warranted, it could have a significant impact on the rehabilitation outcome and ultimate quality of life of the patient recovering from traumatic brain injury. Well-designed studies on replacement therapy are needed in patients with traumatic brain injury and GH insufficiency/deficiency.


   Acknowledgments
 
We thank Julie Norcross for expert technical assistance and Jodie Tefer for database management. The Moody Endowment provided partial funding support. Hormonal screening was conducted at the General Clinical Research Center at the University of Texas Medical Branch at Galveston.


   Footnotes
 
This work was supported by National Center for Research Resources, National Institutes of Health, Public Health Service Grant M01 RR 00073 to the General Clinical Research Center at the University of Texas Medical Branch at Galveston.

Disclosure statement: K.A.M., C.R.G., and R.J.U. have nothing to declare. B.E.M. has equity interest in and received lecture fees from Pfizer.

First Published Online April 15, 2008

Abbreviations: GHD, Deficient GH; GHI, insufficient GH; GHS, sufficient GH; GST, glucagon stimulation test; HR, heart rate; maxGH, maximum serum GH concentration in response to glucagon; rhGH, recombinant human GH; VE, ventilation; VCO2, carbon dioxide production; VO2, oxygen consumption.

Received February 14, 2008.

Accepted April 4, 2008.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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