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Neurally Mediated Hypotension In Fatigued Gulf War Veterans: A Preliminary Report
Neurally Mediated Hypotension In Fatigued Gulf War Veterans: A Preliminary Report S. DIANE DAVIS, PHD, MOl; STEVEN F. KATOR, MD; JAMIE A. WONNETT, RN, BSN, BHA; BONNIE L. PAPPAS, RN, MSN; JAMES L. SALL, RN, BSN 2
ABSTRACT: Background: Many patients with chronic fatigue syndrome (CFS) have neurally mediated hypotension when subjected to head-up tilt, suggesting autonomic nervous system dysfunction. Some Gulf War veterans have symptoms similar to CFS. Whether they also tend to have neurally mediated hypotension is unknown. Methods: We performed 3-stage tilt-table testing on 14 Gulf War veterans with chronic fatigue, 13 unfatigued control Gulf War veterans, and 14 unfatigued control subjects who did not serve in the Gulf War. Isoproterenol was used in stages 2 and 3 of the tilt protocol. Results: More fatigued Gulf War veterans than unfatigued control subjects had hypotensive responses
F
atigue is 1 of the 2 most common complaints listed in the Department of Defense report on 18,598 Gulf War veterans 1 ; 47% of the participants report this symptom. Fatigue is also a common complaint in general medical practice and has been estimated to account for more than 7 million office visits a year.2 In people with fatigue caused by lifestyle, medical, or other identifiable conditions, treatment and management are straightforward. In many of the Gulf War veterans we have evaluated, as in civilian medical practice, the cause offatigue is undetermined. Some fatigued people may meet the criteria for chronic fatigue syndrome (CFS). CFS is now defined as clinically evaluated, unexplained, persistent or From Preventive Medicine (SDD), Ambulatory Services (SFK, and Hospital Services (BLP, JLS), Evans US Army Community Hospital, Fort Carson, Colorado. 1 Current affiliation: Veterans Affairs Outpatient Clinic, Colorado Springs, Colorado. 2 Current affiliation: Uniformed Services University of the Health Sciences, Bethesda, Maryland. The opinions and assertions contained herein are not to be construed as official or reflecting the views of the U.S. Army or the Department of Defense. Submitted October 9, 1998; accepted in revised form April 23, 1999. Correspondence: Dr. S. D. Davis, VA Outpatient Clinic, 25 N. Spruce Street, Colorado Springs, CO 80905 (E-mail: shirley. [email protected]). JAW),
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
to tilt (p < 0.036). A positive response to the drug-free stage 1 of the tilt was observed in 4 of 14 fatigued Gulf War veterans versus 1 of 27 unfatigued control subjects (P < 0.012). Heart rate and heart rate variation during stage 1 was significantly greater in the fatigued group (P < 0.05). Conclusion: We conclude that more fatigued Gulf War veterans have neurally mediated hypotension than unfatigued control subjects, similar to observations in CFS. Autonomic nervous system dysfunction may be present in some fatigued Gulf War veterans. KEY INDEXING TERMS: Chronic fatigue syndrome; Hypotension, orthostatic; Autonomic nervous system diseases; Gulf War syndrome [Am
J Med Sci 2000;319(2):89-95.]
relapsing fatigue that is of new or definite onset, is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities. CFS is also defined by the presence of at least 4 of the following symptoms: memory or concentration difficulties severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities; sore throat; tender cervical or axillary lymph nodes; muscle pain; arthralgias without arthritis; headaches of a new type; unrefreshing sleep; or postexertional malaise lasting more than 24 hours.3 Other symptoms widely reported by patients with chronic fatigue syndrome include depression, malaise, lightheadedness, and other minor neuropsychological complaints. Recent evidence suggests that autonomic nervous system dysfunction may be present in CFS. Bou-Holaigah et al 4 used head-up tilt-table testing to show that neurally mediated hypotension was present in 22 of 23 patients who met strict criteria for CFS. Subsequently, Freeman and KomaroftS found abnormalities in several indices of sympathetic and parasympathetic nervous system function in a group of 23 patients with CFS. In that study, a hypotensive response to a drug-free tilt-table test was found in 9 of 16 patients with CFS. Many Gulf War veterans have reported 1 or more
89
Fatigued Gulf War Veterans
of a constellation of symptoms (fatigue, joint and muscle pains, headache, memory and concentration problems, sleep disturbance, rash, depression, diarrhea, shortness of breath, abdominal pain, hair loss, bleeding gums) that have been called Gulf War syndrome. Other war syndromes have been documented in the English language medical literature from the American Civil War to the Persian Gulf War.6 Shared symptoms among most of these syndromes include fatigue, headache, sleep disturbances, dizziness, joint pains, shortness of breath, and memory and concentration problems. Because of the similarity of these symptoms with the symptoms ofCFS, we suspected that symptomatic Gulf War veterans with prominent complaints offatigue were experiencing a variant of CFS. We hypothesized that more fatigued Gulf War veterans than unfatigued control subjects would have neurally mediated hypotension on tilttable testing. Methods Source of SUbjects. Gulf War veterans were recruited from a group of approximately 1600 Gulf War veterans, mostly active duty soldiers, who were medically evaluated through the Department of Defense Comprehensive Clinical Evaluation Program for Gulf War Veterans (CCEP) at Evans Army Community Hospital between 1994 and 1997. Participants in this ongoing program undergo a physical examination, chest radiograph, laboratory evaluation, and specialty consultations as necessary to define all medical problems. Volunteers were also recruited through notices placed in the post newspaper and by electronic notices on the hospital computer network. Fatigued Gulf War veterans were recruited from the participants in the program who had chronic fatigue (ICD-9-CM code 780.7) as 1 of their top 3 final diagnoses after comprehensive clinical evaluation. Fatigued veterans underwent further screening if they had additional unexplained somatic or neuropsychological symptoms. If they had fatigue not related to ongoing exertion and unrelieved by rest and associated with memory or concentration difficulties, sore throat, tender cervical or axillary lymph nodes, muscle or joint pain, headaches, sleep disturbance, or postexertional malaise lasting more than 24 hours, they were invited to participate in the study. Self-identified healthy, unfatigued volunteers were also recruited. They were not required to undergo comprehensive medical evaluation but their medical history was screened. Unfatigued Gulf War veterans were encouraged to complete the CCEP to ensure a comprehensive health assessment, and all but 1 completed the program. Volunteers we·re excluded if there was recent surgery, heavy alcohol use, major depression, cardiac or cerebrovascular disease, diabetes, or other unresolved major medical problems or if the volunteer was pregnant, breast feeding, using antihypertensive medications, antihistamines, nonsteroidal anti-inflammatory drugs, or antidepressants. Volunteers were also excluded ifthere was a history of frequent or recurrent syncope. Occasional syncope occurring as a result of self-limited illness, physical exhaustion, dehydration, or vasovagal reactions to the sight of blood or the like was not grounds for exclusion. Study Design. The study design was approved by the Human Use Committee and Institutional Review Board at Brooke Army Medical Center, San Antonio, Texas, which has approval authority over clinical research performed at Evans Army Community Hospital. Informed consent was obtained from all volunteers. We predicted that more Gulf War veterans with chronic fatigue would have neurally mediated hypotension compared with unfatigued control subjects. However, we could not exclude the possi-
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bility that service in the Gulf War itself, in the absence of fatigue, could be associated with neurally mediated hypotension. Therefore, we used a 3-group study design to enable a separate analysis of the effect of fatigue and Gulf War service. Gulf War veterans with unexplained fatigue and other associated symptoms were assigned to group Gulf-Fatigue (GF, n = 14). Gulf War veterans who were unfatigued and in good health were assigned to group Gulf-Control (GC, n = 13). Healthy volunteers who did not serve in the Gulf War were enrolled in group Non-Gulf-Control (NC, n = 14). This latter group consisted of 13 volunteers currently or formerly in military service and 1 civilian volunteer with no military experience. Before tilt-table testing, all volunteers completed 2 simple indices used previously4: a general sense of well-being scale (an analog scale where 0 represents death and 100 represents as well as a person could ever feel) and an activity restriction index. The latter index was designed to quantify the effects of fatigue on the ability to engage in 7 activities: exercise, including sports and military physical fitness training; housework/family activities; shopping; work/career/school; social activities; outdoor work, including military field duty; and favorite recreational activities. Each activity was rated on a scale of 1 (no limitations) to 6 (severely limited). The index was scored as the mean of individual items rated. Additionally, the most recent army physical fitness test score, if available, was included in the analysis. Volunteers also indicated the frequency of syncope or presyncope on 2 separate checklists. Possible responses were "never," "once or twice in my life," "several times in my life," and "many times in my life." Responses to the 2 checklists were scored on a scale of 0 ("never") to 3 ("many times in my life"). The scores on the 2 checklists were added to derive a simple "orthostasis index" for each volunteer. Because volunteers who indicated that they had experienced syncope "many times in my life" were excluded from the study, the maximum score on the index could be no higher than 5. Tilt Table Protocol. A 3-stage upright tilt-table test was performed. After a fast from solid foods (oral hydration was permitted) of at least 2 hours, volunteers were placed supine on a tilt-table with a footboard for weight bearing. A slow intravenous infusion of normal saline was started through an intravenous catheter, and an automatic blood pressure cuff was applied to the right arm. The electrocardiogram and transcutaneous pulse oxygen saturation were continuously monitored. After a lO-minute baseline period of monitoring vital signs and cardiac rhythm in the supine position, the table was tilted head-up to 70° (stage 1). The blood pressure and heart rate were measured after 1 minute of upright tilt and thereafter every 5 minutes, or more frequently if symptoms developed. All vital signs and symptoms were recorded on a flow sheet by 1 of the authors. Monitoring continued in the head-up position for 45 minutes or until syncope or severe presyncopal symptoms occurred. If there was not a syncopal or presyncopal response by 45 minutes, the subject was returned to the supine position and an infusion of isoproterenol was begun at a rate of 1 or 2 J.Lg/min, titrated to achieve a 20% increase in baseline heart rate. After 10 minutes of titration, the subject was retilted for a 15-minute period (stage 2). If there was no response, the subject was returned to the supine position and the isoproterenol infusion rate was increased by 2 J.Lg/min. After 10 minutes of equilibration, the subject was retilted (stage 3). If a response was not obtained after another 15 minutes, the subject was returned to the supine position and the test terminated. Presyncopal symptoms included lightheadedness, perspiration, decreased vision or hearing, slowing of response to verbal stimuli, nausea, or loss of postural tone. Testing was not always terminated when presyncopal symptoms were transient. To control for potential bias in the decision to terminate the tilt-table test, each flow sheet was blindly reviewed by both a cardiologist not associated with the study and by 1 of the study authors who did not conduct the test. The test was scored positive if syncope occurred or presyncopal symptoms occurred coincident with a drop in systolic blood pressure of at least 25 mm Hg with no associated increase in heart rate. There was initial agreement between the February 2000 Volume 319 Number 2
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Table 1. Demographic Characteristics and Mean Scores on Activity Restriction Index, Well-Being Scale, and Army Physical Fitness Test for Each Group
MalelFemalea OfficerlEnlistedINonveterana Active dutylRetired-dischargedIN onveterana Age (years)b Activity restriction indexb Well-being scale b Orthostasis indexb Army physical fitness testb
GF
GC
NC
pc
12/2 0/1410 11/3/0 32.1 ± 1.6 3.07 ± 0.22 6.8 ± 0.4 2.07 ± 0.31 254 ± 12.1
12/1 5/8/0 12/1/0 38.9 ± 1.9 1.16 ± 0.09 9.0 ± 0.2 0.92 ± 0.21 262 ± 6.2
11/3 8/5/1 13/0/1 31.9 ± 2.1 1.10 ± 0.04 9.2 ± 0.2 1.43 ± 0.25 252 ± 8.3
0.334 0.001 0.239 0.019 d
GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War Data expressed as number of subjects in each category in each group. Comparisons by Jt test. b Data expressed as mean ± S.E.M. Comparisons by analysis of variance. C P, two-tailed level of significance d P < 0.05, GC vs GF and GC vs NC (Student-Newman-Keuls) e P < 0.05, GF vs GC and GF vs NC (Student-Newman-Keuls) f P < 0.05, GF vs GC (Student-Newman-Keuls) a
2 reviewers on scoring of 39 of the 41 tilt-table results, with consensus on scoring of the remaining 2 developing after discussion. Data Analysis. Comparisons among the 3 groups in terms of demographics, baseline blood pressure and heart rate, minimum and maximum heart rate, and blood pressure during testing and scores on the activity restriction index, well-being scale, and orthostasis index were analyzed using the analysis of variance for continuous variables or the Jt test for dichotomous variables. Further analysis of statistically significant results from the analysis of variance was performed employing the Student-NewmanKeuls test to determine differences between individual groups. Scores on the well-being scale were divided by 10 to allow comparison to the previous study.4 Results of tilt-table testing were scored on an ordinal scale of 1 to 4, where 1, 2, or 3 was a positive response at stages 1, 2, or 3. A negative test was scored 4. Tilt test data were then analyzed using the Mann-Whitney U test for 2 groups or the Kruskal-Wallis test for all 3 groups. A post hoc analysis of positive responses to tilt during stage 1 was performed using the same tests. Correlations between a positive response to tilt versus age, vital signs, scores on the well-being scale, activity restriction index, orthostasis index, and army physical fitness test were determined using either the Pearson rank correlation coefficient or the Kendall partial correlation coefficient, as indicated. Statistical computations were performed using the SPSS computer program (ver. 6.1.1; SPSS, Inc., Chicago, IL). Significance at the I-tailed level of 0.05 or less was accepted in comparing results of the tilt-table tests among the groups for 2 reasons. First, we predicted that, a priori, fatigued Gulf War veterans would have a higher incidence of neurally mediated hypotension than control subjects. Second, we judged that the finding of fewer positive tests in the fatigued group than a control group would be clinically meaningless. All other analyses were performed using a 2-tailed level of significance.
Results
Demographic and Clinical Characteristics Table 1 shows the demographic characteristics and the mean scores on the activity restriction index, the well-being scale, the orthostasis index, and army physical fitness test for each group. Most volunteers were men on active-duty military status. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
The proportions of women and non-active-duty personnel were not significantly different among the 3 groups. There was a significant difference in the proportion of officers versus enlisted members: group GF had the highest proportion of enlisted volunteers (14 of 14), and group NC had the highest proportion of officers (8 of 14, P < 0.001). Group GC was significantly older than the other 2 groups (P < 0.02). Consistent with previous data on people with chronic fatigue,S the fatigued Gulf War veterans in group GF had a mean activity restriction score significantly higher (ie, activities were more restricted) and a well-being score significantly lower (ie, sense of well-being was lower) than either of the 2 control groups (P < 0.001). Additionally, their scores on the orthostasis index were higher, indicating that they experienced more frequent episodes of syncope and pre syncope than did the unfatigued volunteers (P < 0.014). Army physical fitness test scores were available for 12 volunteers in each group. The standard Army physical fitness test consists of push-ups, sit-ups and a 2-mile run. Scoring on each event is dependent upon age and gender. Each event has a minimum passing score of 60 and maximum of 100; the test result is the sum of the scores of the individual events. There was no difference among the 3 groups in the mean of the available physical fitness test scores. There also was no significant difference among the 3 groups in the time between the most recent physical fitness test and the date of the tilttable test (median number of months: GF, 5.0; GC, 4.0; NC, 4.0; P = 0.38, Kruskal-Wallis). Volunteers in the fatigued group were selected in part because of the similarity of their physical and neuropsychological complaints to CFS. Table 2 con91
Fatigued Gulf War Veterans
Table 2. Number of Subjects in Each Group Endorsing Each Physical and Neuropsychological Symptom of CFS Symptom Fatigue >6 months Fatigue unrelieved by rest Memory and concentration problems Arthralgias Post-exertional malaise Tender cervical or axillary nodes Myalgias New type of headaches Frequent sore throats
GF 14 13 12 10 7 6 6 6 5
GC
70%
NC 60%
0 0 2 3 0 0 1 2 0
0 0 0 1 0 0 0 0 0
GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War
50%
40%
30%
20%
trasts the number of volunteers in each group reporting specific symptoms associated with CFS.
10%
Results of Tilt- Table Testing Figure 1 summarizes the results of tilt-table testing. A positive response to tilt was observed in 9 of 14 (64%) of group GF compared with 5 of13 (38%) of group GC and 6 of 14 (43%) of group NC. This trend is not statistically significant when the 3 groups are compared (P = 0.098), but is statistically significant when the fatigued Gulf War veterans are compared with all unfatigued control subjects (P < 0.036). Four of the positive responses to tilt in group GF occurred without drug provocation (ie, during stage 1 of the test). In contrast, only 1 positive response occurred without drug provocation in group GC, and none in group NC. This trend was statistically significant (P = 0.031; P = 0.012, fatigued versus control subjects). Table 3 displays analysis of the baseline vital signs and responses to the stage 1 drug-free tilt. Maximum systolic and diastolic blood pressures and heart rate were the maximums recorded in each volunteer during the 45-minute drug-free stage. Baseline supine vital signs were the median of 3 measurements during the 10-minute baseline observation period. There was no statistically significant difference among the 3 groups in baseline supine systolic or diastolic blood pressure or pulse, although there was a trend toward a higher systolic blood pressure and pulse in the fatigued group, similar to previous observations. 5 During 70° head-up tilt, there were significant differences among the 3 groups in maximum systolic blood pressure, maximum heart rate, and maximum heart rate variation. Further analysis of these responses to tilt disclosed a trend toward a higher maximum systolic blood pressure response in the 2 Gulf War gr{)UPS, with group GC reaching a statistically significant difference from group NC (P < 0.05). The maximum heart-rate response to tilt was significantly higher in the fatigued Gulf War veterans than in each of the control groups (P < 0.05), similar to previous obser-
0%
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*
GF
GC Group
NC
Figure 1. Proportion of tilt-table tests positive in each group. Dark portion of bars represents proportion of tilt-table tests positive at stage 1. *, P < 0.036, fatigued vs unfatigued (MannWhitney D, I-tailed); t, P < 0.031 (Kruskal-Wallis, I-tailed); P < 0.011, fatigued vs unfatigued (Mann-Whitney D, I-tailed). GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War.
vations in chronic fatigue syndrome. 5 The maximum heart-rate variation (maximum minus minimum heart rate) was also highest in the fatigued group (P < 0.05). Although not statistically different among the 3 groups, the fatigued group had a fall in systolic blood pressure with tilt greater than twice the magnitude of the control groups, similar to previous findings in CFS. 5
Correlates of Positive Response to Tilt Among all volunteers, a positive response to tilt was significantly correlated with the orthostasis index (P = 0.05). A positive response to tilt was not significantly correlated with age (P = 0.337), Gulf War service (P = 0.240), well-being score (P = 0.100), physical fitness score (P = 0.091), baseline systolic blood pressure (P = 0.792), diastolic blood pressure (P = 0.564), or heart rate (P = 0.558). A positive response to tilt was almost significantly correlated with the activity restriction index (P = 0.051). Given the 28-year age range of the volunteers, there was possibly an age-related factor in the activity levels; therefore, we calculated the partial correlation coefficient between response to tilt and activity restriction index with the age factor statistically controlled. With age controlled, the correlation between a positive response to tilt and increased activity restriction became statistically significant (P = 0.02). A positive response to tilt at February 2000 Volume 319 Number 2
Davis et al
Table 3. Supine Baseline and Tilt-Table Vital Signs during Stage 1 (No Drug)
GF Supine systolic BP (mm Hg) Supine diastolic BP (mm Hg) Supine heart rate (beats/min) Stage 1 maximum systolic BP (mm Hg) Stage 1 maximum diastolic BP (mm Hg) Stage 1 maximum heart rate (beats/min) Stage 1 maximum heart rate variation (beats/min) Stage 1 maximum systolic BP change from supine (mm Hg) Stage 1 maximum diastolic BP change from supine (mm Hg) Stage 1 maximum heart rate change from supine (beats/min)
126.7;±: 70.2;±: 69.8 ;±: 139.5 ;±: 88.5 ;±: 96.1 ;±: 21.6 ;±: -18.3 ;±: -4.1 ;±: 24.8 ;±:
GC 2.0b 1.7 2.6 2.4 2.1 4.3 2.5 5.8 4.2 2.3
126.7 ;±: 70.2 ;±: 66.2 ;±: 144.0 ;±: 87.8 ;±: 85.4 ;±: 14.4 ;±: -8.8;±: 1.1 ;±: 18.8;±:
NC 3.9 2.2 2.1 3.2 2.0 2.2 8.9 4.6 3.6 1.4
119.6 ;±: 69.1 ;±: 62.7 ;±: 132.6;±: 83.7;±: 84.4;±: 12.4 ;±: -7.0;±: -1.5 ;±: 21.6 ;±:
2.5 1.6 2.0 2.2 1.4 2.9 1.3 1.7 2.7 2.1
0.134 0.891 0.096
0.014c 0.154
0.028d 0.013d 0.157 0.601 0.129
BP, blood pressure; GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War. a Analysis of variance (2-tailed level of significance) b Results expressed as mean ;±: S.E.M. c P < 0.05, GC vs NC (Student-Newman-Keuls) d P < 0.05, GF vs GC and GF vs NC (Student-Newman-Keuls)
stage 1 was not significantly correlated with age (P = 0.415), Gulf War service (P = 0.09), physical fitness score (P = 0.109), baseline systolic blood pressure (P = 0.39), diastolic blood pressure (P = 0.296), or heart rate (P = 0.41), but was negatively correlated with well-being (P = 0.042) and positively correlated with activity restriction (P = 0.019) and the orthostasis index (P = 0.037).
Discussion
This study suggests that, similar to patients with CFS, Gulf War veterans with chronic fatigue are more likely to have neurally mediated hypotension than are unfatigued control subjects. Our results are also consistent with a preliminary report showing diminished resting cardiac output and blood pressure responsiveness in fatigued Gulf War veterans 7 compared with unfatigued Gulf War veteran control subjects. The fatigued Gulf War veterans in our study had physical and neuropsychological complaints very similar to those of the CFS patients studied by Bou-Holaigah et aL4 One difference between the 2 study groups, however, was in the degree of fatigue reported. In this study, the mean activity restriction index score ofthe fatigued veterans, 3.07, was in the range of "somewhat limited." This compares to a mean pretreatment score of 4.9 (5 is "very limited") on the activity restriction index of the fatigued patients in the previous study. Similarly, the mean general sense of well-being index was 6.8 in our fatigued group and 3.6 in the previous study. Only 2 of our fatigued soldiers were unable to perform all military duties and were being processed for medical separation (1 for fibromyalgia and 1 for idiopathic exertional dysequilibrium). The rest were performing all military duties. This suggests that evidence of autonomic dysfunction may be found in other THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
populations of patients who are less severely fatigued than patients with full-blown CFS. Our results were complicated by an unexpectedly high proportion of positive responses to tilt with isoproterenol infusion in our control groups compared with previous studies. 8 ,9 We thus reanalyzed the data considering only the positive responses to drug-free tilt and found a highly significant difference between fatigued and unfatigued groups. Because our study was designed to extend the findings of Bou-Holaigah et al,4 we had been obligated to employ their tilt-table protocol, which used isoproterenoL As illustrated in Figure 1, isoproterenol seemed to increase to a similar degree, in all 3 groups, the number of positive responses to tilt. Although we hesitate to make generalizations from a post hoc analysis, we believe these results are meaningfuL The use of isoproterenol in tilt-table testing has been criticized for increasing test sensitivity at the expense of specificity.1° Part of the reason for the excess of positive responses with isoproterenol may be that Evans U.S. Army Community Hospital is located at an altitude of 1846 m. Because there is an increased incidence of syncope in persons who have recently ascended to elevations greater than 2000 m,11,12 there may be persistent subtle effects of altitude on electrolyte and water balance and adrenergic tone that lower the threshold for syncope. This deserves further study because of the increasing use of tilt-table testing in the clinical setting. Other researchers have confirmed the presence of autonomic nervous system dysfunction with orthostatic intolerance in CFS,4,5 suggesting either a postviral autonomic neuropathy or cardiovascular deconditioning. In our study we were uniquely able to use army physical fitness test scores as an estimate of cardiovascular conditioning. Although we do 93
Fatigued Gulf War Veterans
not have scores on all volunteers, the mean physical fitness test score of the fatigued volunteers was not significantly different from that of the control subjects. We thus conclude that deconditioning is not a strong factor in the positive response to tilt in our fatigued volunteers. How does a finding of autonomic nervous system dYRfunction relate to what is known about war syndromes in general and Gulf War syndrome in particular? There is some evidence that environmental stresses that activate the immune system are important for the expression of both war syndromes and chronic fatigue-like syndromes. Acute febrile illness is cited by many patients with CFS as the precipitating event.13.14 In a study of idiopathic orthostatic postural tachycardia syndrome, a disorder that shares many features with CFS,15 acute viral illness again was cited by 7 of 16 patients as the precipitating event for this syndrome. Also, patients with CFS have well-documented abnormalities in immune function, including elevation in titers of antibody to many viral antigens,16 increased incidence of atopic disorders,17 and subtle alterations in cytokine function. IS War syndromes may likewise be provoked in susceptible persons by the infectious diseases that invariably accompany crowded populations of military personnel. Gastrointestinal illnesses in particular were noted by Hyams et a1 6 to often precede the development of war syndromes. It has also been suggested that the particular immunization protocols used by the U.S., Canadian, and United Kingdom (UK) forces may have predisposed these troops to a nonspecific shift in cytokine function. 19 Various cytokines have been associated with fatigue,20 decreased exercise tolerance,21 depressive symptoms,22 and changes in enteric neuromuscular function23 and have been found in preliminary reports to be elevated in fatigued Gulf War veterans. 7,24 Both war syndromes and CFS could thus be characterized by persistence of abnormal immunologic function after an acute infection or other immunologic stimulus. Further elucidation of the complex interactions between the immune system and the nervous system will no doubt shed further light on the pathophysiology of many chronic fatigue-like syndromes. Our study is also consistent with other studies reporting abnormalities of nervous system function in symptomatic Gulf War veterans. In 1996, Jamal et al reported slowing in nerve conduction velocity in a group of Gulf War veterans randomly selected from the UK registry compared with matched control subjects. 25 A group of more severely symptomatic veterans, many of whom were disabled, from a single navy reserve construction unit was studied in detail by Haley's groUp.26-28 They were found to have neurological and neuropsychological dysfunction suggestive of organophosphate-induced delayed polyneuropathy.
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Thousands of Gulf War veterans were exposed chronically to low levels of pesticides and insect repellents, which are potentially neurotoxic compounds,l,27 Many troops intermittently used pyridostigmine bromide when there were Scud missile attacks or when chemical alarms sounded. Additionally, it has been suggested that thousands of troops may have been exposed to low levels of sarin nerve gas from the demolition of the Iraqi ammunition depot at Khamisiyah. The low levels of exposure to any 1 of these compounds would not normally be expected to result in any morbidity. Although there is no indication that large numbers of Gulf War veterans have developed serious neurological disorders,1 research remains to be done on possible subtle neurological effects of low-level exposure to combinations of neurotoxic chemicals, as well as the role that chemical sensitivity may play in the development of fatigue states. In conclusion, we have observed that in some Gulf War veterans with chronic fatigue, there is evidence of abnormal autonomic function as measured by a positive response to upright tilt. This suggests that fatigue related to Gulf War service may be a variant ofCFS. Causes may include postinfectious, immunerelated, or toxin-related effects on autonomic function. Acknowledgments
We are indebted to David Schwartz, MD, of Pikes Peak Cardiology for reviewing tilt-table flow sheets; John Ward, PhD, of Brooke Army Medical Center for helpful discussions regarding statistical analysis; Robert H. Gates, MD, for review of an earlier draft of the paper; Kathleen Polo, MD, for helpful discussion and for conducting some of the tilt-table tests; and the staff of the Persian Gulf CCEP Section, the Physical Exams Section, and the Cardiopulmonary Section at Evans U.s. Army Community Hospital for its logistical support; and to the volunteers. References 1. Comprehensive Clinical Evaluation Program for Persian Gulf War Veterans: CCEP report on 18,598 participants. Publication no UB 369 C66 1996a. Washington (DC): U.S. Department of Defense; 1996 . 2. Epstein KR. The chronically fatigued patient. Med Clin North Am 1995;79:315-27. 3. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International chronic fatigue syndrome study group. Ann Intern Med 1994;121:953-9. 4. Bou-Holaigah I, Rowe PC, Kan J, et al. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995;274:961-7. 5. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med 1997;102:357-64. 6. Hyams KC, Wignall FS, Roswell R. War syndromes and their evaluation: from the US Civil War to the Persian Gulf War. Ann Intern Med 1996;125:398-405. February 2000 Volume 319 Number 2
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7. Peckerman A, Natelson BH, LaManca JJ, et al. Cardiovascular hyporeactivity and immune system functioning in Gulf War veterans with chronic fatigue syndrome [abstractl. Conference on Federally Sponsored Gulf War Veterans' Illnesses Research; 1998 Jun 17-19; Washington, DC. Washington (DC): United States Department of Veterans Affairs; 1998. p. 185. 8. Morillo CA, Klein GJ, Zandri S, et al. Diagnostic accuracy of a low-dose isoproterenol head-up tilt protocol. Am Heart J 1995;129:901-6. 9. Natale A, Akhtar M, Jazayeri M, et al. Provocation of hypotension during head up tilt testing in subjects with no history of syncope or presyncope. Circulation 1995;92:54-8. 10. Kapoor WN, Brant N. Evaluation of syncope by upright tilt testing with isoproterenol: a nonspecific test. Ann Int Med 1992;116:358-63. 11. Freitas J, Costa 0, Carvalho MJ, et al. High altituderelated neurocardiogenic syncope. Am J Cardiol 1996;77: 1021. 12. Nicholas R, O'Meara PD, Calonge N. Is syncope related to moderate altitude exposure? JAMA 1992;268:904-6. 13. Levine PH, Jacobson S, Pocinki AG, et al. Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome. Arch Intern Med 1992;152:1611-6. 14. Smith MS, Mitchell J, Corey L, et al. Chronic fatigue in adolescents. Pediatrics 1991;88:195-202. 15. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993;43:132-7. 16. Manian FA. Simultaneous measurement of antibodies to Epstein-Barr virus, human herpesvirus 6, herpes simplex virus types 1 and 2, and 14 enteroviruses in chronic fatigue syndrome: is there evidence of activation of a nonspecific polyclonal immune response? Clin Infect Dis 1994;19:448-53. 17. Steinberg P, McNutt BE, Marshall P, et al. Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome. J Allergy Clin Immunol 1996;97:119-26. 18. Rasmussen AK, Nielsen H, Andersen V, et al. Chronic
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19. 20.
21. 22.
23. 24.
25.
26. 27. 28.
fatigue syndrome-a controlled cross sectional study. J Rheumatol 1994;21:1527-31. Rook GA, Zumia A. Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile? Lancet 1997;349:1831-3. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997;82:1313-6. Davis JM, Bailey SP. Possible mechanisms of central nervous system fatigue during exercise. Med Sci Sports Exerc 1997;29:45-57. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H. Increased CD56+- natural killer cells and related cytokines in major depression. Clin Immunol Immunopathol 1996;78:83-5. Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 1996;111:1683-99. Natelson BH, Zhang Q, Zhou XD, et al. Altered immune status in Gulfveterans but not civilians with chronic fatigue syndrome [abstractl. Conference on Federally Sponsored Gulf War Veterans' Illnesses Research; 1998 Jun 17-19; Washington, DC. Washington (DC): United States Department of Veterans Mfairs; 1998. p. 180. Jamal GA, Hansen S, Apartopoulos F, Peden A. The "Gulf War syndrome": is there evidence of dysfunction in the nervous system? J Neurol Neurosurg Psychiatry 1996;60: 449-51. Haley RW, Hom J, Roland PS, et al. Evaluation of neurologic function in Gulf War veterans: a blinded case-control study. JAMA 1997;277:223-30. Haley RW, Kurt TL, Hom J. Is there a Gulf War Syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 1997;277(3):215-22. Hom J, Haley RW, Kurt TL. Neuropsychological correlates of Gulf War syndrome. Arch Clin Neuropsychology 1997; 12: 531-44.
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ABSTRACT: Background: Many patients with chronic fatigue syndrome (CFS) have neurally mediated hypotension when subjected to head-up tilt, suggesting autonomic nervous system dysfunction. Some Gulf War veterans have symptoms similar to CFS. Whether they also tend to have neurally mediated hypotension is unknown. Methods: We performed 3-stage tilt-table testing on 14 Gulf War veterans with chronic fatigue, 13 unfatigued control Gulf War veterans, and 14 unfatigued control subjects who did not serve in the Gulf War. Isoproterenol was used in stages 2 and 3 of the tilt protocol. Results: More fatigued Gulf War veterans than unfatigued control subjects had hypotensive responses
F
atigue is 1 of the 2 most common complaints listed in the Department of Defense report on 18,598 Gulf War veterans 1 ; 47% of the participants report this symptom. Fatigue is also a common complaint in general medical practice and has been estimated to account for more than 7 million office visits a year.2 In people with fatigue caused by lifestyle, medical, or other identifiable conditions, treatment and management are straightforward. In many of the Gulf War veterans we have evaluated, as in civilian medical practice, the cause offatigue is undetermined. Some fatigued people may meet the criteria for chronic fatigue syndrome (CFS). CFS is now defined as clinically evaluated, unexplained, persistent or From Preventive Medicine (SDD), Ambulatory Services (SFK, and Hospital Services (BLP, JLS), Evans US Army Community Hospital, Fort Carson, Colorado. 1 Current affiliation: Veterans Affairs Outpatient Clinic, Colorado Springs, Colorado. 2 Current affiliation: Uniformed Services University of the Health Sciences, Bethesda, Maryland. The opinions and assertions contained herein are not to be construed as official or reflecting the views of the U.S. Army or the Department of Defense. Submitted October 9, 1998; accepted in revised form April 23, 1999. Correspondence: Dr. S. D. Davis, VA Outpatient Clinic, 25 N. Spruce Street, Colorado Springs, CO 80905 (E-mail: shirley. [email protected]). JAW),
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
to tilt (p < 0.036). A positive response to the drug-free stage 1 of the tilt was observed in 4 of 14 fatigued Gulf War veterans versus 1 of 27 unfatigued control subjects (P < 0.012). Heart rate and heart rate variation during stage 1 was significantly greater in the fatigued group (P < 0.05). Conclusion: We conclude that more fatigued Gulf War veterans have neurally mediated hypotension than unfatigued control subjects, similar to observations in CFS. Autonomic nervous system dysfunction may be present in some fatigued Gulf War veterans. KEY INDEXING TERMS: Chronic fatigue syndrome; Hypotension, orthostatic; Autonomic nervous system diseases; Gulf War syndrome [Am
J Med Sci 2000;319(2):89-95.]
relapsing fatigue that is of new or definite onset, is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities. CFS is also defined by the presence of at least 4 of the following symptoms: memory or concentration difficulties severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities; sore throat; tender cervical or axillary lymph nodes; muscle pain; arthralgias without arthritis; headaches of a new type; unrefreshing sleep; or postexertional malaise lasting more than 24 hours.3 Other symptoms widely reported by patients with chronic fatigue syndrome include depression, malaise, lightheadedness, and other minor neuropsychological complaints. Recent evidence suggests that autonomic nervous system dysfunction may be present in CFS. Bou-Holaigah et al 4 used head-up tilt-table testing to show that neurally mediated hypotension was present in 22 of 23 patients who met strict criteria for CFS. Subsequently, Freeman and KomaroftS found abnormalities in several indices of sympathetic and parasympathetic nervous system function in a group of 23 patients with CFS. In that study, a hypotensive response to a drug-free tilt-table test was found in 9 of 16 patients with CFS. Many Gulf War veterans have reported 1 or more
89
Fatigued Gulf War Veterans
of a constellation of symptoms (fatigue, joint and muscle pains, headache, memory and concentration problems, sleep disturbance, rash, depression, diarrhea, shortness of breath, abdominal pain, hair loss, bleeding gums) that have been called Gulf War syndrome. Other war syndromes have been documented in the English language medical literature from the American Civil War to the Persian Gulf War.6 Shared symptoms among most of these syndromes include fatigue, headache, sleep disturbances, dizziness, joint pains, shortness of breath, and memory and concentration problems. Because of the similarity of these symptoms with the symptoms ofCFS, we suspected that symptomatic Gulf War veterans with prominent complaints offatigue were experiencing a variant of CFS. We hypothesized that more fatigued Gulf War veterans than unfatigued control subjects would have neurally mediated hypotension on tilttable testing. Methods Source of SUbjects. Gulf War veterans were recruited from a group of approximately 1600 Gulf War veterans, mostly active duty soldiers, who were medically evaluated through the Department of Defense Comprehensive Clinical Evaluation Program for Gulf War Veterans (CCEP) at Evans Army Community Hospital between 1994 and 1997. Participants in this ongoing program undergo a physical examination, chest radiograph, laboratory evaluation, and specialty consultations as necessary to define all medical problems. Volunteers were also recruited through notices placed in the post newspaper and by electronic notices on the hospital computer network. Fatigued Gulf War veterans were recruited from the participants in the program who had chronic fatigue (ICD-9-CM code 780.7) as 1 of their top 3 final diagnoses after comprehensive clinical evaluation. Fatigued veterans underwent further screening if they had additional unexplained somatic or neuropsychological symptoms. If they had fatigue not related to ongoing exertion and unrelieved by rest and associated with memory or concentration difficulties, sore throat, tender cervical or axillary lymph nodes, muscle or joint pain, headaches, sleep disturbance, or postexertional malaise lasting more than 24 hours, they were invited to participate in the study. Self-identified healthy, unfatigued volunteers were also recruited. They were not required to undergo comprehensive medical evaluation but their medical history was screened. Unfatigued Gulf War veterans were encouraged to complete the CCEP to ensure a comprehensive health assessment, and all but 1 completed the program. Volunteers we·re excluded if there was recent surgery, heavy alcohol use, major depression, cardiac or cerebrovascular disease, diabetes, or other unresolved major medical problems or if the volunteer was pregnant, breast feeding, using antihypertensive medications, antihistamines, nonsteroidal anti-inflammatory drugs, or antidepressants. Volunteers were also excluded ifthere was a history of frequent or recurrent syncope. Occasional syncope occurring as a result of self-limited illness, physical exhaustion, dehydration, or vasovagal reactions to the sight of blood or the like was not grounds for exclusion. Study Design. The study design was approved by the Human Use Committee and Institutional Review Board at Brooke Army Medical Center, San Antonio, Texas, which has approval authority over clinical research performed at Evans Army Community Hospital. Informed consent was obtained from all volunteers. We predicted that more Gulf War veterans with chronic fatigue would have neurally mediated hypotension compared with unfatigued control subjects. However, we could not exclude the possi-
90
bility that service in the Gulf War itself, in the absence of fatigue, could be associated with neurally mediated hypotension. Therefore, we used a 3-group study design to enable a separate analysis of the effect of fatigue and Gulf War service. Gulf War veterans with unexplained fatigue and other associated symptoms were assigned to group Gulf-Fatigue (GF, n = 14). Gulf War veterans who were unfatigued and in good health were assigned to group Gulf-Control (GC, n = 13). Healthy volunteers who did not serve in the Gulf War were enrolled in group Non-Gulf-Control (NC, n = 14). This latter group consisted of 13 volunteers currently or formerly in military service and 1 civilian volunteer with no military experience. Before tilt-table testing, all volunteers completed 2 simple indices used previously4: a general sense of well-being scale (an analog scale where 0 represents death and 100 represents as well as a person could ever feel) and an activity restriction index. The latter index was designed to quantify the effects of fatigue on the ability to engage in 7 activities: exercise, including sports and military physical fitness training; housework/family activities; shopping; work/career/school; social activities; outdoor work, including military field duty; and favorite recreational activities. Each activity was rated on a scale of 1 (no limitations) to 6 (severely limited). The index was scored as the mean of individual items rated. Additionally, the most recent army physical fitness test score, if available, was included in the analysis. Volunteers also indicated the frequency of syncope or presyncope on 2 separate checklists. Possible responses were "never," "once or twice in my life," "several times in my life," and "many times in my life." Responses to the 2 checklists were scored on a scale of 0 ("never") to 3 ("many times in my life"). The scores on the 2 checklists were added to derive a simple "orthostasis index" for each volunteer. Because volunteers who indicated that they had experienced syncope "many times in my life" were excluded from the study, the maximum score on the index could be no higher than 5. Tilt Table Protocol. A 3-stage upright tilt-table test was performed. After a fast from solid foods (oral hydration was permitted) of at least 2 hours, volunteers were placed supine on a tilt-table with a footboard for weight bearing. A slow intravenous infusion of normal saline was started through an intravenous catheter, and an automatic blood pressure cuff was applied to the right arm. The electrocardiogram and transcutaneous pulse oxygen saturation were continuously monitored. After a lO-minute baseline period of monitoring vital signs and cardiac rhythm in the supine position, the table was tilted head-up to 70° (stage 1). The blood pressure and heart rate were measured after 1 minute of upright tilt and thereafter every 5 minutes, or more frequently if symptoms developed. All vital signs and symptoms were recorded on a flow sheet by 1 of the authors. Monitoring continued in the head-up position for 45 minutes or until syncope or severe presyncopal symptoms occurred. If there was not a syncopal or presyncopal response by 45 minutes, the subject was returned to the supine position and an infusion of isoproterenol was begun at a rate of 1 or 2 J.Lg/min, titrated to achieve a 20% increase in baseline heart rate. After 10 minutes of titration, the subject was retilted for a 15-minute period (stage 2). If there was no response, the subject was returned to the supine position and the isoproterenol infusion rate was increased by 2 J.Lg/min. After 10 minutes of equilibration, the subject was retilted (stage 3). If a response was not obtained after another 15 minutes, the subject was returned to the supine position and the test terminated. Presyncopal symptoms included lightheadedness, perspiration, decreased vision or hearing, slowing of response to verbal stimuli, nausea, or loss of postural tone. Testing was not always terminated when presyncopal symptoms were transient. To control for potential bias in the decision to terminate the tilt-table test, each flow sheet was blindly reviewed by both a cardiologist not associated with the study and by 1 of the study authors who did not conduct the test. The test was scored positive if syncope occurred or presyncopal symptoms occurred coincident with a drop in systolic blood pressure of at least 25 mm Hg with no associated increase in heart rate. There was initial agreement between the February 2000 Volume 319 Number 2
Davis et al
Table 1. Demographic Characteristics and Mean Scores on Activity Restriction Index, Well-Being Scale, and Army Physical Fitness Test for Each Group
MalelFemalea OfficerlEnlistedINonveterana Active dutylRetired-dischargedIN onveterana Age (years)b Activity restriction indexb Well-being scale b Orthostasis indexb Army physical fitness testb
GF
GC
NC
pc
12/2 0/1410 11/3/0 32.1 ± 1.6 3.07 ± 0.22 6.8 ± 0.4 2.07 ± 0.31 254 ± 12.1
12/1 5/8/0 12/1/0 38.9 ± 1.9 1.16 ± 0.09 9.0 ± 0.2 0.92 ± 0.21 262 ± 6.2
11/3 8/5/1 13/0/1 31.9 ± 2.1 1.10 ± 0.04 9.2 ± 0.2 1.43 ± 0.25 252 ± 8.3
0.334 0.001 0.239 0.019 d
GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War Data expressed as number of subjects in each category in each group. Comparisons by Jt test. b Data expressed as mean ± S.E.M. Comparisons by analysis of variance. C P, two-tailed level of significance d P < 0.05, GC vs GF and GC vs NC (Student-Newman-Keuls) e P < 0.05, GF vs GC and GF vs NC (Student-Newman-Keuls) f P < 0.05, GF vs GC (Student-Newman-Keuls) a
2 reviewers on scoring of 39 of the 41 tilt-table results, with consensus on scoring of the remaining 2 developing after discussion. Data Analysis. Comparisons among the 3 groups in terms of demographics, baseline blood pressure and heart rate, minimum and maximum heart rate, and blood pressure during testing and scores on the activity restriction index, well-being scale, and orthostasis index were analyzed using the analysis of variance for continuous variables or the Jt test for dichotomous variables. Further analysis of statistically significant results from the analysis of variance was performed employing the Student-NewmanKeuls test to determine differences between individual groups. Scores on the well-being scale were divided by 10 to allow comparison to the previous study.4 Results of tilt-table testing were scored on an ordinal scale of 1 to 4, where 1, 2, or 3 was a positive response at stages 1, 2, or 3. A negative test was scored 4. Tilt test data were then analyzed using the Mann-Whitney U test for 2 groups or the Kruskal-Wallis test for all 3 groups. A post hoc analysis of positive responses to tilt during stage 1 was performed using the same tests. Correlations between a positive response to tilt versus age, vital signs, scores on the well-being scale, activity restriction index, orthostasis index, and army physical fitness test were determined using either the Pearson rank correlation coefficient or the Kendall partial correlation coefficient, as indicated. Statistical computations were performed using the SPSS computer program (ver. 6.1.1; SPSS, Inc., Chicago, IL). Significance at the I-tailed level of 0.05 or less was accepted in comparing results of the tilt-table tests among the groups for 2 reasons. First, we predicted that, a priori, fatigued Gulf War veterans would have a higher incidence of neurally mediated hypotension than control subjects. Second, we judged that the finding of fewer positive tests in the fatigued group than a control group would be clinically meaningless. All other analyses were performed using a 2-tailed level of significance.
Results
Demographic and Clinical Characteristics Table 1 shows the demographic characteristics and the mean scores on the activity restriction index, the well-being scale, the orthostasis index, and army physical fitness test for each group. Most volunteers were men on active-duty military status. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
The proportions of women and non-active-duty personnel were not significantly different among the 3 groups. There was a significant difference in the proportion of officers versus enlisted members: group GF had the highest proportion of enlisted volunteers (14 of 14), and group NC had the highest proportion of officers (8 of 14, P < 0.001). Group GC was significantly older than the other 2 groups (P < 0.02). Consistent with previous data on people with chronic fatigue,S the fatigued Gulf War veterans in group GF had a mean activity restriction score significantly higher (ie, activities were more restricted) and a well-being score significantly lower (ie, sense of well-being was lower) than either of the 2 control groups (P < 0.001). Additionally, their scores on the orthostasis index were higher, indicating that they experienced more frequent episodes of syncope and pre syncope than did the unfatigued volunteers (P < 0.014). Army physical fitness test scores were available for 12 volunteers in each group. The standard Army physical fitness test consists of push-ups, sit-ups and a 2-mile run. Scoring on each event is dependent upon age and gender. Each event has a minimum passing score of 60 and maximum of 100; the test result is the sum of the scores of the individual events. There was no difference among the 3 groups in the mean of the available physical fitness test scores. There also was no significant difference among the 3 groups in the time between the most recent physical fitness test and the date of the tilttable test (median number of months: GF, 5.0; GC, 4.0; NC, 4.0; P = 0.38, Kruskal-Wallis). Volunteers in the fatigued group were selected in part because of the similarity of their physical and neuropsychological complaints to CFS. Table 2 con91
Fatigued Gulf War Veterans
Table 2. Number of Subjects in Each Group Endorsing Each Physical and Neuropsychological Symptom of CFS Symptom Fatigue >6 months Fatigue unrelieved by rest Memory and concentration problems Arthralgias Post-exertional malaise Tender cervical or axillary nodes Myalgias New type of headaches Frequent sore throats
GF 14 13 12 10 7 6 6 6 5
GC
70%
NC 60%
0 0 2 3 0 0 1 2 0
0 0 0 1 0 0 0 0 0
GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War
50%
40%
30%
20%
trasts the number of volunteers in each group reporting specific symptoms associated with CFS.
10%
Results of Tilt- Table Testing Figure 1 summarizes the results of tilt-table testing. A positive response to tilt was observed in 9 of 14 (64%) of group GF compared with 5 of13 (38%) of group GC and 6 of 14 (43%) of group NC. This trend is not statistically significant when the 3 groups are compared (P = 0.098), but is statistically significant when the fatigued Gulf War veterans are compared with all unfatigued control subjects (P < 0.036). Four of the positive responses to tilt in group GF occurred without drug provocation (ie, during stage 1 of the test). In contrast, only 1 positive response occurred without drug provocation in group GC, and none in group NC. This trend was statistically significant (P = 0.031; P = 0.012, fatigued versus control subjects). Table 3 displays analysis of the baseline vital signs and responses to the stage 1 drug-free tilt. Maximum systolic and diastolic blood pressures and heart rate were the maximums recorded in each volunteer during the 45-minute drug-free stage. Baseline supine vital signs were the median of 3 measurements during the 10-minute baseline observation period. There was no statistically significant difference among the 3 groups in baseline supine systolic or diastolic blood pressure or pulse, although there was a trend toward a higher systolic blood pressure and pulse in the fatigued group, similar to previous observations. 5 During 70° head-up tilt, there were significant differences among the 3 groups in maximum systolic blood pressure, maximum heart rate, and maximum heart rate variation. Further analysis of these responses to tilt disclosed a trend toward a higher maximum systolic blood pressure response in the 2 Gulf War gr{)UPS, with group GC reaching a statistically significant difference from group NC (P < 0.05). The maximum heart-rate response to tilt was significantly higher in the fatigued Gulf War veterans than in each of the control groups (P < 0.05), similar to previous obser-
0%
92
*
GF
GC Group
NC
Figure 1. Proportion of tilt-table tests positive in each group. Dark portion of bars represents proportion of tilt-table tests positive at stage 1. *, P < 0.036, fatigued vs unfatigued (MannWhitney D, I-tailed); t, P < 0.031 (Kruskal-Wallis, I-tailed); P < 0.011, fatigued vs unfatigued (Mann-Whitney D, I-tailed). GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War.
vations in chronic fatigue syndrome. 5 The maximum heart-rate variation (maximum minus minimum heart rate) was also highest in the fatigued group (P < 0.05). Although not statistically different among the 3 groups, the fatigued group had a fall in systolic blood pressure with tilt greater than twice the magnitude of the control groups, similar to previous findings in CFS. 5
Correlates of Positive Response to Tilt Among all volunteers, a positive response to tilt was significantly correlated with the orthostasis index (P = 0.05). A positive response to tilt was not significantly correlated with age (P = 0.337), Gulf War service (P = 0.240), well-being score (P = 0.100), physical fitness score (P = 0.091), baseline systolic blood pressure (P = 0.792), diastolic blood pressure (P = 0.564), or heart rate (P = 0.558). A positive response to tilt was almost significantly correlated with the activity restriction index (P = 0.051). Given the 28-year age range of the volunteers, there was possibly an age-related factor in the activity levels; therefore, we calculated the partial correlation coefficient between response to tilt and activity restriction index with the age factor statistically controlled. With age controlled, the correlation between a positive response to tilt and increased activity restriction became statistically significant (P = 0.02). A positive response to tilt at February 2000 Volume 319 Number 2
Davis et al
Table 3. Supine Baseline and Tilt-Table Vital Signs during Stage 1 (No Drug)
GF Supine systolic BP (mm Hg) Supine diastolic BP (mm Hg) Supine heart rate (beats/min) Stage 1 maximum systolic BP (mm Hg) Stage 1 maximum diastolic BP (mm Hg) Stage 1 maximum heart rate (beats/min) Stage 1 maximum heart rate variation (beats/min) Stage 1 maximum systolic BP change from supine (mm Hg) Stage 1 maximum diastolic BP change from supine (mm Hg) Stage 1 maximum heart rate change from supine (beats/min)
126.7;±: 70.2;±: 69.8 ;±: 139.5 ;±: 88.5 ;±: 96.1 ;±: 21.6 ;±: -18.3 ;±: -4.1 ;±: 24.8 ;±:
GC 2.0b 1.7 2.6 2.4 2.1 4.3 2.5 5.8 4.2 2.3
126.7 ;±: 70.2 ;±: 66.2 ;±: 144.0 ;±: 87.8 ;±: 85.4 ;±: 14.4 ;±: -8.8;±: 1.1 ;±: 18.8;±:
NC 3.9 2.2 2.1 3.2 2.0 2.2 8.9 4.6 3.6 1.4
119.6 ;±: 69.1 ;±: 62.7 ;±: 132.6;±: 83.7;±: 84.4;±: 12.4 ;±: -7.0;±: -1.5 ;±: 21.6 ;±:
2.5 1.6 2.0 2.2 1.4 2.9 1.3 1.7 2.7 2.1
0.134 0.891 0.096
0.014c 0.154
0.028d 0.013d 0.157 0.601 0.129
BP, blood pressure; GF, fatigued Gulf War veterans; GC, control Gulf War veterans; NC, control subjects not deployed to Gulf War. a Analysis of variance (2-tailed level of significance) b Results expressed as mean ;±: S.E.M. c P < 0.05, GC vs NC (Student-Newman-Keuls) d P < 0.05, GF vs GC and GF vs NC (Student-Newman-Keuls)
stage 1 was not significantly correlated with age (P = 0.415), Gulf War service (P = 0.09), physical fitness score (P = 0.109), baseline systolic blood pressure (P = 0.39), diastolic blood pressure (P = 0.296), or heart rate (P = 0.41), but was negatively correlated with well-being (P = 0.042) and positively correlated with activity restriction (P = 0.019) and the orthostasis index (P = 0.037).
Discussion
This study suggests that, similar to patients with CFS, Gulf War veterans with chronic fatigue are more likely to have neurally mediated hypotension than are unfatigued control subjects. Our results are also consistent with a preliminary report showing diminished resting cardiac output and blood pressure responsiveness in fatigued Gulf War veterans 7 compared with unfatigued Gulf War veteran control subjects. The fatigued Gulf War veterans in our study had physical and neuropsychological complaints very similar to those of the CFS patients studied by Bou-Holaigah et aL4 One difference between the 2 study groups, however, was in the degree of fatigue reported. In this study, the mean activity restriction index score ofthe fatigued veterans, 3.07, was in the range of "somewhat limited." This compares to a mean pretreatment score of 4.9 (5 is "very limited") on the activity restriction index of the fatigued patients in the previous study. Similarly, the mean general sense of well-being index was 6.8 in our fatigued group and 3.6 in the previous study. Only 2 of our fatigued soldiers were unable to perform all military duties and were being processed for medical separation (1 for fibromyalgia and 1 for idiopathic exertional dysequilibrium). The rest were performing all military duties. This suggests that evidence of autonomic dysfunction may be found in other THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
populations of patients who are less severely fatigued than patients with full-blown CFS. Our results were complicated by an unexpectedly high proportion of positive responses to tilt with isoproterenol infusion in our control groups compared with previous studies. 8 ,9 We thus reanalyzed the data considering only the positive responses to drug-free tilt and found a highly significant difference between fatigued and unfatigued groups. Because our study was designed to extend the findings of Bou-Holaigah et al,4 we had been obligated to employ their tilt-table protocol, which used isoproterenoL As illustrated in Figure 1, isoproterenol seemed to increase to a similar degree, in all 3 groups, the number of positive responses to tilt. Although we hesitate to make generalizations from a post hoc analysis, we believe these results are meaningfuL The use of isoproterenol in tilt-table testing has been criticized for increasing test sensitivity at the expense of specificity.1° Part of the reason for the excess of positive responses with isoproterenol may be that Evans U.S. Army Community Hospital is located at an altitude of 1846 m. Because there is an increased incidence of syncope in persons who have recently ascended to elevations greater than 2000 m,11,12 there may be persistent subtle effects of altitude on electrolyte and water balance and adrenergic tone that lower the threshold for syncope. This deserves further study because of the increasing use of tilt-table testing in the clinical setting. Other researchers have confirmed the presence of autonomic nervous system dysfunction with orthostatic intolerance in CFS,4,5 suggesting either a postviral autonomic neuropathy or cardiovascular deconditioning. In our study we were uniquely able to use army physical fitness test scores as an estimate of cardiovascular conditioning. Although we do 93
Fatigued Gulf War Veterans
not have scores on all volunteers, the mean physical fitness test score of the fatigued volunteers was not significantly different from that of the control subjects. We thus conclude that deconditioning is not a strong factor in the positive response to tilt in our fatigued volunteers. How does a finding of autonomic nervous system dYRfunction relate to what is known about war syndromes in general and Gulf War syndrome in particular? There is some evidence that environmental stresses that activate the immune system are important for the expression of both war syndromes and chronic fatigue-like syndromes. Acute febrile illness is cited by many patients with CFS as the precipitating event.13.14 In a study of idiopathic orthostatic postural tachycardia syndrome, a disorder that shares many features with CFS,15 acute viral illness again was cited by 7 of 16 patients as the precipitating event for this syndrome. Also, patients with CFS have well-documented abnormalities in immune function, including elevation in titers of antibody to many viral antigens,16 increased incidence of atopic disorders,17 and subtle alterations in cytokine function. IS War syndromes may likewise be provoked in susceptible persons by the infectious diseases that invariably accompany crowded populations of military personnel. Gastrointestinal illnesses in particular were noted by Hyams et a1 6 to often precede the development of war syndromes. It has also been suggested that the particular immunization protocols used by the U.S., Canadian, and United Kingdom (UK) forces may have predisposed these troops to a nonspecific shift in cytokine function. 19 Various cytokines have been associated with fatigue,20 decreased exercise tolerance,21 depressive symptoms,22 and changes in enteric neuromuscular function23 and have been found in preliminary reports to be elevated in fatigued Gulf War veterans. 7,24 Both war syndromes and CFS could thus be characterized by persistence of abnormal immunologic function after an acute infection or other immunologic stimulus. Further elucidation of the complex interactions between the immune system and the nervous system will no doubt shed further light on the pathophysiology of many chronic fatigue-like syndromes. Our study is also consistent with other studies reporting abnormalities of nervous system function in symptomatic Gulf War veterans. In 1996, Jamal et al reported slowing in nerve conduction velocity in a group of Gulf War veterans randomly selected from the UK registry compared with matched control subjects. 25 A group of more severely symptomatic veterans, many of whom were disabled, from a single navy reserve construction unit was studied in detail by Haley's groUp.26-28 They were found to have neurological and neuropsychological dysfunction suggestive of organophosphate-induced delayed polyneuropathy.
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Thousands of Gulf War veterans were exposed chronically to low levels of pesticides and insect repellents, which are potentially neurotoxic compounds,l,27 Many troops intermittently used pyridostigmine bromide when there were Scud missile attacks or when chemical alarms sounded. Additionally, it has been suggested that thousands of troops may have been exposed to low levels of sarin nerve gas from the demolition of the Iraqi ammunition depot at Khamisiyah. The low levels of exposure to any 1 of these compounds would not normally be expected to result in any morbidity. Although there is no indication that large numbers of Gulf War veterans have developed serious neurological disorders,1 research remains to be done on possible subtle neurological effects of low-level exposure to combinations of neurotoxic chemicals, as well as the role that chemical sensitivity may play in the development of fatigue states. In conclusion, we have observed that in some Gulf War veterans with chronic fatigue, there is evidence of abnormal autonomic function as measured by a positive response to upright tilt. This suggests that fatigue related to Gulf War service may be a variant ofCFS. Causes may include postinfectious, immunerelated, or toxin-related effects on autonomic function. Acknowledgments
We are indebted to David Schwartz, MD, of Pikes Peak Cardiology for reviewing tilt-table flow sheets; John Ward, PhD, of Brooke Army Medical Center for helpful discussions regarding statistical analysis; Robert H. Gates, MD, for review of an earlier draft of the paper; Kathleen Polo, MD, for helpful discussion and for conducting some of the tilt-table tests; and the staff of the Persian Gulf CCEP Section, the Physical Exams Section, and the Cardiopulmonary Section at Evans U.s. Army Community Hospital for its logistical support; and to the volunteers. References 1. Comprehensive Clinical Evaluation Program for Persian Gulf War Veterans: CCEP report on 18,598 participants. Publication no UB 369 C66 1996a. Washington (DC): U.S. Department of Defense; 1996 . 2. Epstein KR. The chronically fatigued patient. Med Clin North Am 1995;79:315-27. 3. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International chronic fatigue syndrome study group. Ann Intern Med 1994;121:953-9. 4. Bou-Holaigah I, Rowe PC, Kan J, et al. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995;274:961-7. 5. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med 1997;102:357-64. 6. Hyams KC, Wignall FS, Roswell R. War syndromes and their evaluation: from the US Civil War to the Persian Gulf War. Ann Intern Med 1996;125:398-405. February 2000 Volume 319 Number 2
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