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September 27, 1995, Vol 274, No. 12 >
ARTICLE | September 27, 1995

The Relationship Between Neurally Mediated Hypotension and the Chronic Fatigue Syndrome FREE

Issam Bou-Holaigah, MD; Peter C. Rowe, MD; Jean Kan, MD; Hugh Calkins, MD
[+] Author Affiliations

Reprint requests to The Johns Hopkins Hospital, Carnegie 592, 600 N Wolfe St, Baltimore, MD 21287-0409 (Dr Calkins).


JAMA. 1995;274(12):961-967. doi:10.1001/jama.1995.03530120053041
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Published online
Article
References

Objective.  —To compare the clinical symptoms and response evoked by upright tilt-table testing in healthy individuals and in a sample of those satisfying strict criteria for chronic fatigue syndrome.

Design.  —Case-comparison study with mean (SD) follow-up of 24 (5) weeks.

Setting.  —Tertiary care hospital.

Patients and Other Participants.  —A sample of 23 patients with chronic fatigue syndrome (five men and 18 women; mean age, 34 years), each of whom fulfilled the strict diagnostic criteria of the Centers for Disease Control and Prevention, was recruited from regional chronic fatigue support groups and from the investigators' clinical practices. There were 14 healthy controls (four men and 10 women; mean age, 36 years).

Interventions.  —Each subject completed a symptom questionnaire and underwent a three-stage upright tilt-table test (stage 1, 45 minutes at 70° tilt; stage 2, 15 minutes at 70° tilt with 1 to 2 μg/min of isoproterenol; and stage 3, 10 minutes at 70° with 3 to 4 μg/min of isoproterenol). Patients were offered therapy with fludrocortisone, β-adrenergic blocking agents, and disopyramide, alone or in combination, directed at neurally mediated hypotension.

Main Outcome Measures.  —Response to upright tilt and scores on symptom questionnaires prior to and during follow-up.

Results.  —An abnormal response to upright tilt was observed in 22 of 23 patients with chronic fatigue syndrome vs four of 14 controls (P<.001). Seventy percent of chronic fatigue syndrome patients, but no controls, had an abnormal response during stage 1 (P<.001). Nine patients reported complete or nearly complete resolution of chronic fatigue syndrome symptoms after therapy directed at neurally mediated hypotension.

Conclusions.  —We conclude that chronic fatigue syndrome is associated with neurally mediated hypotension and that its symptoms may be improved in a subset of patients by therapy directed at this abnormal cardiovascular reflex.(JAMA. 1995;274:961-967)

REFERENCES

1 +
Gunn WJ, Connell DB, Randall B.  Epidemiology of chronic fatigue syndrome. Ciba Found Symp . 1993;;173:83-101.
2 +
Lloyd AR, Hickie I, Boughton CR, Spencer O, Wakefield D.  Prevalence of chronic fatigue syndrome in an Australian population. Med J Aust . 1990;;153:522-528.
3 +
Bates DW, Schmitt W, Buchwald D, et al.  Prevalence of fatigue and chronic fatigue syndrome in a primary care practice. Arch Intern Med . 1993;;153: 2759-2765.
4 +
Holmes GP, Kaplan JE, Gantz NM, et al.  Chronic fatigue syndrome. Ann Intern Med . 1988;;108:387-389.
5 +
Fukuda K, Straus SE, Hickie I, et al.  The chronic fatigue syndrome. Ann Intern Med . 1994;;121:953-959.
6 +
Komaroff AL.  Clinical presentation of chronic fatigue syndrome. Ciba Found Symp . 1993;;173:43-61.
7 +
Lane RM.  Aetiology, diagnosis and treatment of chronic fatigue syndrome. J Serotonin Res . 1994;; 1:47-60.
8 +
Engel GL. Fainting: Physiological and Psychological Considerations . Springfield, Ill: Charles C Thomas Publisher; 1950;.
9 +
Weissler AM, Warren JV.  Vasodepressor syncope. Am Heart J . 1959;;57:786-794.
10 +
VanLieshout JJ, Wieling W, Karemaker JM, Eckberg DL.  The vasovagal response. Clin Sci (Colch) . 1991;;81:575-586.
11 +
Kosinski DJ, Grubb BP.  Neurally mediated syncope with an update on indications and usefulness of head-upright tilt table testing and pharmacologic therapy. Curr Opin Cardiol . 1994;;9:53-64.
12 +
Sra JS, Jazayeri MR, Dhala A, et al.  Neurocardiogenic syncope: diagnosis, mechanisms, and treatment. Cardiol Clin . 1993;;11:183-191.
13 +
Calkins H, Shyr Y, Frumin H, Schork A, Morady F.  The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and vasodepressor syncope. Am J Med . 1995;;98:365-373.
14 +
Rowe PC, Bou-Holaigah I, Kan JS, Calkins H.  Is neurally mediated hypotension an unrecognized cause of chronic fatigue? Lancet . 1995;;345:623-624.
15 +
Straus SE, Dale JK, Tobi M, et al.  Acyclovir treatment of the chronic fatigue syndrome. N Engl J Med . 1988;;319:1692-1698.
16 +
Grubb BP, Wolfe DA, Samoil D, Temesy-Armos P, Hahn H, Elliott L.  Usefulness of fluoxetine hydrochloride for prevention of resistant upright tilt induced syncope. Pacing Clin Electrophysiol . 1993;;16:458-464.
17 +
Sheldon R, Killam S.  Methodology of isoproterenol-tilt table testing in patients with syncope. J Am Coll Cardiol . 1992;;19:773-779.
18 +
Sra J, Vishnubhakta SM, Jazayeri MR, et al.  Use of intravenous esmolol to predict efficacy of oral beta-adrenergic blocker therapy in patients with neurocardiogenic syncope. J Am Coll Cardiol . 1992;;19:402-408.
19 +
Milstein S, Buetikofer J, Dunnigan A, Benditt DG, Gornick C, Reyes WJ.  Usefulness of disopyramide for prevention of upright tilt-induced hypotension-bradycardia. Am J Cardiol . 1990;;65:1339-1344.
20 +
Ross BA, Hughes S, Anderson E, Gillette PC.  Abnormal responses to orthostatic testing in children and adolescents with recurrent unexplained syncope. Am Heart J . 1991;;122:748-754.
21 +
Thilenius OG, Quinones JA, Husayni TS, Novak J.  Tilt test for diagnosis of unexplained syncope in pediatric patients. Pediatrics . 1991;;87:334-338.
22 +
Stewart AL, Hays RD, Ware JE Jr.  The MOS short-form general health survey. Med Care . 1988;; 26:724-735.
23 +
Bentall RP, Wood GC, Marrinam T, Dears C, Edwards RHT.  A brief mental fatigue questionnaire. Br J Clin Psychol . 1993;;32:375-379.
24 +
Kramer MS, Feinstein AR.  Clinical biostatistics, LIV: the biostatistics of concordance. Clin Pharmacol Ther . 1981;;29:111-123.
25 +
Calkins H, Byrne M, El-Atassi R, Kalbfleisch S, Langberg JL, Morady F.  The economic burden of unrecognized vasodepressor syncope. Am J Med . 1993;;95:473-479.
26 +
Lewis T.  A lecture on vasovagal syncope and the carotid sinus mechanism. BMJ . 1932;;1:873-876.
27 +
Calkins H, Seifert M, Morady F.  Clinical presentation and long term follow-up of athletes with exercise induced vasodepressor syncope. Am Heart J . 1995;;129:1159-1164.
28 +
Grubb BP, Temesy-Armos PN, Samoil D, Wolfe DA, Hahn H, Elliott L.  Tilt table testing in the evaluation and management of athletes with recurrent exercise-induced syncope. J Am Coll Sports Med . 1993;;25:24-28.
29 +
Harrison MH, Kravik SE, Geelen G, Keil L, Greenleaf JE.  Blood pressure and plasma renin activity as predictors of orthostatic tolerance. Aviat Space Environ Med . 1985;;56:1059-1064.
30 +
Kleinknecht RA, Lenz J, Ford G, DeBerard S.  Types and correlates of blood/injury level-related vasovagal syncope. Behav Res Ther . 1990;;28:289-295.
31 +
Camfield PR, Camfield CS.  Syncope in childhood. Can J Neurol Sci . 1990;;17:306-308.
32 +
Kenny RA, Ingram A, Bayliss J, Sutton R.  Head-up tilt: a useful test for investigating unexplained syncope. Lancet . 1986;;1:1352-1355.
33 +
Almquist A, Goldenberg IF, Milstein S, et al.  Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med . 1989;;320:346-351.
34 +
Newman D, Lurie K, Rosenqvist M, Washington C, Schwartz J, Scheinman MM.  Head-up tilt testing with and without isoproterenol infusion in healthy subjects of different ages. Pacing Clin Electrophysiol . 1993;;16:715-721.
35 +
Fitzpatrick AP, Theodorakis G, Vardas P, Sutton R.  Methodology of head-up tilt testing in patients with unexplained syncope. J Am Coll Cardiol . 1991;;17:125-130.
36 +
Kapoor WN, Smith MA, Miller NL.  Upright tilt testing in evaluating syncope: a comprehensive literature review. Am J Med . 1994;;97:78-88.
37 +
Sheldon R, Splawinski J, Killam S.  Reproducibility of isoproterenol tilt-table tests in patients with syncope. Am J Cardiol . 1992;;69:1300-1305.
38 +
Grubb BP, Wolfe D, Temesy-Armos P, Hahn H, Elliott L.  Reproducibility of head upright tilt table test results in patients with syncope. Pacing Clin Electrophysiol . 1992;;15:1477-1481.
39 +
Chen XC, Chen MY, Remole S, et al.  Reproducibility of head-up tilt table testing for eliciting susceptibility to neurally mediated syncope in patients without structural heart disease. Am J Cardiol . 1992;;69:755-760.
40 +
Peterson PK, Shepard J, Macres M, et al.  A controlled trial of intravenous immunoglobulin Gin chronic fatigue syndrome. Am J Med . 1990;;89:554-560.
41 +
Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J.  A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med . 1990;; 89:561-568.
42 +
McEwen OR.  Salt loss as a common cause of ill-health in hot climates. Lancet . 1935;;1:1015.
43 +
McCance RA.  Experimental sodium chloride deficiency in man. Proc R Soc Lond B Biol Sci . 1935-1936;;119:245-268.
44 +
Best JB, Bett JHN, Coghlan JP, Cran EJ, Scoggins BA.  Circulating angiotensin-II and aldosterone levels during dietary sodium restriction. Lancet . 1971;;2:13534.
45 +
Schondorf R, Low PA.  Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology . 1993;;43:132-137.
46 +
Streeten DH, Anderson GH Jr.  Delayed orthostatic intolerance. Arch Intern Med . 1992;;152:1066-1072.
47 +
Rosen SG, Cryer PE.  Postural tachycardia syndrome. Am J Med . 1982;;72:847-850.
48 +
Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC.  Idiopathic hypovolemia. Ann Intern Med . 1986;; 104:298-303.
49 +
Price RK, North CS, Wessely S, Fraser VJ.  Estimating the prevalence of chronic fatigue syndrome and associated symptoms in the community. Public Health Rep . 1992;;107:514-522.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Gunn WJ, Connell DB, Randall B.  Epidemiology of chronic fatigue syndrome. Ciba Found Symp . 1993;;173:83-101.
2 +
Lloyd AR, Hickie I, Boughton CR, Spencer O, Wakefield D.  Prevalence of chronic fatigue syndrome in an Australian population. Med J Aust . 1990;;153:522-528.
3 +
Bates DW, Schmitt W, Buchwald D, et al.  Prevalence of fatigue and chronic fatigue syndrome in a primary care practice. Arch Intern Med . 1993;;153: 2759-2765.
4 +
Holmes GP, Kaplan JE, Gantz NM, et al.  Chronic fatigue syndrome. Ann Intern Med . 1988;;108:387-389.
5 +
Fukuda K, Straus SE, Hickie I, et al.  The chronic fatigue syndrome. Ann Intern Med . 1994;;121:953-959.
6 +
Komaroff AL.  Clinical presentation of chronic fatigue syndrome. Ciba Found Symp . 1993;;173:43-61.
7 +
Lane RM.  Aetiology, diagnosis and treatment of chronic fatigue syndrome. J Serotonin Res . 1994;; 1:47-60.
8 +
Engel GL. Fainting: Physiological and Psychological Considerations . Springfield, Ill: Charles C Thomas Publisher; 1950;.
9 +
Weissler AM, Warren JV.  Vasodepressor syncope. Am Heart J . 1959;;57:786-794.
10 +
VanLieshout JJ, Wieling W, Karemaker JM, Eckberg DL.  The vasovagal response. Clin Sci (Colch) . 1991;;81:575-586.
11 +
Kosinski DJ, Grubb BP.  Neurally mediated syncope with an update on indications and usefulness of head-upright tilt table testing and pharmacologic therapy. Curr Opin Cardiol . 1994;;9:53-64.
12 +
Sra JS, Jazayeri MR, Dhala A, et al.  Neurocardiogenic syncope: diagnosis, mechanisms, and treatment. Cardiol Clin . 1993;;11:183-191.
13 +
Calkins H, Shyr Y, Frumin H, Schork A, Morady F.  The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and vasodepressor syncope. Am J Med . 1995;;98:365-373.
14 +
Rowe PC, Bou-Holaigah I, Kan JS, Calkins H.  Is neurally mediated hypotension an unrecognized cause of chronic fatigue? Lancet . 1995;;345:623-624.
15 +
Straus SE, Dale JK, Tobi M, et al.  Acyclovir treatment of the chronic fatigue syndrome. N Engl J Med . 1988;;319:1692-1698.
16 +
Grubb BP, Wolfe DA, Samoil D, Temesy-Armos P, Hahn H, Elliott L.  Usefulness of fluoxetine hydrochloride for prevention of resistant upright tilt induced syncope. Pacing Clin Electrophysiol . 1993;;16:458-464.
17 +
Sheldon R, Killam S.  Methodology of isoproterenol-tilt table testing in patients with syncope. J Am Coll Cardiol . 1992;;19:773-779.
18 +
Sra J, Vishnubhakta SM, Jazayeri MR, et al.  Use of intravenous esmolol to predict efficacy of oral beta-adrenergic blocker therapy in patients with neurocardiogenic syncope. J Am Coll Cardiol . 1992;;19:402-408.
19 +
Milstein S, Buetikofer J, Dunnigan A, Benditt DG, Gornick C, Reyes WJ.  Usefulness of disopyramide for prevention of upright tilt-induced hypotension-bradycardia. Am J Cardiol . 1990;;65:1339-1344.
20 +
Ross BA, Hughes S, Anderson E, Gillette PC.  Abnormal responses to orthostatic testing in children and adolescents with recurrent unexplained syncope. Am Heart J . 1991;;122:748-754.
21 +
Thilenius OG, Quinones JA, Husayni TS, Novak J.  Tilt test for diagnosis of unexplained syncope in pediatric patients. Pediatrics . 1991;;87:334-338.
22 +
Stewart AL, Hays RD, Ware JE Jr.  The MOS short-form general health survey. Med Care . 1988;; 26:724-735.
23 +
Bentall RP, Wood GC, Marrinam T, Dears C, Edwards RHT.  A brief mental fatigue questionnaire. Br J Clin Psychol . 1993;;32:375-379.
24 +
Kramer MS, Feinstein AR.  Clinical biostatistics, LIV: the biostatistics of concordance. Clin Pharmacol Ther . 1981;;29:111-123.
25 +
Calkins H, Byrne M, El-Atassi R, Kalbfleisch S, Langberg JL, Morady F.  The economic burden of unrecognized vasodepressor syncope. Am J Med . 1993;;95:473-479.
26 +
Lewis T.  A lecture on vasovagal syncope and the carotid sinus mechanism. BMJ . 1932;;1:873-876.
27 +
Calkins H, Seifert M, Morady F.  Clinical presentation and long term follow-up of athletes with exercise induced vasodepressor syncope. Am Heart J . 1995;;129:1159-1164.
28 +
Grubb BP, Temesy-Armos PN, Samoil D, Wolfe DA, Hahn H, Elliott L.  Tilt table testing in the evaluation and management of athletes with recurrent exercise-induced syncope. J Am Coll Sports Med . 1993;;25:24-28.
29 +
Harrison MH, Kravik SE, Geelen G, Keil L, Greenleaf JE.  Blood pressure and plasma renin activity as predictors of orthostatic tolerance. Aviat Space Environ Med . 1985;;56:1059-1064.
30 +
Kleinknecht RA, Lenz J, Ford G, DeBerard S.  Types and correlates of blood/injury level-related vasovagal syncope. Behav Res Ther . 1990;;28:289-295.
31 +
Camfield PR, Camfield CS.  Syncope in childhood. Can J Neurol Sci . 1990;;17:306-308.
32 +
Kenny RA, Ingram A, Bayliss J, Sutton R.  Head-up tilt: a useful test for investigating unexplained syncope. Lancet . 1986;;1:1352-1355.
33 +
Almquist A, Goldenberg IF, Milstein S, et al.  Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med . 1989;;320:346-351.
34 +
Newman D, Lurie K, Rosenqvist M, Washington C, Schwartz J, Scheinman MM.  Head-up tilt testing with and without isoproterenol infusion in healthy subjects of different ages. Pacing Clin Electrophysiol . 1993;;16:715-721.
35 +
Fitzpatrick AP, Theodorakis G, Vardas P, Sutton R.  Methodology of head-up tilt testing in patients with unexplained syncope. J Am Coll Cardiol . 1991;;17:125-130.
36 +
Kapoor WN, Smith MA, Miller NL.  Upright tilt testing in evaluating syncope: a comprehensive literature review. Am J Med . 1994;;97:78-88.
37 +
Sheldon R, Splawinski J, Killam S.  Reproducibility of isoproterenol tilt-table tests in patients with syncope. Am J Cardiol . 1992;;69:1300-1305.
38 +
Grubb BP, Wolfe D, Temesy-Armos P, Hahn H, Elliott L.  Reproducibility of head upright tilt table test results in patients with syncope. Pacing Clin Electrophysiol . 1992;;15:1477-1481.
39 +
Chen XC, Chen MY, Remole S, et al.  Reproducibility of head-up tilt table testing for eliciting susceptibility to neurally mediated syncope in patients without structural heart disease. Am J Cardiol . 1992;;69:755-760.
40 +
Peterson PK, Shepard J, Macres M, et al.  A controlled trial of intravenous immunoglobulin Gin chronic fatigue syndrome. Am J Med . 1990;;89:554-560.
41 +
Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J.  A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med . 1990;; 89:561-568.
42 +
McEwen OR.  Salt loss as a common cause of ill-health in hot climates. Lancet . 1935;;1:1015.
43 +
McCance RA.  Experimental sodium chloride deficiency in man. Proc R Soc Lond B Biol Sci . 1935-1936;;119:245-268.
44 +
Best JB, Bett JHN, Coghlan JP, Cran EJ, Scoggins BA.  Circulating angiotensin-II and aldosterone levels during dietary sodium restriction. Lancet . 1971;;2:13534.
45 +
Schondorf R, Low PA.  Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology . 1993;;43:132-137.
46 +
Streeten DH, Anderson GH Jr.  Delayed orthostatic intolerance. Arch Intern Med . 1992;;152:1066-1072.
47 +
Rosen SG, Cryer PE.  Postural tachycardia syndrome. Am J Med . 1982;;72:847-850.
48 +
Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC.  Idiopathic hypovolemia. Ann Intern Med . 1986;; 104:298-303.
49 +
Price RK, North CS, Wessely S, Fraser VJ.  Estimating the prevalence of chronic fatigue syndrome and associated symptoms in the community. Public Health Rep . 1992;;107:514-522.

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