CFS: Another Hypothesis Leads to a Dead End
ABSTRACT & COMMENTARY
Synopsis: The mineralocorticoid, fludrocortisone, failed to improve the symptoms of chronic fatigue syndrome patients.
Source: Rowe PC, et al. JAMA. 2001;285:52-59.
This study, a joint effort of rowe and associates at the Johns Hopkins Hospital and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, evaluated the potential effect of the mineralocorticoid, fludrocortisone (Florinef) in patients with chronic fatigue syndrome (CFS). Subjects were highly selected on the basis of a strict definition of CFS, and criteria that excluded those with other specified medical and psychiatric conditions or use of any medications that might interfere with tilt-table testing or other elements of the study. Tilt-table testing identified subjects with neurally mediated hypotension (NMH), a sustained 25-mm Hg reduction of systolic blood pressure from baseline supine readings when tilted to a 70º upright position for up to 45 minutes (stage 1 testing) or when similarly tilted following isoproterenol infusion (stage 2). Most patients had CFS for at least 3 years (mean duration, 6 and 6.9 years in the placebo and treated groups, respectively). Fifty subjects received oral fludrocortisone in doses escalating from 0.025 mg/d for the first week to 0.1 mg/d from weeks 3 through 9; an identical number received placebo. Liberal water consumption was encouraged, but no change in the subjects’ salt intake was recommended.
Subjects’ well being was frequently assessed throughout the 9-week treatment period and a 2-week follow-up phase using standardized self-rating measures, including the SF-36 survey, the Beck Depression Inventory, and the Wood Mental Fatigue Inventory, and a unidimensional global wellness scale that has been used by the investigators in other studies of CFS patients. All patients had NMH as defined above. Tilt-table testing was repeated in most subjects at completion of the treatment period.
Rowe et al found in an intention-to-treat analysis that neither wellness scores nor any other self-rating measure improved over the course of the study. Likewise, tilt-table responses were not affected by fludrocortisone treatment.
Significant adverse effects were not observed. Interestingly, when subjects were asked whether they thought they were receiving placebo or active drug, incorrect assessments were slightly more frequent than correct responses, testament to the effective blinding of the study.
COMMENT BY JERRY D. SMILACK, MD
NMH refers to a disorder of blood pressure regulation in which a significant decrease in systolic blood pressure occurs upon assuming an upright body position, after other causes of orthostatic hypotension (such as dehydration or other states of intravascular volume contraction, medication, etc) can be excluded. Several investigators1,2 have observed NMH to be a frequent accompaniment of CFS, a disorder that affects large numbers of individuals.3 Although its cause is unknown, CFS has been the focus of much research, and investigators have identified a variety of objective markers that might provide a clue to the etiology of this perplexing syndrome.4
The suspicion that an altered hypothalamic-pituitary-adrenal axis is fundamental to CFS has been suggested by research demonstrating abnormal serum or urine adrenal hormone concentrations in some patients, either spontaneously measured or determined after provocative testing. To test the hypothesis that this arm of the endocrine system may play a role in CFS, several studies have examined the effect of administration of adrenal hormone in such patients. Cleare and associates, for example, found that low-dose hydrocortisone treatment (5 or 10 mg daily) resulted in improved fatigue and disability scores but had a less impressive effect on clinicians’ assessment of patients’ global depression.5 This study used a crossover design but involved a relatively small number of subjects, and entailed only a short course (28 days) of treatment. On the other hand, McKenzie and associates conducted a study using a higher dose of hydrocortisone (25-35 mg/d) and found measurable benefit to be minimal.6 They cautioned that adrenal suppression, observed in one-third of hydrocortisone recipients, might outweigh any slight benefit.7
The present study by Rowe et al, as well as a crossover, placebo-controlled trial conducted in Minnesota a few years ago,8 examined the use of mineralocorticoid therapy in patients with CFS. Neither study demonstrated a beneficial effect of fludrocortisone. Overall, symptoms failed to improve significantly, and there was no measurable improvement in a variety of performance indices. Rowe et al concluded that the role of NMH in CFS remains an open question, but they were unable to show that fludrocortisone could ameliorate subjective or objective measures of illness, or improve tilt-table performance, in patients with CFS.
References
1. Bou-Holaigah I, et al. JAMA. 1995;274:961-967.
2. Freeman R, et al. Am J Med. 1997;102:357-364.
3. Jason LA, et al. Arch Intern Med. 1999;159: 2129-2137.
4. Komaroff AL. Am J Med. 2000;108:169-171.
5. Cleare AJ, et al. Lancet. 1999;353:455-458.
6. McKenzie R, et al. JAMA. 1998;80:1061-1066.
7. Smilack J. Infectious Disease Alert. 1999;18:49-50.
8. Peterson PK, et al. Arch Intern Med. 1998;158:908-914.
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