Neurally Mediated Hypotension in Chronic Fatigue Syndrome
Neurally Mediated Hypotension in Chronic Fatigue Syndrome
Abstract & Commentary
Synopsis: The therapy of neurally mediated hypotension with fludrocortisone does not provide reliable symptomatic improvement in patients with chronic fatigue syndrome.
Source: Rowe PC, et al. JAMA 2001;285:52-59.
Rowe and colleagues conducted a study of the effect of fludrocortisone acetate in patients with neurally mediated hypotension in the setting of chronic fatigue syndrome. Patients who met Center For Disease Control (CDC) criteria for chronic fatigue syndrome were screened for other reversible causes of fatigue and had four or more of the following symptoms: impaired memory or concentration, sore throat, tender adenopathy, muscle pain, multi-joint pain, headaches, unrefreshing sleep, and postexercise malaise. All patients had had symptoms for at least six months. A Beck Depression Inventory (BDI) was completed by all patients on two occasions before the initial tilt study. A BDI score of 65 or less on the unidimensional global wellness scale was required for entry into the study. Patients then underwent tilt table tests using, in stage I, an upright tilt of 70° for up to 45 minutes. Vital signs were monitored noninvasively. If patients completed stage I of the test without symptoms or hypotension, they proceeded to stage II, which involved head-up tilt during a 2 mcg/min infusion of isoproterenol for a maximum of 15 minutes. In order to enter the study, all patients were required to manifest neurally mediated hypotension as defined as a 25 mm Hg reduction in systolic blood pressure with no associated increase in heart rate and associated symptoms of presyncope or syncope.
One hundred patients were eventually randomized in the study—50 to fludrocortisone and 50 to placebo. The mean age for the group was 37 years. Seventy-eight percent of the patients were older than age 30. Their mean weight was 69 kg. Ninety-eight percent of the patients were white and 66% were women. The mean duration of chronic fatigue syndrome was 6.4 years and 71% of the patients had a duration of symptoms greater than three years. Patients were randomized to receive fludrocortisone acetate titrated to a dose of 0.1 mg/d. Repeat tilt table testing was performed during the ninth week of treatment. Multiple measures of depression, medical fatigue, and medical symptoms were made in the days before the first and second tilt table study and the mean for these measurements during seven days prior to the first and second study were used for the primary outcome.
There was no significant difference in the proportion of subjects with at least a 15-point improvement in wellness scores over the course of the study. Fourteen percent of the subjects in the fludrocortisone group showed this degree of improvement compared with 10% of those in the placebo group. Age, duration of therapy, and compliance with medications did not identify responders. There were no significant changes in any of the secondary outcomes as well. At the second tilt table study, a normal response was seen in nine of 48 placebo patients vs. four out of 42 patients in the fludrocortisone group.
Rowe et al conclude that therapy of neurally mediated hypotension with fludrocortisone does not provide reliable symptomatic improvement in patients with chronic fatigue syndrome.
Comment by John P. DiMarco, MD, PhD
Chronic fatigue syndrome is a frustrating condition with no identifiable cause. Patients with this syndrome have a number of other complaints in addition to fatigue and the system can be physically and psychologically disabling. Several years ago, the groups at Johns Hopkins reported that a large proportion of patients with chronic fatigue syndrome had neurally mediated hypotension. The hypothesis that therapy of neurally mediated hypotension would reverse the symptoms of chronic fatigue syndrome led to the present study. Unfortunately, as shown by the data here, fludrocortisone did not have a statistical effect on either mental status or tilt table responses in patients with this syndrome.
Rowe et al admit that there are some limitations to their trial. Higher doses of fludrocortisone may have been required but many patients cannot tolerate higher doses. Some patients were excluded from participation because of either prior therapy or because of primary psychiatric or medical conditions. However, if neurally mediated hypotension was the primary physiologic abnormality in patients with chronic fatigue syndrome, one would have expected a positive result to this study.
Another major limitation of this study is the fact that both chronic fatigue syndrome and neurally mediated hypotension are quite difficult to treat. In this study, fludrocortisone did not effectively reverse either changes during tilt table testing or improve measures of fatigue or mental health. If the causal relationship between the two syndrome is to be ruled out, it would have been necessary to normalize the tilt table responses without affecting the patients symptoms. Thus, it remains possible that truly effective treatment of neurally mediated hypotension might have some effect in this condition.
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