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A substantial body of clinical evidence now supports an association between various forms of hypotension and both idiopathic chronic fatigue and the chronic fatigue syndrome (CFS). Patients with CFS have a high prevalence of neurally mediated hypotension, and open treatment of this autonomic dysfunction has been associated with improvements in CFS symptoms. Randomized trials are now in progress to evaluate the efficacy of treatments directed at neurally mediated hypotension in those with CFS patients, and the results of these trials should help guide more basic inquiries into the mechanisms of orthostatic intolerance in affected individuals.
Recent research has identified a high prevalence of abnormal hemodynamic responses to upright posture among individuals with chronic fatigue and chronic fatigue syndrome (CFS).
The most frequently reported of these autonomic disorders among those with CFS is neurally mediated hypotension (NMH)—a term preferable to the synonyms “neurocardiogenic syncope,” “vasodepressor syncope,” and “vasovagal syncope,” because it emphasizes that symptoms can occur without complete loss of consciousness. This article discusses selected issues in the clinical overlap of CFS and autonomic dysfunction, briefly reviews current understandings of the pathophysiology, diagnosis, and treatment of NMH, and addresses some of the scientific challenges involved in determining whether the association between NMH and CFS is causal.
Hypotension, autonomic dysfunction, and chronic fatigue
Although a low resting blood pressure in the absence of orthostatic symptoms does not represent disease, it can no longer be claimed, as the title of an influential study in 1940 stated, that hypotension is “the ideal normal blood pressure.”
In a study of 10,314 British civil servants, the lowest quartile of systolic blood pressure was associated with the highest prevalence of dizziness, tiredness, and somatic complaints, the odds ratio for unexplained tiredness being 1.2 times higher for men and 1.33 times higher for women in the lowest quartile compared with the highest. The mechanism of the association between low blood pressure and fatigue was not investigated in these studies.
Chronic fatigue has long been described in those with orthostatic hypotension (or primary autonomic failure) in whom hypotension occurs rapidly within the first 5 minutes of standing or upright tilt.
chronic fatigue was reported by 72% with orthostatic hypotension, defined strictly as a ≥30 mm Hg drop in systolic (or a 15 mm Hg drop in diastolic) pressure in response to 5 minutes of upright tilt to 80°. Other frequent symptoms in this group included lightheadedness in 88%, cognitive difficulties (problems thinking and concentrating) in 47%, blurred vision in 47%, tremulousness in 38%, pallor in 31%, and anxiety in 29%. Such neurocognitive symptoms have been attributed to cerebral hypoperfusion. As in the epidemiologic studies, the relatively low prevalence of chronic fatigue in the setting of a substantial degree of hypotension emphasizes that the relation between low blood pressure and fatigue is neither simple nor direct.
In those with more delayed orthostatic hypotension
described 7 patients with delayed orthostatic hypotension, 6 of whom had chronic fatigue. Plasma volume and red blood cell mass were subnormal in the 3 patients in whom these assessments were made. After treatment with fludrocortisone or octreotide, 3 of 4 patients who had a substantial reduction or complete correction of the delayed orthostatic hypotension also experienced a substantial improvement in their chronic fatigue. Whether these subjects satisfied criteria for CFS was not recorded, although these investigators speculated at the time that the fatigue and exhaustion associated with other conditions, including the CFS, might result in some individuals from a failure to maintain blood pressure in the upright position.
In their series of 16 patients with postural orthostatic tachycardia syndrome (POTS), 3 of whom also had hypotension during a brief tilt test, Schondorf and Low
identified 13 with chronic fatigue and 3 with postprandial bloating and delayed gastric emptying. All 16 experienced an acute onset of symptoms, and in 7, the fatigue and lightheadedness appeared after an apparent viral infection. Symptomatic improvement in subjects with POTS has been noted with sodium loading, fludrocortisone, and other medications.
Neurally mediated hypotension and chronic fatigue syndrome
That fatigue can be associated with neurally mediated hypotension has been appreciated at least since 1932, when Sir Thomas Lewis described a young soldier in whom syncope and relative bradycardia developed during a venipuncture.
The soldier had a long history of exhaustion soon after starting to exercise and the blood sample was being drawn to evaluate an episode of loss of consciousness while he had been on guard duty. After the venipuncture, he became hypotensive and unresponsive for several minutes, during which time his heart rate was 50–60 beats/min and his systolic blood pressure was 50 mm Hg. He remained tremulous and tired for the next 36 hours, demonstrating that a long period of acute fatigue could follow a single episode of vasovagal (or neurally mediated) hypotension.
Several comprehensive reviews of NMH are available.
NMH has come to be regarded as the most common cause of recurrent syncope. It is seen with a somewhat greater frequency in women, with greater prevalence in those younger than 50, and evidence from small studies suggests a higher risk of NMH in those with a lower resting blood pressure.
The routine physical examination and laboratory tests usually are normal, and hypotension is not detected in most instances unless the orthostatic stress is prolonged and individuals are kept from using postural countermeasures. There is an overlap between NMH and panic attacks.
One of the patients who prompted our investigations into whether chronic fatigue could follow chronic, early activation of this reflex pathway was a 16-year-old who had developed the insidious onset of fatigue 18 months earlier. She described becoming tired, shaky, lightheaded, and pale after walking more than 10 minutes, would get more tired if she stood quietly or sat upright, and had to lie down on her bed for 30 minutes after a shower. She said her head felt foggy and thick all the time, and her memory and reading comprehension had deteriorated. One notable physical finding was that her legs and arms developed a purple discoloration after a short period of quiet standing, a feature reported several decades ago in those with epidemic neuromyasthenia,
and indicative of abnormal venous pooling. A tilt-table test performed to evaluate her recurrent presyncope was consistent with NMH. She had a normal blood pressure and heart rate at baseline but got lightheaded at 10 minutes, and at 20 minutes had severe lightheadedness, pallor, and general discomfort. Her blood pressure decreased to 65/40, with an inappropriate but characteristic slowing of her heart rate.
Similar abnormalities were present in the next 6 adolescents we evaluated for chronic fatigue, none of whom had experienced syncope.
Four met the 1988 criteria for CFS, and 4 of the 7 had a substantial improvement in symptoms when treated with increased intakes of fluid and sodium, and medications directed against NMH. These improvements suggested that the symptoms in CFS could be approached, not from the dominant paradigm of viral infection and immune activation, but rather from the standpoint of autonomic dysfunction. The findings also prompted us to examine in a larger group of patients whether neurally mediated hypotension is an unrecognized cause of symptoms in CFS.
Case control study with tilt test
To estimate the proportion of CFS patients with abnormal tilt tests and the proportion with a response to fludrocortisone, we recruited 23 individuals who had been diagnosed with CFS. Features that exacerbated their fatigue included physical exertion, a hot shower, prolonged standing (such as waiting in line at the grocery store), and a warm environment.
Recalling Lewis’ observation, participants also reported being more tired after a lightheaded episode. An abnormal drop in blood pressure in response to upright tilt was observed in 22 of 23 patients with CFS (96%) versus 4 of 14 healthy controls (29%). During the first 45 minutes of upright tilt to 70°, 16 patients (or 70%) with CFS developed hypotension, while all controls maintained a normal blood pressure. Perhaps more importantly, all 23 with CFS, but none of the controls, developed orthostatic symptoms during this first stage of tilt testing, suggesting that orthostatic intolerance may be a defining feature of the illness.
With open treatment of the NMH, 9 of 19 patients (47%) reported a substantial improvement in symptoms, which was defined carefully as a score or ≥7 on a 10-point wellness scale, along with similar degrees of improvement in activity and cognitive function. A further 7 reported being at least somewhat better. To determine whether the subjective report of improvement in symptoms was associated with objective improvement in tolerance of upright tilt, 6 of the patients with an almost complete resolution of symptoms on therapy agreed to undergo repeat tilt testing. Five of 6 had normal tilt test responses while on therapy, and the sixth had a marked improvement. Three others with mild improvements in symptoms continued to have abnormal tilt tests.
One of the possible interpretations of these abnormal responses to tilt testing was that they represented a consequence of physical deconditioning, which would be assumed to be present in most, but not all, of those with CFS. Although this is a complicated question to study and was not the subject of this investigation, the improvements in symptoms occurred within a few days in some patients, and in all patients, the improvement in orthostatic tolerance preceded return of their ability to exercise. Among those who have experienced a substantial improvement in symptoms, and in whom a resumption of more normal activity and exercise has been possible, attempts to stop medical therapy have been followed within days by a resumption of profound fatigue.
Randomized trial with tilt test
In this preliminary study, neither patients nor investigators were blinded as to treatment, and although the tilt response was more objective, it was not interpreted in a blinded manner. Nonetheless, the pilot results allowed us to design a randomized trial that we are conducting in collaboration with colleagues in Dr. Stephen Straus’s Laboratory of Clinical Investigation in the National Institute of Allergy and Infectious Disease. The main study question is: will individuals with CFS and neurally mediated hypotension have a greater improvement in (1) self-reported well-being; and (2) objective orthostatic tolerance 9 weeks after starting treatment with fludrocortisone than they will after treatment with placebo? Patients are eligible if they are 18–50 years old, satisfy the 1994 criteria for the diagnosis of CFS, and have hypotension documented during stage 1 or 2 of an upright tilt-table test. After tilt testing, patients will be stratified by duration of CFS symptoms (with a cut-point at 3 years), then randomized to fludrocortisone or a look-alike placebo capsule. Treatment will continue for 9 weeks; in the ninth week, subjects will have a repeat tilt test. Study participants will then be observed off medications for 2 weeks. The primary outcome measure is the proportion with a clinically important 15-point improvement in well-being on a 100-point wellness scale. Secondary outcomes are the proportion of patients who are able to tolerate one further stage of upright tilt, and symptom changes on a variety of standardized measures.
Physiology of neurally mediated hypotension
What is the mechanism by which individuals develop early provocation of hypotension during upright tilt (i.e., early activation of the vasovagal reflex)? Three factors that predispose to the development of NMH are a low resting blood volume, excessive pooling of blood in the dependent vessels, and excessive loss of plasma volume during upright posture
—all of which can decrease venous return to the heart. When cardiac output is decreased in this setting, a reflex increase in sympathetic neural outflow and an increased secretion of epinephrine normally results in an increase in peripheral vascular resistance and in heart rate, thereby leading to maintenance of a normal blood pressure. In those with abnormal responses to upright tilt, there seems to be a failure to mobilize blood effectively from the dependent splanchnic and limb vasculature. The normal response both to upright tilt testing and exercise ought to involve prompt vasoconstriction, but in response to these stresses several groups have identified impaired vasoconstrictor responses in the forearm and splanchnic bed, and in microvascular flow to the skin.
It is not known why the normal response to orthostatic stress fails to occur.
The decreased venous return leads to an exaggerated sympathetic output, which in turn causes vigorous ventricular contractions. In the setting of an underfilled ventricular chamber, this increased inotropy triggers firing of mechanically sensitive C-fibers normally activated under conditions of severe hypertension. The central nervous system response, appropriate for hypertension, involves withdrawal of sympathetic tone and relatively unopposed vagal tone, resulting in vasodilation and bradycardia. If the individual remains upright, the ultimate event can be either a profound drop in blood pressure or syncope.
). Several aspects of the hypothesis of mechanoreceptor-mediated bradycardia and hypotension have been questioned, and it must be acknowledged that this model may not adequately account for the development of NMH after cardiac transplantation.
Factors that can contribute to early activation of the vasovagal reflex include prolonged sitting or standing, mental arithmetic stress, emotional stress (including gory scenes and the sight of blood), a warm environment, and sodium depletion. Studies earlier in this century
Fortney SM, Schneider VS, Greenleaf JE. The physiology of bed rest. In: Fregley MJ, Blatters CM, eds. Handbook of Physiology. Vol II. Section 4: Environmental Physiology, Ed. New York: Oxford University Press, 1996:889–939.
confirmed that both plasma volume and red blood cell mass are decreased with enforced, prolonged bed rest. The degree to which this sort of deconditioning occurs in CFS has not been studied, but any drop in plasma and red blood cell volume would further increase susceptibility to NMH: being intolerant of upright posture during an illness begets further orthostatic intolerance. Various medications (including phenothiazines, diuretics, vasodilating agents, tricyclic antidepressants—some of which have been used in the treatment of CFS symptoms) and conditions with increased histamine release can also cause a decreased return of blood to the heart. Factors such as emotional stress, pain, exercise, and drug treatments (notably the β-agonist drugs, such as albuterol, used for asthma) can contribute to early activation of NMH through raising catecholamine concentrations. Although cognitive stresses should elicit peripheral vasoconstriction, over half of subjects with neurally mediated syncope in a study by Manyari and colleagues
had inappropriate lack of vasoconstriction when asked to perform mental arithmetic tasks. Such inappropriate venous responses could provoke worse orthostatic tolerance in response to common, everyday cognitive stresses, and provide an attractive explanation for why some patients with NMH describe worse fatigue after reading or concentrating.
Few randomized trials are available to guide the long-term therapy of NMH.
Such small samples are inadequate for assessing all but an implausibly large treatment effect. These studies usually have not controlled for sodium intake as a cointervention, and are further complicated by the infrequent occurrence of the primary outcome (syncope) in the follow-up period; only 30% of placebo recipients in one study developed syncope in the year after enrollment.
It should prove simpler to evaluate the response to therapy among subjects with more frequent symptoms, such as those with CFS and daily fatigue or lightheadedness.
The empiric treatment of NMH usually begins with education about avoiding potential triggers of symptoms, and advice to expand blood volume using increased intakes of sodium chloride and fluids. There is no consensus about which of the medications in Table 1is most effective for neurally mediated syncope, and the efficacy of each remains to be established. In open treatment trials, selective serotonin reuptake inhibitors (SSRI) improve both the tolerance of upright tilt and the frequency of clinical symptoms in nondepressed patients with NMH refractory to other measures,
suggesting that a symptomatic improvement in association with SSRI administration does not provide the necessary evidence by itself to support a diagnosis of atypical depression. Nonpharmacologic treatments of postural hypotension include physical maneuvers such as standing in a legs-crossed position, squatting, sitting in the knee-chest position, bending forward, or putting a foot on a chair while standing.
Biofeedback can help decrease fainting after blood drawing, but its role in less specific circumstances remains to be defined. Other therapies used in the setting of orthostatic hypotension may have a role for those with NMH, including erythropoietin, cimetidine, octreotide, and yohimbine.
It increases the proportion of symptomatic subjects who will develop hypotension, but as isoproterenol doses increase, increasing numbers of healthy subjects develop activation of the vasovagal reflex,
Tilt testing is performed in a quiet room, with as little external stimulation as possible. To provoke the abnormality in venous pooling and loss of plasma volume, it is important for patients to remain still, with their feet on a footboard. Allowing excessive leg muscle movement can result in a mechanical enhancement of venous return, a helpful compensation in everyday life to prevent lightheadedness, but not an efficient use of time when trying to assess the degree of venous pooling. Other than the degree of movement permitted, features peculiar to each laboratory include whether an intravenous catheter is present, the duration of pretest fasting, and the drop in blood pressure required before the test is considered abnormal. Another factor that may influence rates of positive tests is the degree to which subjects have already initiated treatment before the test (for example, by increasing their salt and fluid intakes). Mangru and colleagues
administered normal saline solution (10 mL/kg) immediately after documentation of tilt-induced hypotension, and the fluid load resulted in a normalization of the tilt responses for 42/50 children. Whether dietary-sodium loading before the test could cause similar results has not been adequately studied.
The outcome point for an abnormal test varies between centers. In our studies, an abnormal test requires a drop of at least 25 mm Hg in systolic blood pressure, with no associated increase in heart rate, accompanied by reproduction of the patient’s usual symptoms.
Syncope is not necessary for the test to be considered abnormal.
In the last 3 years, we have evaluated >600 CFS patients, and approximately 77% have abnormal tilt tests using the protocol described above. In the first 100 patients studied, the prevalence of abnormal tilts was 95%, with 53% developing hypotension in stage 1.
Whether this represents a biased sample of patients referred with CFS remains to be seen and will require studies in other centers using an identical testing protocol. Nonetheless, a focus on the proportion with hypotension has the potential to miss an important finding: virtually all CFS patients, regardless of their hemodynamic responses in stage 1, have their symptoms provoked by the simple process of assuming an upright posture. Among 23 subjects reported in 1995, all had increased fatigue and lightheadedness during stage 1, as well as other symptoms typical of CFS, including cognitive dysfunction and sore throat.
In a study of 20 fibromyalgia patients using the same tilt protocol, one of the most interesting responses was the provocation or worsening of typical fibromyalgia pain in all except the 2 patients who developed syncope within the first 10 minutes.
The mechanism by which symptoms develop well before the onset of hypotension needs further study, especially focusing on disturbances in cerebral blood flow induced by orthostatic stress.
Among those whose characteristic symptoms are provoked during stage 1, but who do not go on to develop hypotension during upright tilt, other forms of autonomic dysfunction have been observed, including postural orthostatic tachycardia syndrome (Figure 1 ). Fredman and colleagues
of abnormal cerebral blood flow velocity in those with recurrent syncope. Studies are now in progress to assess whether simultaneous transcranial Doppler ultrasound (TCD) and upright tilt testing will improve diagnostic accuracy and understanding of the pathophysiology of symptoms during upright tilt in those with CFS.
Even if NMH proves to be a proximal cause of symptoms in those with CFS, it will beg the question of what provokes the NMH. Why do people suddenly develop orthostatic intolerance, often after apparent infection? Is the hypotensive response initiated by a primary problem in peripheral or in central control of autonomic tone? Is the early activation of NMH in CFS and fibromyalgia patients itself secondary to a more generalized abnormality in the central nervous system? What hemodynamic or genetic factors differentiate those with an acute versus an insidious onset of CFS symptoms? How does apparent genetic susceptibility to NMH affect the age at onset and range of symptoms? Do specific patterns of response during upright tilt predict response to treatment? If NMH is as common among those with CFS as our studies would suggest, then formal evaluation of therapies other than fludrocortisone will be needed.
Any theory that purports to explain the development of CFS symptoms must be able to reconcile specific epidemiologic risk factors in those with the disease. For example, there is a high prevalence of allergic disease among those with CFS.
If the association between CFS and NMH is valid, then one would expect to find a mechanism by which allergic disease increases the activation of this reflex pathway. It is generally assumed that the C-fiber mechanoreceptors in the left ventricle are crucial for initiating the afferent limb of the vasovagal reflex. In an animal model of airway disease, Undem and his coworkers
have shown that both viral infection and allergic reactions to food antigens enhance the excitability of mechanically sensitive vagal afferents in the airway. Upon exposure to ovalbumin, animals allergic to this protein develop a 5-fold decrease in the strength of the mechanical stimulus required to cause a burst of action potentials. The ability of allergen exposure and viral upper respiratory infection to enhance the discharge of mechanically sensitive fibers, including C-fibers, provides a potential link between these clinical situations and the development of NMH in patients with allergy. If this link is confirmed, it suggests that the effort to prevent activation of NMH would need to include general medical management techniques to prevent exacerbations of food and inhalant allergies and asthma in those with CFS.
Investigations into the high prevalence of neurally mediated hypotension and other forms of autonomic dysfunction among those with CFS should improve our understanding of this disorder. Preliminary, unblinded studies suggest that a subset of patients experience a substantial improvement in fatigue and other CFS symptoms when the NMH is successfully treated. The important question of whether neurally mediated hypotension can be regarded as a cause of symptoms in CFS awaits data from randomized, controlled trials, now in progress.
We thank our colleagues Issam Bou-Holaigah, Jean Kan, Kevin Kelly, John Flynn, Sally Snader, Karen DeBusk, Carol Tunin, and Jackie Kaczmarczyk for their assistance with these studies.
Is neurally mediated hypotension an unrecognised cause of chronic fatigue?.
Fortney SM, Schneider VS, Greenleaf JE. The physiology of bed rest. In: Fregley MJ, Blatters CM, eds. Handbook of Physiology. Vol II. Section 4: Environmental Physiology, Ed. New York: Oxford University Press, 1996:889–939.