Amy Weldon

Orthostatic intolerance in adolescent chronic fatigue syndrome

Objectives. To demonstrate the association between orthostatic intolerance and the chronic fatigue syndrome (CFS) in adolescents and to delineate the form that orthostatic intolerance takes in these children. Study Design. We investigated the heart rate and blood pressure (BP) responses to head-up tilt (HUT) in 26 adolescents aged 11 to 19 years with CFS compared with responses in adolescents referred for the evaluation of simple faint and to responses in 13 normal healthy control children of similar age. Results. A total of 4/13 of the controls and 18/26 simple faint patients experienced typical faints with an abrupt decrease in BP and heart rate associated with loss of consciousness. One CFS patient had a normal HUT. A total of 25/26 CFS patients experienced severe orthostatic symptoms associated with syncope in 7/25, orthostatic tachycardia with hypotension in 15/25, and orthostatic tachycardia without significant hypotension in 3/25. Acrocyanosis, cool extremities, and edema indicated venous pooling in 18/25. None of the control or simple faint patients experienced comparable acral or tachycardic findings. Conclusions. We conclude that chronic fatigue syndrome is highly related to orthostatic intolerance in adolescents. The orthostatic intolerance of CFS often has heart rate and BP responses similar to responses in the syndrome of orthostatic tachycardia suggesting that a partial autonomic defect may contribute to symptomatology in these patients.

Patterns of orthostatic intolerance: The orthostatic tachycardia syndrome and adolescent chronic fatigue

OBJECTIVES To describe the orthostatic tachycardia syndrome (OTS) in adolescents, similarities to and differences from chronic fatigue syndrome (CFS), and patterns of orthostatic intolerance during head-up tilt (HUT). STUDY DESIGN Using electrocardiography and arterial tonometry, we investigated the heart rate and blood pressure responses during HUT in 20 adolescents with OTS compared with 25 adolescents with CFS, 13 healthy control subjects, and 20 patients with simple faint. RESULTS Of the control subjects, 4 of 13 experienced typical vasovagal faints with an abrupt fall in blood pressure and heart rate, and 14 of 20 patients with simple faint experienced similar HUT responses. All patients with CFS (25/25) experienced severe orthostatic symptoms with syncope in 2 of 25, early orthostatic tachycardia during HUT in 16 of 23 (13/16 hypotensive), and delayed orthostatic tachycardia in 7 of 23 (6/7 hypotensive). Acrocyanosis and edema occurred in 18 of 25. Early orthostatic tachycardia occurred in 10 of 20 patients with OTS. Of these, 9 of 10 were hypotensive, but hypotension was delayed in 4 of 9. Delayed tachycardia occurred in 10 of 20 (all hypotensive). Acrocyanosis and edema occurred in most patients with CFS, fewer patients with OTS, and in one patient with simple faint. Orthostatic symptoms were similar but more severe in patients with CFS compared with patients with OTS. CONCLUSIONS Symptoms and patterns of orthostatic heart rate and blood pressure change in OTS overlap strongly with those of CFS. Orthostatic intolerance in OTS may represent an attenuated form of chronic fatigue pathophysiology.

Clinical and Physiological Effects of an Acute α-1 Adrenergic Agonist and a β-1 Adrenergic Antagonist in Chronic Orthostatic Intolerance

Background—Adrenergic agents are commonly used in the treatment of chronic orthostatic intolerance with postural tachycardia syndrome (POTS). POTS may be associated with increased limb blood flow (“high flow”) and defective orthostatic vasoconstriction or decreased limb blood flow (“low flow”) and potentially with small blood volume. Methods and Results—We investigated the consequences of short-term intravenous administration of an &agr;-1 adrenergic agonist, phenylephrine, and a &bgr;-1 adrenergic antagonist, esmolol, in 14 patients with POTS aged 13 to 19 years. Indices of heart rate and blood pressure variability, peripheral blood flow, and arterial resistance were assessed, and the capacitance relation was computed for every subject using venous occlusion plethysmography. Patients were tilted to 35° upright while medicated and while unmedicated, and measurements were repeated. Phenylephrine improved orthostatic tolerance and normalized hemodynamics and indices of heart rate/blood pressure variability while supine and while upright, producing significant peripheral vasoconstriction and venoconstriction (20% capacitance change). Esmolol did not improve orthostatic tolerance or hemodynamics. A subgroup of low-flow POTS patients had exaggerated venoconstriction to phenylephrine (50% capacitance change) but others had no response. Conclusions—Phenylephrine, but not esmolol, improves orthostatic tolerance and hemodynamics in POTS. This lends support to the use of oral &agr;-1 agonists in the treatment of patients with chronic orthostatic intolerance.

Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome.

Recent investigations suggest a role for neurally mediated hypotension (NMH) in the symptomatology of chronic fatigue syndrome (CFS) in adults. Our previous observations in children with NMH and syncope (S) unrelated to CFS indicate that the modulation of sympathetic and parasympathetic tone measured by indices of heart rate variability (HRV) is abnormal in children who faint during head-up tilt (HUT). In order to determine mine the effects of autonomic tone on HUT in children with CFS we performed measurements of HRV during HUT in 16 patients aged 11–19 with CFS. Data were compared to 26 patients evaluated for syncope and with 13 normal control subjects. After 30 minutes supine, patients were tilted to 80° for 40 minutes or until syncope occurred. Time domain indices included RR interval, SDNN, RMSSD, and pNN50. An autoregressive model was used to calculate power spectra. LFP (.04–.15 Hz), HFP (.15–.40Hz), and TP (.01–.40Hz). Data were obtained supine (baseline) and after HUT. Thirteen CFS patients fainted (CFS+, 5/13 pure vasodepressor syncope) and three patients did not (CFS-). Sixteen syncope patients fainted (S+, all mixed vasodepressor-cardioinhibitory) and 10 did not (S-). Four control patients fainted (Control+, all mixed vasodepressor-cardioinhibitory) and nine did not (Control-). Baseline indices of HRV were not different between Control+ and S+, and between Control- and S-, but were depressed in S+ compared to S-. HRV indices were strikingly decresed in CFS patients compared to all other groups. With tilt, SDNN, RMSSD, and pNN50 and spectral indices decreased in all groups, remaining much depressed in CFS compared to S or control subjects. With HUT, sympathovagal indices (LFP/HFP, nLFP, and nHFP) were relatively unchanged in CFS, which contrasts with the increase in nLFP with HUT in all other groups. With syncope RMSSD, SDNN, LFP, TP, and HFP increased in S+ (and Control+), suggesting enhanced vagal heart rate regulation. These increases were not observed in CFS+ patients. CFS is associated with NMH during HUT in children. All indices of HRV are markedly depressed in CFS patients, even when compared with already low HRV in S+ or Control+ patients. Sympathovagal balance does not shift toward enhanced sympathetic modulation of heart rate with HUT and there is blunting in the overall HRV response with syncope during HUT. Taken together these data may indicate autonomic impairment in patients with CFS.

Inappropriate Early Hypotension in Adolescents: A Form of Chronic Orthostatic Intolerance with Defective Dependent Vasoconstriction

Instantaneous orthostatic hypotension (INOH) has been reported in children and adolescents as a new entity of orthostatic intolerance in children who underwent rapid standing as an orthostatic stress test. Children with INOH were discovered among patients presenting with symptoms of chronic orthostatic intolerance, which is often related to orthostatic tachycardia. We used head-up tilt table testing at 70° to investigate children presenting with symptoms of chronic orthostatic intolerance. We compared 24 patients aged 12–17 y, with chronic orthostatic intolerance and symptoms for ≥3 mo, with 13 healthy normal control patients. We recorded continuous heart rate, blood pressure, and respiratory rate and used venous occlusion strain gauge plethysmography to measure calf and forearm blood flow while supine and calf blood flow during head-up tilt. Patients with chronic orthostatic intolerance fulfilled criteria for the postural orthostatic tachycardia syndrome. Postural orthostatic tachycardia syndrome patients were divided into two groups by the occurrence of INOH. Supine forearm and calf arterial resistance was decreased in patients with INOH (n = 8) compared with postural orthostatic tachycardia syndrome patients without INOH (n = 16) and compared with control (n = 13). Resting calf venous pressure was elevated, suggesting excess venous filling because of vasodilation. During early head-up tilt, calf blood flow increased markedly in INOH, less in No-INOH, postural orthostatic tachycardia syndrome patients and least in control patients. Flow was temporally related to calf swelling and negatively correlated to hypotension. The data suggest that INOH occurs in patients with chronic orthostatic intolerance and orthostatic tachycardia and is related to rapid caudal blood flow when upright because of a vasoconstrictor defect.

Neurally Mediated Hypotension and Autonomic Dysfunction Measured by Heart Rate Variability in Children with the Chronic Fatigue Syndrome † 144

Recent investigations strongly suggest a role for neurally mediated hypotension (NMH) in the symptomatology of Chronic Fatigue Syndrome (CFS) in adults. Our previous work indicate that autonomic activity measured by heart rate variability (HRV) is abnormal in children with syncope (S) due to NMH during head-up tilt testing (HUT). Therefore, we performed measurements of HRV at HUT in 13 patients aged 11-18 y with CFS defined by CDC guidelines and compared results to 29 S patients. After 30 min supine, patients were tilted to 80° for 30 min or until syncope occurred. Time domain indices included standard deviation (SDNN), root mean square successive differences (RMSSD), percent exceeding 50msec (pNN50). An autoregressive model was used to calculate power spectra. Low frequency power (LFP,.04-.15Hz), high frequency power (HFP,.15-.40Hz), and total power (TP,.01-.40Hz) were compared. HRV data were obtained supine before tilt (baseline), and 5-10 min after HUT. Ten CFS patients fainted (CFS+), and 3 did not (CFS-). HRV indices were not different at baseline for CFS- vs CFS+: SDNN was 52±10 vs 62±7ms, RMSSD was 44±11 vs 51±7ms, pNN50 was 17±7 vs 25±4%, respectively. LFP, HFP, and TP were 442±143, 448±275, and 1287±461ms2 in CFS- vs 589±51, 398±86, and 1686±262 in CFS+. However, these data were strikingly decreased compared to S patients, - 17 fainted during HUT (S+) 12 did not (S-) - in which HRV indices were normal and much higher for S- compared to S+: SDNN was 123±17 vs 78±6ms, RMSSD was 127±23 vs 64±6 ms, pNN50 was 51±6 vs 31±4%, LFP, was 834±133 vs 3433±840, HFP was 3433±840 vs 834±133 and TP was 7062±1500 vs 2855±420 ms. With tilt, SDNN, RMSSD and pNN50 and spectral indices decreased in all groups. We conclude: 1. Chronic Fatigue Syndrome is associated with neurally mediated syncope; 2. All indices of HRV are markedly depressed in CFS patients whether or not syncope is induced during HUT and even when compared with already abnormally low HRV in syncopal patients without CFS. These data suggest severe autonomic impairment in all patients with the Chronic Fatigue Syndrome.