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1.  Blood Pressure Variability and Closed-loop Baroreflex Assessment in Adolescent Chronic Fatigue Syndrome during Supine Rest and Orthostatic Stress 
Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS.
We included a consecutive sample of 14 adolescents 12 to 18 years old with CFS diagnosed according to a thorough and standardized set of investigations, and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of −20 mm Hg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04–0.15 Hz) and the high-frequency (HF) band (0.15–0.50 Hz), using an autoregressive algorithm.
Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control.
CFS in adolescents is characterized by reduced systolic blood pressure variability, and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.
doi:10.1007/s00421-010-1670-9
PMCID: PMC3037975  PMID: 20890710
Blood pressure variability; baroreflex sensitivity; chronic fatigue syndrome; autonomic nervous system; cardiovascular regulation
2.  Autonomic Heart Rate Control at Rest and During Unloading of the Right Ventricle in Repaired Tetralogy of Fallot in Adolescents 
The American journal of cardiology  2008;102(8):1085-1089.
Arrhythmias in patients with repaired tetralogy of Fallot (ToF) might be due in part to altered autonomic heart rate (HR) control caused by altered right ventricle hemodynamics. This study investigated autonomic HR control in ToF adolescents at rest and during unloading of the right ventricle. A total of 17 ToF patients and 56 healthy controls aged 12 to 18 years underwent orthostatic stress with lower body negative pressure (LBNP) of −20 mm Hg. HR, blood pressure and stroke volume were recorded non-invasively. Indices of HR variability were computed in time and frequency domains. All ToF patients also underwent cardiac magnetic resonance imaging, demonstrating pulmonary regurgitation and right ventricular dilation. At rest, HR variability indices of vagal heart rate control were non-significantly lower in the ToF patients compared to controls. During LBNP, HR increased more in controls than ToF patients (p ≤ 0.001). Further, most HR variability indices decreased among controls, but increased among ToF patients (p ≤ 0.01 or p ≤ 0.001 for all variables), suggesting vagal activation in the ToF patients. In conclusion, adolescents after ToF repair have fairly normal HR control at rest despite altered right ventricular hemodynamics. During unloading of the right ventricle, however, vagal HR control increases in the ToF patients and decreases in the controls.
doi:10.1016/j.amjcard.2008.05.065
PMCID: PMC2645862  PMID: 18929714
Tetralogy of Fallot; autonomic nervous system; heart rate variability; adolescence
3.  Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study 
BMJ Open  2014;4(10):e005920.
Objectives
Although pain is a significant symptom in chronic fatigue syndrome (CFS), pain is poorly understood in adolescents with CFS. The aim of this study was to explore pain distribution and prevalence, pain intensity and its functional interference in everyday life, as well as pressure pain thresholds (PPT) in adolescents with CFS and compare this with a control group of healthy adolescents (HC).
Methods
This is a case–control, cross-sectional study on pain including 120 adolescents with CFS and 39 HCs, aged 12–18 years. We measured pain frequency, pain severity and pain interference using self-reporting questionnaires. PPT was measured using pressure algometry. Data were collected from March 2010 until October 2012 as part of the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial.
Results
Adolescents with CFS had significantly lower PPTs compared with HCs (p<0.001). The Pain Severity Score and the Pain Interference Score were significantly higher in adolescents with CFS compared with HCs (p<0.001). Almost all adolescents with CFS experienced headache, abdominal pain and/or pain in muscles and joints. Moreover, in all sites, the pain intensity levels were significantly higher than in HCs (p<0.001).
Conclusions
We found a higher prevalence of severe pain among adolescents with CFS and lowered pain thresholds compared with HCs. The mechanisms, however, are still obscure. Large longitudinal population surveys are warranted measuring pain thresholds prior to the onset of CFS.
Trial registration number
Clinical Trials, NCT01040429; The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) http://www.clinicaltrials.gov.
doi:10.1136/bmjopen-2014-005920
PMCID: PMC4187660  PMID: 25287104
PAIN MANAGEMENT; PUBLIC HEALTH
4.  Orthostatic responses in adolescent chronic fatigue syndrome: contributions from expectancies as well as gravity 
Background
Orthostatic intolerance is common in chronic fatigue syndrome (CFS), and several studies have documented an abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli. The aim of this study was to explore whether the expectancies towards standing are contributors to autonomic responses in addition to the gravitational stimulus itself.
Methods
A total of 30 CFS patients (12–18 years of age) and 39 healthy controls underwent 20° head-up tilt test and a motor imagery protocol of standing upright. Beat-to-beat cardiovascular variables were recorded.
Results
At supine rest, CFS patients had significantly higher heart rate, diastolic blood pressure, and mean arterial blood pressure, and lower stroke index and heart rate variability (HRV) indices. The response to 20° head-up tilt was identical in the two groups. The response to imaginary upright position was characterized by a stronger increase of HRV indices of sympathetic predominance (power in the low-frequency range as well as the ratio low-frequency: high-frequency power) among CFS patients.
Conclusions
These results suggest that in CFS patients expectancies towards orthostatic challenge might be additional determinants of autonomic cardiovascular modulation along with the gravitational stimulus per se.
doi:10.1186/1751-0759-8-22
PMCID: PMC4166398  PMID: 25237387
Adolescence; Autonomic nervous system; Chronic fatigue syndrome; Expectancies; Orthostatic intolerance
5.  Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial 
BMC Research Notes  2012;5:418.
Background
This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.
Findings
Five adolescent CFS patients (14–19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.
After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.
Conclusion
Clonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).
doi:10.1186/1756-0500-5-418
PMCID: PMC3461473  PMID: 22871021
Chronic fatigue syndrome; Adolescents; Clonidine; Adverse effects; Head-up tilt test; Autonomic nervous system
6.  Adolescent chronic fatigue syndrome; a follow-up study displays concurrent improvement of circulatory abnormalities and clinical symptoms 
Background
The pathophysiology of chronic fatigue syndrome (CFS) in adolescents is unknown, and the clinical course and prognosis is still questioned. Recent research indicates that abnormalities of autonomic cardiovascular control may play an important role. The aim of this research project was to perform a follow-up study of adolescents with chronic fatigue syndrome, focusing on clinical symptoms and autonomic cardiovascular control.
Methods
47 adolescents (12-18 years old) with CFS were recruited from the outpatient clinic at the Department of Pediatrics, Oslo University Hospital. In a primary visit and a follow-up visit (3-17 months later), we evaluated: a) a wide range of complaints and symptoms and b) cardiovascular variables at baseline and during a 20° head-up tilt-test (HUT).
Results
At the second visit, patients reported significant improvement regarding functional impairments, fatigue severity, muscular pain, concentration problems, post-exertional malaise and the problem of non-relieving rest. Also, at the second visit, baseline heart rate (HR), blood pressure, total peripheral resistance index (TPRI) and LF/HF (low-frequency:high-frequency heart rate variability ratio, an index of sinus node sympathovagal balance derived from spectral analyses of heart rate) were significant lower, and the increases in HR, mean blood pressure (MBP), diastolic blood pressure (DBP) and TPRI during tilt were significantly less pronounced as compared to the first visit. There was a significant correlation between changes in autonomic symptom score, fatigue severity score and functional impairment score from the first to the second visit.
Conclusions
The majority of adolescents with CFS experienced an improvement over time in functional impairment, self-reported fatigue and additional symptoms, and a concurrent improvement of autonomic cardiovascular control. A possible connection between clinical symptoms and abnormal autonomic control in CFS might represent a focus for further research.
doi:10.1186/1751-0759-6-10
PMCID: PMC3337799  PMID: 22436201
Chronic fatigue syndrome; Fatigue severity scale; Autonomic symptom profile; Cardiovascular autonomic control; Adolescents
7.  No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls 
Chronic fatigue syndrome (CFS) is a disabling disease with unknown etiology. There is accumulating evidence of altered cardiovascular autonomic responses to different somatic stressors, in particular orthostatic stress, whereas autonomic responses to mental stress remain to be investigated. In this study, we explored cardiovascular autonomic responses to a simple mental stress test in CFS patients and healthy controls.
A consecutive sample of 13 patients with CFS, aged 12 to 18 years, and a volunteer sample of 53 healthy control subjects of equal age and gender distribution were included. Blood pressure, heart rate and acral skin blood flow were continuously recorded during an arithmetic exercise.
At baseline, heart rate was significantly higher among CFS patients than controls (p = 0.02). During the arithmetic exercise, however, there were no significant differences in the responses between the two groups.
In conclusion, CFS patients have unaltered autonomic responses to simple mental stress as compared to healthy control subjects.
doi:10.1186/1751-0759-4-22
PMCID: PMC3012010  PMID: 21156045
8.  Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress 
Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS. We included a consecutive sample of 14 adolescents 12–18 years old with CFS diagnosed according to a thorough and standardized set of investigations and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of –20 mmHg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04–0.15 Hz) and the high–frequency (HF) band (0.15–0.50 Hz), using an autoregressive algorithm. Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP, compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control. CFS in adolescents is characterized by reduced systolic blood pressure variability and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.
doi:10.1007/s00421-010-1670-9
PMCID: PMC3037975  PMID: 20890710
Blood pressure variability; Baroreflex sensitivity; Chronic fatigue syndrome; Autonomic nervous system; Cardiovascular regulation

Results 1-8 (8)