Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Pediatrics
Published in: BMC Pediatrics 1/2015

Open Access 01-12-2015 | Research article

Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial

Authors: Even Fagermoen, Dag Sulheim, Anette Winger, Anders M. Andersen, Johannes Gjerstad, Kristin Godang, Peter C. Rowe, J. Philip Saul, Eva Skovlund, Vegard Bruun Wyller

Published in: BMC Pediatrics | Issue 1/2015

Login to get access

Abstract

Background

Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A–adrenoceptor agonist clonidine.

Methods

A total of 176 adolescent CFS patients (12–18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. 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 (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model.

Results

A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period.

Conclusions

Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.

Trial registration

Clinical Trials ID: NCT01040429, date of registration 12/28/2009.
Literature
1.
Nijhof SL, Maijer K, Bleijenberg G, Uiterwaal CS, Kimpen JL, van der Putte EM. Adolscent chronic fatigue syndrome: prevalence, incidence, and morbidity. Pediatrics. 2011;127:e1169–75.CrossRefPubMed
2.
Crawley E. The epidemiology of chronic fatigue syndrome/myalgic encephalitis in children. Arch Dis Child. 2014;99:171–4.CrossRefPubMed
3.
Rowe KS. Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents. J Psychiatr Res. 1997;31:133–47.CrossRefPubMed
4.
Hoad A, Spickett G, Elliott J, Newton J. Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. QJM. 2008;101:961–5.CrossRefPubMed
5.
Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics. 1999;103:116–21.CrossRefPubMed
6.
Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: The orthostatic tachycardia syndrome and adolescent chronic fatigue. J Pediatrics. 1999;135:218–25.CrossRef
7.
Okamoto LE, Raj SR, Peltier A, Gamboa A, Shibao C, Diedrich A, et al. Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clin Sci. 2012;122:183–92.CrossRefPubMed
8.
Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:961–7.CrossRefPubMed
9.
Wyller VB, Due R, Saul JP, Amlie JP, Thaulow E. Usefulness of an abnormal cardiovascular response during low-grade head-up tilt-test for discriminating adolescents with chronic fatigue from healthy controls. Am J Cardiol. 2007;99:997–1001.CrossRefPubMed
10.
Wyller VB, Barbieri R, Thaulow E, Saul JP. Enhanced vagal withdrawal during mild orthostatic stress in adolescents with chronic fatigue. Ann Noninvasive Electrocardiol. 2008;13:67–73.CrossRefPubMed
11.
Wyller VB, Barbieri R, Saul P. Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress. Eur J Appl Physiol. 2011;111:497–502.CrossRefPubMed
12.
Boneva RS, Decker MJ, Maloney EM, Lin JM, Jones JF, Helgason HG, et al. Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: a population-based study. Auton Neurosci. 2007;137:94–101.CrossRefPubMed
13.
Lewis I, Pairman J, Spickett G, Newton JL. Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome. J Intern Med. 2013;273:501–10.CrossRefPubMed
14.
Szabo B. Imidazoline antihypertensive drugs: a critical review on their mechanism of action. Pharmacol Ther. 2002;93:1–35.CrossRefPubMed
15.
Anavekar SN, Jarrott B, Toscano M, Louis WJ. Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects. Eur J Clin Pharmacol. 1982;23:1–5.CrossRefPubMed
16.
Cividjian A, Toader E, Wesseling KH, Karemaker JM, McAllen R, Quintin L. Effect of clonidine on cardiac baroreflex delay in humans and rats. Am J Physiol Regul Integr Comp Physiol. 2011;300:949–57.CrossRef
17.
Fagermoen E, Sulheim D, Winger A, Andersen AM, Vethe NT, Saul JP, et al. Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial. BMC Res Notes. 2012;5:418.CrossRefPubMedPubMedCentral
18.
Small KM, Liggett SB. Identification and functional characterixation of alpha2-adrenoceptor polymorphisms. Trend Pharm Sci. 2001;22:471–7.CrossRef
19.
National Institute for Health and Clinical Excellence. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy). Diagnosis and management of CFS/ME in adults and children. NICE clinical guideline 2007, no. 53. London, England: Royal College of Pediatrics and Child Health.
20.
Royal College of Paediatrics and Child Health. Evidence Based Guideline for the Management of CFS/ME in Children and Young People. London England: National Institute for Health and Clinical Excellence; 2004.
21.
Sulheim D, Hurum H, Helland IB, Thaulow E, Wyller VB. Concurrent improvement of circulatory abnormalities and clinical symptoms in adolescent chronic fatigue syndrome. Biopsychosoc Med. 2012;6:10.CrossRefPubMedPubMedCentral
22.
Tsunoda M. Recent advances in methods for the analysis of catecholamines and their metabolites. Anal Bioanal Chem. 2006;386:506–14.CrossRefPubMed
23.
Kågedal B, Goldstein DS. Catecholamines and their metabolites. J Chromatogr. 1988;29:177–233.CrossRef
24.
Hjemdahl P. Catecholamine measurements by high-performance liquid chromatography. Am J Physiol. 1984;247:E13–20.PubMed
25.
Müller C, Ramic M, Harlfinger S, Hünseler C, Theisohn M, Roth B. Sensitive and convenient method for the quantification of clonidine in serum of pediatric patients using liquid chromatography/tandem mass spectrometry. J Chromatogr A. 2007;1139:221–7.CrossRefPubMed
26.
27.
Olsen MB, Jacobsen LM, Schistad EI, Pedersen LM, Rygh LJ, Røe C, et al. Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: evidence of a sex and genotype interaction. J Neurosci. 2012;32:9831–4.CrossRefPubMed
28.
Sulheim D, Fagermoen E, Winger A, Andersen AM, Godang K, Müller F, et al. Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial. JAMA Pediatr. 2014;168:351–60.CrossRefPubMed
29.
de Jong-de Vos van Steenwijk CC, Wieling W, Johannes JM, Harms MP, Kuis W, Wesseling KH. Incidence and hemodynamic characteristics of near-fainting in healthy6- to 16-year old subjects. J Am Coll Cardiol. 1995;25:1615–21.CrossRef
30.
Fortin J, Habenbacher W, Heller A, Hacker A, Grüllenberger R, Innerhover J, et al. Non-invasive beat-to-beat cardiac output monitoring by an improved method of transthoracic bioimpedance measurement. Comput Biol Med. 2006;36:1185–203.CrossRefPubMed
31.
Bianchi AM, Mainardi LT, Meloni C, Chierchia S, Cerutti S. Continuous monitoring of the sympatho-vagal balance through spectral analysis. Eng Med Biol Mag. 1997;16:64–73.CrossRef
32.
Task force of the European society of cardiology and the North American society of pacing electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Circulation. 1996;93:1043–65.CrossRef
33.
Malpas S. Neural influences on cardiovascular variability: possibilities and pitfalls. Am J Physiol Heart Circ Physiol. 2002;282:H6–20.PubMed
34.
Suarez GA, Opfer-Gehrking TL, Offord KP, Atkinson EK, O’Brien PC, Low PA. The autonomic symptom profile: a new instrument to assess autonomic symptoms. Neurology. 1999;52:523–8.CrossRefPubMed
35.
Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC. Psychometric properties of the CDC symptom inventory for assessment for Chronic Fatigue Syndrome. Popul Health Metr. 2005;3:8.CrossRefPubMedPubMedCentral
36.
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Int Med. 1994;121:953–9.CrossRefPubMed
37.
38.
Pagani M, Lucini D, Mela GS, Langewitz W, Malliani A. Sympathetic overactivity in subjects complaining of unexplained fatigue. Clin Sci. 1994;87:655–61.CrossRefPubMed
39.
Stewart J, Weldon A, Arlievsky N, Li K, Munoz J. Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome. Clin Auton Res. 1998;8:221–30.CrossRefPubMed
40.
Timmers HJ, Wieling W, Soetekouw PM, Bleijenberg G, Van Der Meer JW, Lenders JW. Hemodynamic and neurohumoral responses to head-up tilt in patients with chronic fatigue syndrome. Clin Auton Res. 2002;12:273–80.CrossRefPubMed
41.
Wyller VB, Saul JP, Walløe L, Thaulow E. Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome. Eur J Appl Physiol. 2008;102:623–32.CrossRefPubMed
42.
De Becker P, Dendale P, De Meirleir K, Campine I, Vandenborne K, Hagers Y. Autonomic testing in patients with chronic fatigue syndrome. Am J Med. 1998;105:22S–6.CrossRefPubMed
43.
Grouzmann E, Lamine F. Determination of catecholamines in plasma and urine. Best Pract Res Clin Endocrinol Metab. 2013;5:713–23.CrossRef
44.
Lazzeri C, La Villa G, Mannelli M, Janni L, Franchi F. Effects of acute clonidine administration on power spectral analysis of heart rate variability in healthy humans. J Auton Pharmacol. 1998;18:307–12.CrossRefPubMed
45.
Anavekar SN, Howes LG, Jarrott B, Syrjanen M, Conway EL, Louis WJ. Pharmacokinetics and antihypertensive effects of low dose clonidine during chronic therapy. J Clin Pharmacol. 1989;29:32.CrossRef
46.
Arndts D, Doevendans J, Kiersten R, Heintz B. New aspects of the pharmacokinetics and pharmacodynamics of clonidine in man. Eur J Clin Pharmacol. 1983;24:21–30.CrossRefPubMed
47.
Veith RC, Beset JD, Halter JB. Dose-dependent supression of norepineprhine appearance rate in plasma by clonidine in man. J Clin Endocrinol Metab. 1984;59:151.CrossRefPubMed
48.
Lazzeri C, La Villa G, Mannelli M, Janni L, Barletta G, Montano N, et al. Effects of clonidine on power spectral analysis of heart rate variability in mild essential hypertension. J Auton Nerv Syst. 1998;74:152–9.CrossRefPubMed
49.
Saul JP. Beat-to-beat variations of heart rate reflect modulation of cardiac autonomic outflow. News Physiol Sci. 1990;5:32–7.
50.
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, et al. Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Int Med. 2012;271:64–81.CrossRef
51.
Streeten DH, Anderson Jr GH. Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma. Am J Hypertens. 1996;9:760–9.CrossRefPubMed
52.
Zhou Y, Xie G, Wang J, Yang S. Cardiovascular risk factors significantly correlate with autonomic nervous system activity in children. Can J Cardiol. 2012;28:477–82.CrossRefPubMed
53.
Hurum H, Sulheim D, Thaulow E, Wyller VB. Elevated nocturnal blood pressure and heart rate in adolescent chronic fatigue syndrome. Acta Paediatr. 2011;100:289–92.CrossRefPubMed
Metadata
Title
Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial
Authors
Even Fagermoen
Dag Sulheim
Anette Winger
Anders M. Andersen
Johannes Gjerstad
Kristin Godang
Peter C. Rowe
J. Philip Saul
Eva Skovlund
Vegard Bruun Wyller
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2015
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-015-0428-2

Other articles of this Issue 1/2015

BMC Pediatrics 1/2015 Go to the issue

Research article

Parent/caregiver health literacy among children with special health care needs: a systematic review of the literature

Study protocol

Intestinal microbiota composition after antibiotic treatment in early life: the INCA study

Research article

The Acute Chest Syndrome in Cameroonian children living with sickle cell disease

Research article

Evaluation of adherence measures of antiretroviral prophylaxis in HIV exposed infants in the first 6 weeks of life

Research article

A modified Bilirubin-induced neurologic dysfunction (BIND-M) algorithm is useful in evaluating severity of jaundice in a resource-limited setting

Case report

Premature baby with extreme hyponatraemia (95 mmol per litre): a case report