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Pediatrics International (2014) 56, 813–816
doi: 10.1111/ped.12392
Original Article
Clinical features of hyperadrenergic postural tachycardia syndrome in children Qingyou Zhang,1* Xia Chen,2* Jiawei Li1 and Junbao Du1 1 Department of Pediatrics, Peking University First Hospital, Beijing, and 2Department of Pediatrics, Langfang Municipal People’s Hospital, Langfang, Hebei, China Abstract
Background: Hyperadrenergic postural tachycardia syndrome (POTS) is the main phenotype of POTS. The aim of this study was to present our single-center experience of hyperadrenergic POTS in children and adolescents. Methods: Thirty-seven patients who met the diagnostic criteria for POTS were enrolled in our study. Their orthostatic serum norepinephrine levels were determined by high-performance liquid chromatography. In a retrospective analysis, based on clinical and serum norepinephrine criteria, we analyzed the clinical features of POTS cases between the POTS-alone group and the hyperadrenergic POTS group. Results: Nineteen patients (51.35%) met the diagnostic criteria for hyperadrenergic POTS and 18 patients were assigned to the POTS-alone group. Compared with the POTS-alone patients, dizziness, headache and tremulousness were more frequent in patients with hyperadrenergic POTS (P < 0.05). During the tilt table test, children with hyperadrenergic POTS had a greater increment of systolic blood pressure and heart rate than POTS-alone patients. Conclusion: Patients with hyperadrenergic POTS should be identified and differentiated from those with neuropathic POTS. Hyperadrenergic POTS in children and adolescents should be considered when POTS patients suffer from frequent dizziness, headache, and tremulousness. In head-up tilt testing, children and adolescents with hemodynamic characteristics of hyperadrenergic POTS had greater increments of systolic blood pressure and heart rate.
Key words children, hyperadrenergic, postural tachycardia syndrome.
Postural tachycardia syndrome (POTS) is a form of orthostatic intolerance and a chronic condition.1 POTS is increasingly recognized in children and adolescents.2,3 This disorder is characterized by symptoms of fatigue, tachycardia, shortness of breath, and even syncope on standing. Previous studies showed that POTS could negatively affect an individual’s physical and emotional well-being.2–6 POTS is defined in adults as the development of orthostatic symptoms associated with a heart rate (HR) increment ≥ 30 b.p.m. (or a rate that exceeds 120 b.p.m.) of standing or head-up tilt in the absence of orthostatic hypotension.7–9 An HR increment of 40 b.p.m. is considered excessive in children and adolescents.10–15 The pathophysiology of POTS varies according to dynamic physiological, neural, humoral, or fluid balance states, as well as possible genetic or acquired disorders. Patients with POTS may belong to one of several phenotypes based on mechanisms for potential pathophysiology, and these phenotypes include: (i) hyperadrenergic POTS; (ii) hypovolemic and deconditioned
Correspondence: Junbao Du, MD, Department of Pediatrics, Peking University First Hospital, Xi-An Men Street no. 1, West District, Beijing 100034, China. Email: [email protected] *These authors contributed to this work equally. Received 7 February 2014; revised 2 April 2014; accepted 13 May 2014.
© 2014 Japan Pediatric Society
POTS; (iii) neuropathic POTS; and (iv) POTS with joint hypermobility.15 Patients with hyperadrenergic POTS have an increment of ≥10 mmHg in systolic blood pressure (SBP) within 10 min of standing up or tilt and an orthostatic serum norepinephrine level ≥ 600 pg/mL.3,16 Hyperadrenergic outflow emanates from the brain and traverses baroreflex mechanisms.17 Moreover, there is increased sympathovagal index and marked increase of HR response to isoproterenol.15 Autonomic, sympathetic storms may occur in this subset of patients, with extreme rise in blood pressure (BP), anxiety, headache, and other features of sympathetic activation. Potential causes of this subtype are norepinephrine transporter deficiency,18 pheochromocytoma,19 mast cell activation disorders,20 and baroreflex failure, which may result from trauma or irradiation to the neck.21 But in clinical practice, distinguishing among POTS variants may be difficult for the pediatrician despite apparent straightforward differences. To our knowledge, there have been no studies on the clinical features of hyperadrenergic POTS in children and adolescents. Due to the special pathogenesis of hyperadrenergic POTS, our hypothesis is that hyperadrenergic POTS patients would have specific clinical manifestations as compared with other subtypes of POTS. We present here our single-center experience of hyperadrenergic POTS patients, in order to identify the clinical features of hyperadrenergic POTS in children and adolescents.
814
Q Zhang et al.
Methods Patients
Between January 2011 and March 2013, 37 children were diagnosed with POTS at the Department of Pediatrics, Peking University First Hospital. The criterion for diagnosis of POTS was mainly based on a consensus statement on the definition POTS by the American Autonomic Society. POTS is defined as the development of orthostatic symptoms associated with an HR increment ≥ 40 b.p.m., or an HR exceeding 120 b.p.m. during the first 10 min of upright posture or head-up tilt in the absence of orthostatic hypotension.13,14 Patients were diagnosed as having the hyperadrenergic form based on an increase in their SBP of ≥10 mmHg during the head-up tilt test (HUTT) with concomitant tachycardia or their serum catecholamine levels (serum norepinephrine level ≥ 600 pg/mL) upon standing.3,15,16,20,22 If patients with POTS did not confirm the above criterion, they were diagnosed with POTS-alone. Subjects were excluded from enrollment if there was: (i) absence of an underlying cause, including debilitating disease, substantial weight loss, prolonged bed rest, previous history of any disease producing peripheral neuropathy, or any medication impairing autonomic reflexes; or (ii) systemic illness that could affect study results or the subject’s ability to co-operate. Pheochromocytoma was ruled out in all the patients through a detailed examination. Regarding the study design, according to their serum catecholamine levels and upright SBP, 37 patients were divided into two groups: the hyperadrenergic POTS (n = 19) and POTS-alone (n = 18) groups. The criteria of the grouping are mentioned above. Clinical history was then reviewed blindly, without knowledge of the patients’ group assignment. Informed consent was obtained from each individual and their parents and the study protocol was approved by the Ethics Committee of Peking University First Hospital. Assay standing serum norepinephrine
After patients rested for 30 min or longer, they remained in a standing position for 5 min or longer, and then blood samples were collected. Blood samples were centrifuged at 3000 r.p.m. for 10 min immediately after collection, and serum was frozen until analysis. Serum catecholamine levels were determined by high-performance liquid chromatography with electrochemical detection.23
syncope or syncope. A sustained HR increase ≥ 40 b.p.m. or a sustained rate of 120 b.p.m. in the first 10 min of passive upright tilt is considered diagnostic.24 Statistical analysis
Statistical analysis was done using spss 13.0 (spss, Chicago, IL, USA). Continuous variables were compared using the Student’s t-test and anova; categorical variables were compared using Fisher’s exact test, and qualitative variables were compared using Pearson’s χ2-test. A P-value < 0.05 was considered to be statistically significant.
Results Symptoms of hyperadrenergic POTS
Clinical characteristics of hyperadrenergic POTS and POTSalone are presented in Figure 1. Nineteen patients suffered from hyperadrenergic POTS and 18 patients had POTS-alone. In the hyperadrenergic POTS group, 12 (63%) patients were female with an age range from 6 to 14 years. In the POTS-alone group, 11 (61%) patients were female with an age range from 6 to 15 years. There was no significant difference in age, weight, and body mass index between the groups. Symptoms during episodes included dizziness, shortness of breath, syncope, palpitations, lightheadedness, headache, fatigue and gastrointestinal symptoms. Dizziness occurred in all 19 (100%) patients with hyperadrenergic POTS, followed by fatigue (85.21%). Dizziness, headache and tremulousness were more frequent in patients with hyperadrenergic POTS than in POTS-alone patients (P < 0.05). HUTT
Table 1 shows the hemodynamic data of the POTS patients’ responses to the HUTT. On the HUTT, the mean standing SBP of patients with hyperadrenergic POTS was 119.39 ± 8.66 mmHg, which was significantly higher than in the POTS-alone group (P < 0.05). The mean rise in HR on the HUTT was higher in patients with hyperadrenergic POTS than in the POTS-alone
HUTT protocol
All patients underwent HUTT. All examinations occurred between 08.00 am and 10.00 am in a quiet, blandly lit room at a comfortable constant ambient temperature (22°C, 50–55% humidity). Patients were secured to a tilt table, and HR and BP were monitored for 10 min. Patients were then tilted upward at an angle of 60° for 45 min. Then BP and HR were monitored and an electrocardiogram was recorded simultaneously during the test (Dash 2000 Monitor, GE Company, Schenectady, NY, USA). The patients were moved to the supine position from standing as soon as the positive response or symptoms of orthostatic intolerance (OI) occurred. The symptoms of OI included lightheadedness, diminished concentration, tremulousness, nausea, headache, near © 2014 Japan Pediatric Society
Fig. 1 Clinical comparison of patients with ( ) postural tachycardia syndrome (POTS)-alone and ( ) hyperadrenergic POTS. Data: proportion (%). *Symptoms of dizziness (P = 0.002), headache (P = 0.046) and tremulousness (P = 0.043) were most significant in the hyperadrenergic POTS group. GI, gastrointestinal.
Hyperadrenergic POTS
815
Table 1 Baseline characteristics and hemodynamic parameters in patients with hyperadrenergic POTS and POTS alone Items Age (years) Sex ratio (M/F) BMI, kg/m2 Supine SBP (mmHg) Supine DBP (mmHg) Supine HR (b.p.m.) Standing SBP (mmHg) Standing DBP (mmHg) Standing HR (b.p.m.) ΔHR (b.p.m.) Standing serum norepinephrine (pg/mL)
Hyperadrenergic POTS (n = 19) 11.47 ± 2.06 7/12 19.39 ± 3.78 102.44 ± 9.05 57.28 ± 7.71 73.78 ± 10.15 119.39 ± 8.66 66.67 ± 6.25 127.47 ± 13.07 54.05 ± 13.51 961.61 ± 343.07
POTS alone (n = 18) 10.61 ± 2.55 7/11 18.13 ± 3.72 97.89 ± 8.10 56.22 ± 8.29 73.78 ± 10.55 105.50 ± 7.91 64.89 ± 5.45 117.94 ± 13.19 44.16 ± 12.54 420.81 ± 145.34
P 0.264 0.140 0.316 0.121 0.695 1.000 0.000 0.370 0.034 0.027 0.000
BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; POTS, postural tachycardia syndrome; SBP, systolic blood pressure; ΔHR, changes of heart rate from supine position to standing.
group (54.05 ± 13.51 vs 44.16 ± 12.54 b.p.m., P < 0.05). There was no difference in supine SBP, DBP, supine HR, or standing DBP between the hyperadrenergic POTS and POTS-alone patients. Norepinephrine levels
The mean standing norepinephrine levels in these patients with hyperadrenergic POTS were higher than those of patients with POTS alone (961.61 ± 343.07 pg/mL vs 420.81 ± 145.34 pg/mL, P < 0.001).
Discussion Our findings suggest that hyperadrenergic POTS was common in children and adolescents with POTS. About 50% of patients (19/37, 51.35%) suffered from a hyperadrenergic condition. Hyperadrenergic POTS differed clinically from those with POTS alone; and frequent dizziness, headache, fatigue, and tremulousness were prominent in hyperadrenergic POTS in children and adolescents. On the HUTT, hyperadrenergic POTS patients had a higher increment of SBP and HR than POTS-alone patients. Similar to previous reports,6,8 our study confirmed the female preponderance in both groups. In our series, the percentage of patients suffering from hyperadrenergic POTS was higher than that previously reported. About 50% of our patients had a hyperadrenergic condition, but recently Kimpinski et al. reported that 20% of their adult patients were classified as having hyperadrenergic POTS.25 The reason for the relatively higher percentage of hyperadrenergic POTS in our study might be associated with the fact that the study subjects in our research were children (the median age of our subjects was 11 years [range: 6–15 years]) who had a high sympathetic activity compared with adults. These findings may help to explain why β-blockers were more effective in children and adolescents with POTS than in adult patients.26,27 In our study, symptoms of hyperadrenergic POTS included dizziness (100%), fatigue (84.21%), shortness of breath (57.89%), gastrointestinal symptoms (47.37%), headache (47.37%), sweating (47.37%), pallor (42.11%), blurred vision (42.11%), tremulousness (31.57%), and palpitations (21.11%).
Compared with POTS-alone patients, dizziness, fatigue, headache and tremulousness were more frequent in patients with hyperadrenergic POTS. Headache and tremulousness were considered as symptoms of a hyperadrenergic state as described in a previous study.28 Kanjwal et al. also reported that fatigue was one of the commonest symptoms in adult patients with hyperadrenergic POTS.16 The higher incidence of dizziness might be related to an increase in cerebrovascular resistance, reducing cerebral oxygenation in children with orthostatic stress.28 Gastrointestinal symptoms were reported in almost 47% of the patients in this study. There have been reports of gastrointestinal symptoms in patients suffering from POTS. In our series, patients had gastrointestinal symptoms in the form of nausea, vomiting and diarrhea. Although some investigators considered gastrointestinal symptoms in POTS as symptoms of sympathetic overactivity,16,29 these symptoms had no difference between hyperadrenergic POTS and POTS-alone in our study. The hemodynamic responses to posture in hyperadrenergic POTS in our study were in accordance with previously published data.16 The baseline HR and BP had no difference between children with hyperadrenergic POTS and those with POTS alone, but the standing HR and BP were higher in hyperadrenergic POTS patients than in those with POTS alone, and the HR increment was also higher than in POTS-alone patients. This was in accordance with the fact that hyperadrenergic outflow emanates from the brain and traverses baroreflex mechanisms. Moreover, there is an increased sympathovagal index and marked increase in HR response to isoproterenol.15,30 In recent years there has been a substantial improvement of our understanding of POTS. Although Kanjwal et al. have reported their single-center experience of 27 adult patients with hyperadrenergic POTS, to our knowledge, the current study is the first study on hyperadrenergic POTS in children and adolescents. Patients with hyperadrenergic POTS should be identified and differentiated from those with neuropathic POTS. Hyperadrenergic POTS in children and adolescents should be considered in POTS patients with frequent dizziness, headache, and tremulousness. In HUTT testing, a higher increment of SBP and HR © 2014 Japan Pediatric Society
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were the hemodynamic characteristics of hyperadrenergic POTS in children and adolescents.
Acknowledgments This research was supported by Beijing Municipal Science & Technology Commission, China (D121107001012051), the National Twelfth 5-Year Plan for Science and Technology Support (2012BAI03B03) and the Major Basic Research Project of China (2012CB517806). None of the authors has anything to disclose.
References 1 Stewart JM. Orthostatic intolerance in pediatrics. J. Pediatr. 2002; 140: 404–11. 2 Medow MS. Postural tachycardia syndrome from a pediatrics perspective. J. Pediatr. 2011; 158: 4–6. 3 Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J. Cardiovasc. Electrophysiol. 2009; 20: 352–8. 4 Benrud-Larson LM, Dewar MS, Sandroni P, Rummans TA, Haythornthwaite JA, Low PA. Quality of life in patients with postural tachycardia syndrome. Mayo Clin. Proc. 2002; 77: 531– 637. 5 Karas B, Grubb BP, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive impairment in adolescents. Pacing Clin. Electrophysiol. 2000; 23: 344–51. 6 Ojha A, Chelimsky TC, Chelimsky G. Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome. J. Pediatr. 2011; 158: 20–3. 7 Raj S. The postural tachycardia syndrome (POTS): pathophysiology, diagnosis and management. Indian Pacing Electrophysiol. J. 2006; 6: 84–99. 8 Thieben M, Sandroni P, Sletten D et al. Postural tachycardia syndrome: the Mayo Clinic experience. Mayo Clin. Proc. 2007; 82: 308–13. 9 Grubb B. Postural tachycardia syndrome. Circulation 2008; 117: 2814–17. 10 Yamaguchi H, Tanaka H, Adachi K, Mino M. Beat-to-beat blood pressure and heart rate responses to active standing in Japanese children. Acta Paediatr. 1996; 85: 577–83. 11 Horam WJ, Roscelli JD. Establishing standards of orthostatic measurements in normovolemic adolescents. Am. J. Dis. Child. 1992; 146: 848–51. 12 Skinner JE, Driscoll SW, Porter CB et al. Orthostatic heart rate and blood pressure in adolescents: reference ranges. J. Child Neurol. 2010; 25: 1210–15. 13 Freeman R, Wieling W, Axelrod FB et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton. Neurosci. 2011; 161: 46–8.
© 2014 Japan Pediatric Society
14 Singer W, Sletten DM, Opfer-Gehrking TL, Brands CK, Fischer PR, Low PA. Postural tachycardia in children and adolescents: what is abnormal? J. Pediatr. 2012; 160: 222–6. 15 Jarjour IT. Postural tachycardia syndrome in children and adolescents. Semin. Pediatr. Neurol. 2013; 20: 18–26. 16 Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience. Cardiol. J. 2011; 18: 527–31. 17 Robertson D. The epidemic of orthostatic tachycardia and orthostatic intolerance. Am. J. Med. Sci. 1999; 317: 75–7. 18 Shannon JR, Flattem NL, Jordan J et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N. Engl. J. Med. 2000; 342: 541–9. 19 Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Pheochromocytoma. Lancet 2005; 366: 665–75. 20 Shibao C, Arzubiaga C, Roberts LJ II et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005; 45: 385–90. 21 Ketch T, Biaggioni I, Robertson R, Robertson D. Four faces of baroreflex failure hypertensive crisis, volatile hypertension, orthostatic tachycardia, and malignant vagotonia. Circulation 2002; 105: 2518–23. 22 Grubb BP, Kanjwal Y, Kosinski DJ. The postural tachycardia syndrome: a concise guide to diagnosis and management. J. Cardiovasc. Electrophysiol. 2006; 17: 108–12. 23 Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ. Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J. Clin. Invest. 1988; 81: 213– 20. 24 Qingyou Z, Junbao D, Chaoshu T. The efficacy of midodrine ehydrochloride in the treatment of children with vasovagal syncope. J. Pediatr. 2006; 149: 777–80. 25 Kimpinski K, Figueroa JJ, Singer W et al. A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin. Proc. 2012; 87: 746–52. 26 Qingyou Z, Junbao D, Yuli W. Efficacy of beta-receptor blocker plus oral saline in the treatment of postural orthostatic tachycardia syndrome in children. Lin Chuang Er Ke Za Zhi 2006; 24: 357–60. 27 Fu Q, Vangundy TB, Shibata S, Auchus RJ, Williams GH, Levine BD. Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome. Hypertension 2011; 58: 167–75. 28 Jordan J, Shannon JR, Black BK, Paranjape SY, Barwise J, Robertson D. Raised cerebrovascular resistance in idiopathic orthostatic intolerance: evidence for sympathetic vasoconstriction. Hypertension 1998; 32: 699–704. 29 Sousa A, Lebreiro A, Freitas J, Maciel MJ. Long-term follow-up of patients with postural tachycardia syndrome. Clin. Auton. Res. 2012; 22: 151–3. 30 Garland EM, Raj SR, Black BK, Harris PA, Robertson D. The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome. Neurology 2007; 21 (69): 790–8.
Pediatrics International (2014) 56, 813–816
doi: 10.1111/ped.12392
Original Article
Clinical features of hyperadrenergic postural tachycardia syndrome in children Qingyou Zhang,1* Xia Chen,2* Jiawei Li1 and Junbao Du1 1 Department of Pediatrics, Peking University First Hospital, Beijing, and 2Department of Pediatrics, Langfang Municipal People’s Hospital, Langfang, Hebei, China Abstract
Background: Hyperadrenergic postural tachycardia syndrome (POTS) is the main phenotype of POTS. The aim of this study was to present our single-center experience of hyperadrenergic POTS in children and adolescents. Methods: Thirty-seven patients who met the diagnostic criteria for POTS were enrolled in our study. Their orthostatic serum norepinephrine levels were determined by high-performance liquid chromatography. In a retrospective analysis, based on clinical and serum norepinephrine criteria, we analyzed the clinical features of POTS cases between the POTS-alone group and the hyperadrenergic POTS group. Results: Nineteen patients (51.35%) met the diagnostic criteria for hyperadrenergic POTS and 18 patients were assigned to the POTS-alone group. Compared with the POTS-alone patients, dizziness, headache and tremulousness were more frequent in patients with hyperadrenergic POTS (P < 0.05). During the tilt table test, children with hyperadrenergic POTS had a greater increment of systolic blood pressure and heart rate than POTS-alone patients. Conclusion: Patients with hyperadrenergic POTS should be identified and differentiated from those with neuropathic POTS. Hyperadrenergic POTS in children and adolescents should be considered when POTS patients suffer from frequent dizziness, headache, and tremulousness. In head-up tilt testing, children and adolescents with hemodynamic characteristics of hyperadrenergic POTS had greater increments of systolic blood pressure and heart rate.
Key words children, hyperadrenergic, postural tachycardia syndrome.
Postural tachycardia syndrome (POTS) is a form of orthostatic intolerance and a chronic condition.1 POTS is increasingly recognized in children and adolescents.2,3 This disorder is characterized by symptoms of fatigue, tachycardia, shortness of breath, and even syncope on standing. Previous studies showed that POTS could negatively affect an individual’s physical and emotional well-being.2–6 POTS is defined in adults as the development of orthostatic symptoms associated with a heart rate (HR) increment ≥ 30 b.p.m. (or a rate that exceeds 120 b.p.m.) of standing or head-up tilt in the absence of orthostatic hypotension.7–9 An HR increment of 40 b.p.m. is considered excessive in children and adolescents.10–15 The pathophysiology of POTS varies according to dynamic physiological, neural, humoral, or fluid balance states, as well as possible genetic or acquired disorders. Patients with POTS may belong to one of several phenotypes based on mechanisms for potential pathophysiology, and these phenotypes include: (i) hyperadrenergic POTS; (ii) hypovolemic and deconditioned
Correspondence: Junbao Du, MD, Department of Pediatrics, Peking University First Hospital, Xi-An Men Street no. 1, West District, Beijing 100034, China. Email: [email protected] *These authors contributed to this work equally. Received 7 February 2014; revised 2 April 2014; accepted 13 May 2014.
© 2014 Japan Pediatric Society
POTS; (iii) neuropathic POTS; and (iv) POTS with joint hypermobility.15 Patients with hyperadrenergic POTS have an increment of ≥10 mmHg in systolic blood pressure (SBP) within 10 min of standing up or tilt and an orthostatic serum norepinephrine level ≥ 600 pg/mL.3,16 Hyperadrenergic outflow emanates from the brain and traverses baroreflex mechanisms.17 Moreover, there is increased sympathovagal index and marked increase of HR response to isoproterenol.15 Autonomic, sympathetic storms may occur in this subset of patients, with extreme rise in blood pressure (BP), anxiety, headache, and other features of sympathetic activation. Potential causes of this subtype are norepinephrine transporter deficiency,18 pheochromocytoma,19 mast cell activation disorders,20 and baroreflex failure, which may result from trauma or irradiation to the neck.21 But in clinical practice, distinguishing among POTS variants may be difficult for the pediatrician despite apparent straightforward differences. To our knowledge, there have been no studies on the clinical features of hyperadrenergic POTS in children and adolescents. Due to the special pathogenesis of hyperadrenergic POTS, our hypothesis is that hyperadrenergic POTS patients would have specific clinical manifestations as compared with other subtypes of POTS. We present here our single-center experience of hyperadrenergic POTS patients, in order to identify the clinical features of hyperadrenergic POTS in children and adolescents.
814
Q Zhang et al.
Methods Patients
Between January 2011 and March 2013, 37 children were diagnosed with POTS at the Department of Pediatrics, Peking University First Hospital. The criterion for diagnosis of POTS was mainly based on a consensus statement on the definition POTS by the American Autonomic Society. POTS is defined as the development of orthostatic symptoms associated with an HR increment ≥ 40 b.p.m., or an HR exceeding 120 b.p.m. during the first 10 min of upright posture or head-up tilt in the absence of orthostatic hypotension.13,14 Patients were diagnosed as having the hyperadrenergic form based on an increase in their SBP of ≥10 mmHg during the head-up tilt test (HUTT) with concomitant tachycardia or their serum catecholamine levels (serum norepinephrine level ≥ 600 pg/mL) upon standing.3,15,16,20,22 If patients with POTS did not confirm the above criterion, they were diagnosed with POTS-alone. Subjects were excluded from enrollment if there was: (i) absence of an underlying cause, including debilitating disease, substantial weight loss, prolonged bed rest, previous history of any disease producing peripheral neuropathy, or any medication impairing autonomic reflexes; or (ii) systemic illness that could affect study results or the subject’s ability to co-operate. Pheochromocytoma was ruled out in all the patients through a detailed examination. Regarding the study design, according to their serum catecholamine levels and upright SBP, 37 patients were divided into two groups: the hyperadrenergic POTS (n = 19) and POTS-alone (n = 18) groups. The criteria of the grouping are mentioned above. Clinical history was then reviewed blindly, without knowledge of the patients’ group assignment. Informed consent was obtained from each individual and their parents and the study protocol was approved by the Ethics Committee of Peking University First Hospital. Assay standing serum norepinephrine
After patients rested for 30 min or longer, they remained in a standing position for 5 min or longer, and then blood samples were collected. Blood samples were centrifuged at 3000 r.p.m. for 10 min immediately after collection, and serum was frozen until analysis. Serum catecholamine levels were determined by high-performance liquid chromatography with electrochemical detection.23
syncope or syncope. A sustained HR increase ≥ 40 b.p.m. or a sustained rate of 120 b.p.m. in the first 10 min of passive upright tilt is considered diagnostic.24 Statistical analysis
Statistical analysis was done using spss 13.0 (spss, Chicago, IL, USA). Continuous variables were compared using the Student’s t-test and anova; categorical variables were compared using Fisher’s exact test, and qualitative variables were compared using Pearson’s χ2-test. A P-value < 0.05 was considered to be statistically significant.
Results Symptoms of hyperadrenergic POTS
Clinical characteristics of hyperadrenergic POTS and POTSalone are presented in Figure 1. Nineteen patients suffered from hyperadrenergic POTS and 18 patients had POTS-alone. In the hyperadrenergic POTS group, 12 (63%) patients were female with an age range from 6 to 14 years. In the POTS-alone group, 11 (61%) patients were female with an age range from 6 to 15 years. There was no significant difference in age, weight, and body mass index between the groups. Symptoms during episodes included dizziness, shortness of breath, syncope, palpitations, lightheadedness, headache, fatigue and gastrointestinal symptoms. Dizziness occurred in all 19 (100%) patients with hyperadrenergic POTS, followed by fatigue (85.21%). Dizziness, headache and tremulousness were more frequent in patients with hyperadrenergic POTS than in POTS-alone patients (P < 0.05). HUTT
Table 1 shows the hemodynamic data of the POTS patients’ responses to the HUTT. On the HUTT, the mean standing SBP of patients with hyperadrenergic POTS was 119.39 ± 8.66 mmHg, which was significantly higher than in the POTS-alone group (P < 0.05). The mean rise in HR on the HUTT was higher in patients with hyperadrenergic POTS than in the POTS-alone
HUTT protocol
All patients underwent HUTT. All examinations occurred between 08.00 am and 10.00 am in a quiet, blandly lit room at a comfortable constant ambient temperature (22°C, 50–55% humidity). Patients were secured to a tilt table, and HR and BP were monitored for 10 min. Patients were then tilted upward at an angle of 60° for 45 min. Then BP and HR were monitored and an electrocardiogram was recorded simultaneously during the test (Dash 2000 Monitor, GE Company, Schenectady, NY, USA). The patients were moved to the supine position from standing as soon as the positive response or symptoms of orthostatic intolerance (OI) occurred. The symptoms of OI included lightheadedness, diminished concentration, tremulousness, nausea, headache, near © 2014 Japan Pediatric Society
Fig. 1 Clinical comparison of patients with ( ) postural tachycardia syndrome (POTS)-alone and ( ) hyperadrenergic POTS. Data: proportion (%). *Symptoms of dizziness (P = 0.002), headache (P = 0.046) and tremulousness (P = 0.043) were most significant in the hyperadrenergic POTS group. GI, gastrointestinal.
Hyperadrenergic POTS
815
Table 1 Baseline characteristics and hemodynamic parameters in patients with hyperadrenergic POTS and POTS alone Items Age (years) Sex ratio (M/F) BMI, kg/m2 Supine SBP (mmHg) Supine DBP (mmHg) Supine HR (b.p.m.) Standing SBP (mmHg) Standing DBP (mmHg) Standing HR (b.p.m.) ΔHR (b.p.m.) Standing serum norepinephrine (pg/mL)
Hyperadrenergic POTS (n = 19) 11.47 ± 2.06 7/12 19.39 ± 3.78 102.44 ± 9.05 57.28 ± 7.71 73.78 ± 10.15 119.39 ± 8.66 66.67 ± 6.25 127.47 ± 13.07 54.05 ± 13.51 961.61 ± 343.07
POTS alone (n = 18) 10.61 ± 2.55 7/11 18.13 ± 3.72 97.89 ± 8.10 56.22 ± 8.29 73.78 ± 10.55 105.50 ± 7.91 64.89 ± 5.45 117.94 ± 13.19 44.16 ± 12.54 420.81 ± 145.34
P 0.264 0.140 0.316 0.121 0.695 1.000 0.000 0.370 0.034 0.027 0.000
BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; POTS, postural tachycardia syndrome; SBP, systolic blood pressure; ΔHR, changes of heart rate from supine position to standing.
group (54.05 ± 13.51 vs 44.16 ± 12.54 b.p.m., P < 0.05). There was no difference in supine SBP, DBP, supine HR, or standing DBP between the hyperadrenergic POTS and POTS-alone patients. Norepinephrine levels
The mean standing norepinephrine levels in these patients with hyperadrenergic POTS were higher than those of patients with POTS alone (961.61 ± 343.07 pg/mL vs 420.81 ± 145.34 pg/mL, P < 0.001).
Discussion Our findings suggest that hyperadrenergic POTS was common in children and adolescents with POTS. About 50% of patients (19/37, 51.35%) suffered from a hyperadrenergic condition. Hyperadrenergic POTS differed clinically from those with POTS alone; and frequent dizziness, headache, fatigue, and tremulousness were prominent in hyperadrenergic POTS in children and adolescents. On the HUTT, hyperadrenergic POTS patients had a higher increment of SBP and HR than POTS-alone patients. Similar to previous reports,6,8 our study confirmed the female preponderance in both groups. In our series, the percentage of patients suffering from hyperadrenergic POTS was higher than that previously reported. About 50% of our patients had a hyperadrenergic condition, but recently Kimpinski et al. reported that 20% of their adult patients were classified as having hyperadrenergic POTS.25 The reason for the relatively higher percentage of hyperadrenergic POTS in our study might be associated with the fact that the study subjects in our research were children (the median age of our subjects was 11 years [range: 6–15 years]) who had a high sympathetic activity compared with adults. These findings may help to explain why β-blockers were more effective in children and adolescents with POTS than in adult patients.26,27 In our study, symptoms of hyperadrenergic POTS included dizziness (100%), fatigue (84.21%), shortness of breath (57.89%), gastrointestinal symptoms (47.37%), headache (47.37%), sweating (47.37%), pallor (42.11%), blurred vision (42.11%), tremulousness (31.57%), and palpitations (21.11%).
Compared with POTS-alone patients, dizziness, fatigue, headache and tremulousness were more frequent in patients with hyperadrenergic POTS. Headache and tremulousness were considered as symptoms of a hyperadrenergic state as described in a previous study.28 Kanjwal et al. also reported that fatigue was one of the commonest symptoms in adult patients with hyperadrenergic POTS.16 The higher incidence of dizziness might be related to an increase in cerebrovascular resistance, reducing cerebral oxygenation in children with orthostatic stress.28 Gastrointestinal symptoms were reported in almost 47% of the patients in this study. There have been reports of gastrointestinal symptoms in patients suffering from POTS. In our series, patients had gastrointestinal symptoms in the form of nausea, vomiting and diarrhea. Although some investigators considered gastrointestinal symptoms in POTS as symptoms of sympathetic overactivity,16,29 these symptoms had no difference between hyperadrenergic POTS and POTS-alone in our study. The hemodynamic responses to posture in hyperadrenergic POTS in our study were in accordance with previously published data.16 The baseline HR and BP had no difference between children with hyperadrenergic POTS and those with POTS alone, but the standing HR and BP were higher in hyperadrenergic POTS patients than in those with POTS alone, and the HR increment was also higher than in POTS-alone patients. This was in accordance with the fact that hyperadrenergic outflow emanates from the brain and traverses baroreflex mechanisms. Moreover, there is an increased sympathovagal index and marked increase in HR response to isoproterenol.15,30 In recent years there has been a substantial improvement of our understanding of POTS. Although Kanjwal et al. have reported their single-center experience of 27 adult patients with hyperadrenergic POTS, to our knowledge, the current study is the first study on hyperadrenergic POTS in children and adolescents. Patients with hyperadrenergic POTS should be identified and differentiated from those with neuropathic POTS. Hyperadrenergic POTS in children and adolescents should be considered in POTS patients with frequent dizziness, headache, and tremulousness. In HUTT testing, a higher increment of SBP and HR © 2014 Japan Pediatric Society
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were the hemodynamic characteristics of hyperadrenergic POTS in children and adolescents.
Acknowledgments This research was supported by Beijing Municipal Science & Technology Commission, China (D121107001012051), the National Twelfth 5-Year Plan for Science and Technology Support (2012BAI03B03) and the Major Basic Research Project of China (2012CB517806). None of the authors has anything to disclose.
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