Salivary Cortisol Levels Predict Therapeutic Response to a Sleep- Promoting Method in Children with Postural Tachycardia Syndrome
Salivary Cortisol Levels Predict Therapeutic Response to a Sleep- Promoting Method in Children with Postural Tachycardia Syndrome
Jing Lin, MD, PhD1,*, Huacai Zhao, MD2,*, Jie Shen, MD3, and Fuyong Jiao, MD4
Objective To determine the value of salivary cortisol concentrations in predicting the efficacy of sleep-promoting treatment in children with postural tachycardia syndrome (POTS).
Study design This prospective study involved 40 children with POTS and 20 healthy children (controls). POTS was diagnosed using the head-up or head-up tilt test. Patients with POTS received a sleep-promoting treat- ment: >8 hours of sleep every night and a midday nap in an appropriate environment; no drinking water or exer- cising before bedtime; and urination before bedtime. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality, and symptom scores were used to assess POTS severity. Salivary samples were collected upon awaken- ing, 30 minutes after awakening, at 12:00 p.m., 4:00 p.m., and 8:00 p.m., and at bedtime before treatment. Enzyme- linked immunosorbent assay was used to measure salivary cortisol concentrations.
Results Cortisol concentrations were significantly higher in patients with POTS than in the controls at all time points (P < .05 for all). PSQI scores were significantly higher in patients with POTS (7.2 ± 3.0) than in the controls (1.35 ± 1.39; t = -10.370, P < .001). Salivary cortisol concentrations at awakening were significantly higher in re- sponders than in nonresponders (4.83 ± 0.73 vs 4.05 ± 0.79 ng/mL, t = -3.197, P = .003). The area under the re- ceiver operating characteristic curve was 75.8%, (95% CI 59.3%-92%). Cut-off at-awakening salivary cortisol concentrations of >4.1 ng/mL yielded 83.3% sensitivity and 68.7% specificity in predicting therapeutic efficacy.
Conclusions At-awakening salivary cortisol concentrations may predict the efficacy of sleep-promoting treat-
ment in patients with POTS (J Pediatr 2017;191:91-5).
ostural tachycardia syndrome (POTS) is a subtype of orthostatic intolerance. Children and adolescents with POTS show an increase in heart rate of ≥40 beats·minute−1 or a maximum heart rate of >120 beats·minute−1 during the head-up test or head-up tilt test.1 Orthostatic symptoms include dizziness or vertigo, chest tightness, headache, palpitations, pallor,
blurred vision, fatigue, and syncope. These symptoms last for more than 1 month. Some children with POTS have severe clini- cal symptoms that impact their daily life. POTS is a multisystemic condition with heterogeneous clinical features and patho- physiology that can be disabling. Therefore, timely and effective treatment or prevention of the condition is important. The risk of POTS has been shown to be almost 6 times greater in those who sleep for <8 hours/day than in those who sleep for
>8 hours/day.2 However, the specific nature of the sleep problems in patients with POTS is not fully understood.
Follenius et al found that increased cortisol levels were not concomitant with a specific sleep stage but generally accompa- nied prolonged waking periods.3 This implies that cortisol-releasing mechanisms may be involved in sleep regulation. In healthy subjects, increased cortisol accompanies waking periods and stage-N1 sleep, whereas slow-wave sleep is associated with declin- ing plasma cortisol levels. Therefore, decreased slow-wave sleep increases cortisol levels, which might induce syndromes similar to POTS. Song et al reported that sleep deprivation could significantly increase serum cortisol level and affect mental health in service men.4 Therefore, we speculated that cortisol may reflect sleep quality. We sought to determine if the cortisol rhythm differed between patients with POTS and healthy children, and if this rhythm predicted the efficacy of sleep-promoting treat- ments in children with POTS.
91
Jing Lin, MD, PhD1,*, Huacai Zhao, MD2,*, Jie Shen, MD3, and Fuyong Jiao, MD4
Objective To determine the value of salivary cortisol concentrations in predicting the efficacy of sleep-promoting treatment in children with postural tachycardia syndrome (POTS).
Study design This prospective study involved 40 children with POTS and 20 healthy children (controls). POTS was diagnosed using the head-up or head-up tilt test. Patients with POTS received a sleep-promoting treat- ment: >8 hours of sleep every night and a midday nap in an appropriate environment; no drinking water or exer- cising before bedtime; and urination before bedtime. The Pittsburgh Sleep Quality Index was used to evaluate sleep quality, and symptom scores were used to assess POTS severity. Salivary samples were collected upon awaken- ing, 30 minutes after awakening, at 12:00 p.m., 4:00 p.m., and 8:00 p.m., and at bedtime before treatment. Enzyme- linked immunosorbent assay was used to measure salivary cortisol concentrations.
Results Cortisol concentrations were significantly higher in patients with POTS than in the controls at all time points (P < .05 for all). PSQI scores were significantly higher in patients with POTS (7.2 ± 3.0) than in the controls (1.35 ± 1.39; t = -10.370, P < .001). Salivary cortisol concentrations at awakening were significantly higher in re- sponders than in nonresponders (4.83 ± 0.73 vs 4.05 ± 0.79 ng/mL, t = -3.197, P = .003). The area under the re- ceiver operating characteristic curve was 75.8%, (95% CI 59.3%-92%). Cut-off at-awakening salivary cortisol concentrations of >4.1 ng/mL yielded 83.3% sensitivity and 68.7% specificity in predicting therapeutic efficacy.
Conclusions At-awakening salivary cortisol concentrations may predict the efficacy of sleep-promoting treat-
ment in patients with POTS (J Pediatr 2017;191:91-5).
ostural tachycardia syndrome (POTS) is a subtype of orthostatic intolerance. Children and adolescents with POTS show an increase in heart rate of ≥40 beats·minute−1 or a maximum heart rate of >120 beats·minute−1 during the head-up test or head-up tilt test.1 Orthostatic symptoms include dizziness or vertigo, chest tightness, headache, palpitations, pallor,
blurred vision, fatigue, and syncope. These symptoms last for more than 1 month. Some children with POTS have severe clini- cal symptoms that impact their daily life. POTS is a multisystemic condition with heterogeneous clinical features and patho- physiology that can be disabling. Therefore, timely and effective treatment or prevention of the condition is important. The risk of POTS has been shown to be almost 6 times greater in those who sleep for <8 hours/day than in those who sleep for
>8 hours/day.2 However, the specific nature of the sleep problems in patients with POTS is not fully understood.
Follenius et al found that increased cortisol levels were not concomitant with a specific sleep stage but generally accompa- nied prolonged waking periods.3 This implies that cortisol-releasing mechanisms may be involved in sleep regulation. In healthy subjects, increased cortisol accompanies waking periods and stage-N1 sleep, whereas slow-wave sleep is associated with declin- ing plasma cortisol levels. Therefore, decreased slow-wave sleep increases cortisol levels, which might induce syndromes similar to POTS. Song et al reported that sleep deprivation could significantly increase serum cortisol level and affect mental health in service men.4 Therefore, we speculated that cortisol may reflect sleep quality. We sought to determine if the cortisol rhythm differed between patients with POTS and healthy children, and if this rhythm predicted the efficacy of sleep-promoting treat- ments in children with POTS.
Methods
A total of 60 subjects, including 40 children with POTS and 20 healthy children, were recruited from the outpatient and inpatient pediatric departments of Shaanxi Provincial People’s Hospital and Children’s hospital of Zhejiang University School of Medicine, China. The children with POTS had the following manifestations: dizziness or vertigo, chest tightness, headache, palpitations, paleness, blurred vision,91
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 191 • December 2017
fatigue, or syncope. They underwent a thorough history taking, physical examination, and laboratory investigations, includ- ing electrocardiography, electroencephalography, blood glucose and blood biochemistry tests, and cranial computed tomog- raphy or magnetic resonance imaging to exclude cardiac, neu- rologic, metabolic, and psychogenic causes. The 20 healthy children had normal findings on medical history, physical ex- amination, electrocardiography, electroencephalogram, head- up test, and head-up tilt test. All children were informed about the purposes of the research and agreed to participate. Written informed consent was obtained from the parents or guard- ians of all the study subjects. The study was approved by the ethics committees of Shaanxi Provincial People’s Hospital and Children’s Hospital, Zhejiang University School of Medicine. Before the head-up test, the children were instructed to stop taking any drugs that might affect autonomic function. The test was performed in a quiet room at a suitable tempera- ture. Heart rate and blood pressure were continuously moni- tored during the test with a Dash 2000 Multi-Lead Physiological Monitor (General Electric, New York, New York). The chil- dren were required to lie down for at least 10 minutes and were then asked to stand up for 10 minutes. The test was discon- tinued if a positive response appeared within 10 minutes of standing. If the changes in the heart rate and blood pressure were within the normal range during the head-up test, the head-
up tilt test was performed on the following day.
All children fasted at least 4 hours before the head-up tilt test and instructed to not use any drugs that might affect au- tonomic function. The children lay on the tilt table (HUT- 821; Beijing Juchi, Beijing, China), and their heart rate and blood pressure were continuously monitored with a Dash 2000 Multi-Lead Physiological Monitor (General Electric). Once the heart rate had stabilized, the table was tilted to a 60° angle, and the heart rate and blood pressure were monitored until either a positive response appeared or the test was complete (at the end of 45 minutes). A positive response consisted of an in- crease in heart rate of ≥40 beats·minute−1 or a maximum heart rate of >120 beats·minute−1 accompanied with any 2 of the fol- lowing symptoms: dizziness or vertigo, chest tightness, head- ache, palpitations, pallor, blurred vision, fatigue, or syncope during tilting. POTS was diagnosed if a positive response was obtained.5
The diagnostic criteria for POTS are (1) normal heart rate in the supine position; (2) more than 2 clinical symptoms on standing, such as dizziness or vertigo, lightheadedness, head- ache, fatigue, pallor, blurred vision, chest tightness, palpita- tions, hand tremors, and syncope; (3) increment in heart rate
≥40 beats·minute−1 or maximum heart rate >120 beats·minute−1 after standing during the head-up test or head-up tilt test, with
at least 2 of the above symptoms; (4) symptoms relieved or diminished by recumbence and symptoms persisting for ≥1 month; and (5) exclusion of other cardiovascular, neuro- logic, or metabolic diseases.6
Sleep quality was measured prior to the head-up and head- up tilt tests. The Pittsburgh Sleep Quality Index (PSQI), stan- dardized for this population and language, was used to evaluate sleep quality. The PSQI is an 18-item, self-reported question-
naire used to evaluate habitual sleep quality. The 18 indi- vidual items generate 7 “component” scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep effi- ciency, sleep disturbances, use of sleep medications, and daytime dysfunction. Each of these 7 scores is weighted equally on a scale from 0 to 3, with 0 indicating no difficulty and 3 indi- cating severe difficulty. The global score ranges from 0 to 21, with high scores indicating poor sleep quality; scores >5 suggest clinically significant sleep complaints.7
All patients were treated with the following sleep-promoting methods: (1) more than 8 hours of sleep every night, from 10:00
p.m. to 6:30 a.m. or 7:00 a.m.; (2) 40 minutes to 1 hour of a midday nap after lunch; (3) no exercise before bedtime; (4) choose one of the following measures to help fall asleep: quiet music, reading, yoga, and a hot bath; (5) an appropriate environment/temperature; (6) little or no water 1 hour before bedtime; and (7) urination before bedtime.
All patients were evaluated using symptom scores and the head-up test or head-up tilt test before the treatment. Symp- toms were also scores during outpatient follow-up visits after 3 months of the sleep-promoting treatment. The 10 main clini- cal symptoms of POTS are syncope, dizziness, lightheadedness, nausea, heart palpitations, headaches, hand tremors, sweat- ing, blurred vision, and inattention. Symptom scores were as- signed as follows: no POTS symptoms, 0 points; 1 symptom once a month, 1 point; 1 symptom 2-4 times per month, 2
points; 1 symptom 2-7 times per week, 3 points; and 1 symptom at least once per day, 4 points. Symptom scoring was re- peated to evaluate the overall severity of the disease. Patients were considered as responders if their symptom scores de- creased by 2 or more points after treatment; they were con- sidered nonresponders if their symptom scores decreased by
<2 points.8
Saliva samples were collected from each participant before the treatment. The salivary sample–collection protocol was ex- plained to each study participant, and they were shown the correct use of the Salivette saliva-collection device (Sarsted, Leic- ester, United Kingdom). Participants were told not to eat, drink, smoke, brush their teeth, or use mouthwash in the 30 minutes before salivary collection and not to drink alcohol on the day of sample collection. Salivary specimens were collected when the children awakened, 30 minutes after awakening, at 12:00 p.m., 4:00 p.m., 8:00 p.m., and at bedtime. These time points were expected to span the peak and nadir of cortisol release during waking hours.9 No saliva stimulants were used to en- courage salivation. Salivettes were placed into the mouth, on top of the tongue for 2 minutes per sampling time point. After collection, the saliva samples were immediately refrigerated and stored at -80°C until being assayed. Enzyme-linked immunosorbent assays were used to measure salivary corti- sol concentrations.
up tilt test was performed on the following day.
All children fasted at least 4 hours before the head-up tilt test and instructed to not use any drugs that might affect au- tonomic function. The children lay on the tilt table (HUT- 821; Beijing Juchi, Beijing, China), and their heart rate and blood pressure were continuously monitored with a Dash 2000 Multi-Lead Physiological Monitor (General Electric). Once the heart rate had stabilized, the table was tilted to a 60° angle, and the heart rate and blood pressure were monitored until either a positive response appeared or the test was complete (at the end of 45 minutes). A positive response consisted of an in- crease in heart rate of ≥40 beats·minute−1 or a maximum heart rate of >120 beats·minute−1 accompanied with any 2 of the fol- lowing symptoms: dizziness or vertigo, chest tightness, head- ache, palpitations, pallor, blurred vision, fatigue, or syncope during tilting. POTS was diagnosed if a positive response was obtained.5
The diagnostic criteria for POTS are (1) normal heart rate in the supine position; (2) more than 2 clinical symptoms on standing, such as dizziness or vertigo, lightheadedness, head- ache, fatigue, pallor, blurred vision, chest tightness, palpita- tions, hand tremors, and syncope; (3) increment in heart rate
≥40 beats·minute−1 or maximum heart rate >120 beats·minute−1 after standing during the head-up test or head-up tilt test, with
at least 2 of the above symptoms; (4) symptoms relieved or diminished by recumbence and symptoms persisting for ≥1 month; and (5) exclusion of other cardiovascular, neuro- logic, or metabolic diseases.6
Sleep quality was measured prior to the head-up and head- up tilt tests. The Pittsburgh Sleep Quality Index (PSQI), stan- dardized for this population and language, was used to evaluate sleep quality. The PSQI is an 18-item, self-reported question-
naire used to evaluate habitual sleep quality. The 18 indi- vidual items generate 7 “component” scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep effi- ciency, sleep disturbances, use of sleep medications, and daytime dysfunction. Each of these 7 scores is weighted equally on a scale from 0 to 3, with 0 indicating no difficulty and 3 indi- cating severe difficulty. The global score ranges from 0 to 21, with high scores indicating poor sleep quality; scores >5 suggest clinically significant sleep complaints.7
All patients were treated with the following sleep-promoting methods: (1) more than 8 hours of sleep every night, from 10:00
p.m. to 6:30 a.m. or 7:00 a.m.; (2) 40 minutes to 1 hour of a midday nap after lunch; (3) no exercise before bedtime; (4) choose one of the following measures to help fall asleep: quiet music, reading, yoga, and a hot bath; (5) an appropriate environment/temperature; (6) little or no water 1 hour before bedtime; and (7) urination before bedtime.
All patients were evaluated using symptom scores and the head-up test or head-up tilt test before the treatment. Symp- toms were also scores during outpatient follow-up visits after 3 months of the sleep-promoting treatment. The 10 main clini- cal symptoms of POTS are syncope, dizziness, lightheadedness, nausea, heart palpitations, headaches, hand tremors, sweat- ing, blurred vision, and inattention. Symptom scores were as- signed as follows: no POTS symptoms, 0 points; 1 symptom once a month, 1 point; 1 symptom 2-4 times per month, 2
points; 1 symptom 2-7 times per week, 3 points; and 1 symptom at least once per day, 4 points. Symptom scoring was re- peated to evaluate the overall severity of the disease. Patients were considered as responders if their symptom scores de- creased by 2 or more points after treatment; they were con- sidered nonresponders if their symptom scores decreased by
<2 points.8
Saliva samples were collected from each participant before the treatment. The salivary sample–collection protocol was ex- plained to each study participant, and they were shown the correct use of the Salivette saliva-collection device (Sarsted, Leic- ester, United Kingdom). Participants were told not to eat, drink, smoke, brush their teeth, or use mouthwash in the 30 minutes before salivary collection and not to drink alcohol on the day of sample collection. Salivary specimens were collected when the children awakened, 30 minutes after awakening, at 12:00 p.m., 4:00 p.m., 8:00 p.m., and at bedtime. These time points were expected to span the peak and nadir of cortisol release during waking hours.9 No saliva stimulants were used to en- courage salivation. Salivettes were placed into the mouth, on top of the tongue for 2 minutes per sampling time point. After collection, the saliva samples were immediately refrigerated and stored at -80°C until being assayed. Enzyme-linked immunosorbent assays were used to measure salivary corti- sol concentrations.
Statistical Analyses
The data were analyzed with the SPSS v 13.0 software (SPSS Inc, Chicago, Illinois). Categorical data were expressed as number of cases, and continuous data were expressed as mean ± SD. The c2 test and t test were used to analyze between-| subjects | ||||||
| Items | Control subjects (n = 20) | Patients with POTS (n = 40) | t/c2 | P | ||
| Sex (male/female) | 7/13 | 17/23 | 0.313 | .576 | ||
| Age, y | 13.0 ± 1.9 | 12.0 ± 1.8 | 1.95 | .056 | ||
| Height, cm | 157.0 ± 9.8 | 151.3 ± 13.0 | 1.898 | .064 | ||
| Weight, kg | 47.2 ± 9.0 | 43.8 ± 7.7 | 1.527 | .132 | ||
| Supine SBP, mm Hg | 109 ± 10 | 103 ± 8 | 2.194 | .032 | ||
| Supine DBP, mm Hg | 66 ± 9 | 62 ± 8 | 1.932 | .058 | ||
| Upright SBP, mm Hg | 114 ± 11 | 107 ± 11 | 2.351 | .022 | ||
| Upright DBP, mm Hg | 74 ± 9 | 69 ± 8 | 2.227 | .03 | ||
| Supine HR, beats/min | 84 ± 9 | 78 ± 9 | 2.117 | .039 | ||
| Upright HR, beats/min | 104 ± 11 | 117 ± 14 | −3.88 | <.001 | ||
| DHR, beats/min | 20 ± 8 | 39 ± 11 | −7.86 | <.001 | ||
| PSQI | 1.35 ± 1.39 | 7.2 ± 3.0 | −10.370 | <.001 | ||
| SSQ | 0.3 ± 0.47 | 1.15 ± 0.80 | −4.367 | <.001 | ||
| SL | 0.35 ± 0.49 | 1.1 ± 0.71 | −4.244 | <.001 | ||
| Sleep duration | 0.25 ± 0.55 | 1.23 ± 0.89 | −5.213 | <.001 | ||
| HSE | 0.4 ± 0.6 | 1.03 ± 0.62 | −3.725 | <.001 | ||
| Sleep disturbances | .05 ± 0.224 | 0.98 ± 0.77 | −7.047 | <.001 | ||
| SM | 0 | 0.13 ± 0.40 | −2.0 | .058 | ||
| DD | 0 | 1.6 ± 0.87 | −11.615 | <.001 | ||
DBP, diastolic blood pressure; DD, daytime dysfunction; HR, heart rate; HSE, habitual sleep efficiency; SBP, systolic blood pressure; SL, sleep latency; SM, sleep medications; SSQ, subjective sleep quality; DHR, upright heart rate—supine heart rate.
group differences in categorical and continuous data, respec- tively. A paired t-test was used to analyze differences in continuous data before and after the treatment in a given patient. The receiver operating characteristic (ROC) curve was used to evaluate the value of salivary cortisol concentrations in predicting the therapeutic effects of the sleep-promoting method. A P value of < .05 was considered statistically significant.
Results
Among the 40 children with POTS, there were 17 boys and 23 girls. Their ages ranged from 9 to 17 years (mean, 12.0 ± 1.8 years). Among the 20 control subjects, there were 7 boys and 13 girls, whose ages ranged from 6 to 15 years (mean, 13.0 ± 1.9 years). There were no statistical differences between the 2 groups in terms of sex, age, height, or weight (P > .05). However, sig- nificant differences were detected in heart rate and blood pres- sure (P < .05). Global PSQI scores were significantly higher in the patients with POTS (7.2 ± 3.0) than in the control sub- jects (1.35 ± 1.39; t = -10.370, P < .001). The 7 component scores were also higher in the patient with POTS than in the con- trols (Table I).Both groups showed the expected diurnal curve, with sali- vary cortisol concentrations peaking shortly after waking and decreasing during the evening hours. At all time points, sali- vary cortisol concentrations were significantly higher in the patients with POTS than in the control subjects (waking up, P < .001; waking + 30 minutes, P < .001; 12:00 p.m., P < .001;
4:00 p.m. P < .001; and 8:00 p.m., P < .05; Figure 1).
We explored whether salivary cortisol concentrations re- flected POTS severity or poor sleep quality. We found that the symptom scores and PSQI scores positively correlated with sali- vary cortisol concentration at waking (symptom scores: r = 0.62,
P < .001; PSQI: r = 0.60, P < .001; Figure 2; available at www.jpeds.com).
Compared with the pretreatment symptom scores, the scores after the sleep-promoting treatment were significantly de- creased (6.1 ± 2.7 vs 3.0 ± 2.6, t = 8.1, P < .001). The incre- ment in heart rate induced by postural changes was also significantly reduced after treatment (39 ± 11 vs 27 ± 11 beats·minute−1; t = 5.0, P < .001). The maximum heart rate within 10 minutes after standing also decreased (117 ± 14 vs 110 ± 12 beats·minute−1; t = 2.66, P = .01; Table II).
The salivary cortisol concentrations at awakening were sig- nificantly higher in responders (4.83 ± 0.73 ng/mL) than in nonresponders (4.05 ± 0.79 ng/mL, t = -3.197, P = .003). However, the concentrations at the rest of the time points did not differ between responders and nonresponders. In
Figure 1. Salivary cortisol levels in patients with POTS and healthy control subjects. Cortisol concentrations are signifi- cantly higher in patients with POTS than in control subjects.
| (n = 40) | (n = 40) | (n = 40) | |
| Before treatment | 39 ± 11 | 117 ± 14 | 6.1 ± 2.7 |
| Post-treatment | 27 ± 11 | 110 ± 12 | 3.0 ± 2.6 |
| T | 5 | 2.66 | 8.1 |
| P | <.001 | .01 | <.001 |
addition, age, height, weight, and PSQI scores all signifi- cantly differed between responders and nonresponders (P < .05) (Table III; available at www.jpeds.com).
To determine the usefulness of salivary cortisol concentra- tions at awakening in predicting the efficacy of the sleep- promoting method, we calculated the area under the ROC curve. This area was 75.8% (95% CI 59.3%–92%), indicating a high predictive value. At-awakening salivary cortisol con- centrations of >4.1 ng/mL were associated with 83.3% sensi- tivity and 68.7% specificity for predicting the efficacy of the sleep-promoting method (Figure 3).
Discussion
The present study showed that PSQI scores and salivary cor- tisol concentrations were significantly increased in patients with POTS compared with control subjects. Furthermore, salivary cortisol concentrations reflected the severity of POTS. The pre- treatment salivary cortisol concentration at awakening might serve as a useful predictor of the therapeutic efficacy of the sleep-promoting method used in children with POTS, with
 |
Figure 3. Value of salivary cortisol concentration at awaken- ing in predicting the therapeutic efficacy of the sleep-promoting method. The area under the ROC curve is 75.8% (95% CI 59.3%-92%), indicating that pretreatment salivary cortisol con- centrations at awakening have a high predictive value in as- sessing the efficacy of the sleep-promoting method in patients with POTS.
concentrations >4.1 ng/mL indicating possible clinical im- provement after sleep-promoting treatment. In addition, the sleep-promoting method was a useful treatment to cope with the clinical symptoms of POTS.
The mechanisms underlying POTS are unclear. Absolute hy- povolemia, hyperadrenergic responses, autonomic imbal- ance, and impaired regulation of peripheral vascular resistance were thought to be involved in the pathogenesis.
One cross-sectional study has shown that the risk of POTS is 5.905 times greater in those who sleep for <8 hours/day than in those who sleep >8 hours/day.2 The reason for this is not fully understood. Irwin et al found that patients with insom- nia had increased nocturnal catecholamine levels compared
with controls, which might contribute to the pathophysiol- ogy of POTS.10 Pengo et al showed that patients with POTS do not exhibit polysomnographic findings consistent with rel- evant sleep pathologies nor objective daytime sleepiness; sub- jective daytime sleepiness is associated with enhanced activation of the parasympathetic nervous system.11 Miglis et al12 showed that sleep problems contribute significantly to the dimin- ished quality of life in patients with POTS. Follenius et al3 showed that insufficient sleep or sleep disruption is associ- ated with significant increases in plasma cortisol levels.
Recurrent sleep problems are associated with adverse sali- vary cortisol patterns throughout the day.13 Guyon et al14 showed that insufficient sleep dampens the circadian rhythm of cor- tisol, a major internal synchronizer of central and peripheral clocks. Dina et al found that women with breast cancer who often experienced sleep disturbances or fatigue had dis- rupted cortisol rhythm.15 In epidemiologic studies, habitual short sleep, usually 6 hours or less, has been linked to in- creased mortality and increased incidence and prevalence of several conditions, including obesity, diabetes, cardiovascu- lar diseases, as well as vulnerability to infection, depression, and anxiety.16-23
Insufficient sleep or sleep disruption is associated with sig- nificant increases in plasma cortisol levels.3 The levels of the catecholamines norepinephrine and dopamine have been found to correlate with cortisol levels.24 Cortisol levels are posi- tively correlated with norepinephrine levels.24 Finally, sali- vary cortisol levels reflect serum cortisol levels.25 So, salivary cortisol could reflect the severity of POTS or quality of sleep, and may be a biomarker to reflect catecholamine levels, which are linked to the clinical manifestations of POTS.
To promote health, and prevent and manage sleep prob- lems, the American Academy of Pediatrics recommends that parents start promoting good sleep hygiene, with a sleep- promoting environment and a bedtime routine in infancy and throughout childhood.26
In our study, salivary cortisol concentrations were in- creased in patients with POTS, and clinical symptoms could be relieved in some patients with the sleep-promoting method. The underlying mechanism may be that the sleep-promoting method normalized/improved the cortisol secretion rhythm and reduced the high day-time salivary cortisol concentra- tions. In this study, the salivary cortisol concentration was sig- nificantly higher in children with POTS than in healthy children.
Furthermore, these concentrations were positively correlated with clinical severity (symptom and PSQI scores). More im- portantly, the pretreatment salivary cortisol concentrations were significantly higher in responders to sleep-promoting treat- ment than in nonresponders. ROC curve analysis showed that salivary cortisol could be a predictive biomarker of the effi- cacy of sleep treatment in patients with POTS.
There are limitations to this study. This is a single-center study. More studies with larger sample sizes are needed in the future. The findings of our study may be of clinical rel- evance, as they may provide an approach for individualized POTS treatment. ■
We thank Dr S.S. Seshia of the Department of Pediatrics, University of Saskatchewan, Canada for his excellent technical assistance during the preparation of the manuscript.
Submitted for publication May 7, 2017; last revision received Jul 7, 2017;
accepted Aug 16, 2017
Reprint requests: Jing Lin, MD, PhD, Department of Child and Adolescent Health Science Center, School of Public Health, Xi’an Jiaotong University, Xi’an 710061, China. E-mail: linjkaoyan2008@163.com
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12. Miglis MG, Muppidi S, Feakins C, Fong L, Prieto T, Jaradeh S. Sleep dis- orders in patients with postural tachycardia syndrome. Clin Auton Res 2016;26:67-73.
13. Abell JG, Shipley MJ, Ferrie JE, Kivimäki M, Kumari M. Recurrent short sleep, chronic insomnia symptoms and salivary cortisol: a 10-year follow-up in the Whitehall II study. Psychoneuroendocrinology 2016;68:91- 9.
14. Guyon A, Balbo M, Morselli LL, Tasali E, Leproult R, L’Hermite- Balériaux M, et al. Adverse Effects of Two Nights of Sleep Restriction on the Hypothalamic-Pituitary-Adrenal Axis in Healthy Men. J Clin Endocrinol Metab 2014;99:2861-8.
15. Tell D, Mathews HL, Janusek LW. Day-to-day dynamics of associations between sleep, napping, fatigue and the cortisol diurnal rhythm in women diagnosed with breast cancer. Psychosom Med 2014;76:519- 28.
16. Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol 2009;5:253-61.
17. Cappuccio FP, D’Elia L, Strazzullo P, Miller MA. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta- analysis. Diabetes Care 2010;33:414-20.
18. Cappuccio FP, Cooper D, D’Elia L, Strazzullo P, Miller MA. Sleep dura- tion predicts cardiovascular outcomes: a systematic review and meta- analysis of prospective studies. Eur Heart J 2011;32:1484-92.
19. Nielsen LS, Danielsen KV, Sørensen TI. Short sleep duration as a pos- sible cause of obesity: critical analysis of the epidemiological evidence. Obes Rev 2011;12:78-92.
20. Morselli LL, Guyon A, Spiegel K. Sleep and metabolic function. Pflugers Arch 2012;463:139-60.
21. Faraut B, Boudjeltia KZ, Vanhamme L, Kerkhofs M. Immune, inflam- matory and cardiovascular consequences of sleep restriction and recov- ery. Sleep Med Rev 2012;16:137-49.
22. Cappuccio FP, Miller MA. Sleep and mortality: cause, consequence, or symptom? Sleep Med 2013;14:587-8.
23. Alvaro PK, Roberts RM, Harris JK. A systematic review assessing bidirectionality between sleep disturbances, anxiety, and depression. Sleep 2013;36:1059-68.
24. Zipursky RT, Press MC, Srikanthan P, Gornbein J, McClelland R, Watson K, et al. Relation of stress hormones (urinary catecholamines/cortisol) to coronary artery calcium in men versus women (from the Multi- Ethnic Study of Atherosclerosis [MESA]. Am J Cardiol 2017;119:1963- 71.
25. Forclaz MV, Moratto E, Pennisi A, Falco S, Olsen G, Rodríguez P, et al. Salivary and serum cortisol levels in newborn infants. Arch Argent Pediatr 2017;115:262-6.
26. Bathory E, Tomopoulos S. Sleep regulation, physiology and develop- ment, sleep duration and patterns, and sleep hygiene in infants, tod- dlers, and preschool-age children. Curr Probl Pediatr Adolesc Health Care 2017;47:29-42.
There are limitations to this study. This is a single-center study. More studies with larger sample sizes are needed in the future. The findings of our study may be of clinical rel- evance, as they may provide an approach for individualized POTS treatment. ■
We thank Dr S.S. Seshia of the Department of Pediatrics, University of Saskatchewan, Canada for his excellent technical assistance during the preparation of the manuscript.
 |
Submitted for publication May 7, 2017; last revision received Jul 7, 2017;
accepted Aug 16, 2017
Reprint requests: Jing Lin, MD, PhD, Department of Child and Adolescent Health Science Center, School of Public Health, Xi’an Jiaotong University, Xi’an 710061, China. E-mail: linjkaoyan2008@163.com
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12. Miglis MG, Muppidi S, Feakins C, Fong L, Prieto T, Jaradeh S. Sleep dis- orders in patients with postural tachycardia syndrome. Clin Auton Res 2016;26:67-73.
13. Abell JG, Shipley MJ, Ferrie JE, Kivimäki M, Kumari M. Recurrent short sleep, chronic insomnia symptoms and salivary cortisol: a 10-year follow-up in the Whitehall II study. Psychoneuroendocrinology 2016;68:91- 9.
14. Guyon A, Balbo M, Morselli LL, Tasali E, Leproult R, L’Hermite- Balériaux M, et al. Adverse Effects of Two Nights of Sleep Restriction on the Hypothalamic-Pituitary-Adrenal Axis in Healthy Men. J Clin Endocrinol Metab 2014;99:2861-8.
15. Tell D, Mathews HL, Janusek LW. Day-to-day dynamics of associations between sleep, napping, fatigue and the cortisol diurnal rhythm in women diagnosed with breast cancer. Psychosom Med 2014;76:519- 28.
16. Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol 2009;5:253-61.
17. Cappuccio FP, D’Elia L, Strazzullo P, Miller MA. Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta- analysis. Diabetes Care 2010;33:414-20.
18. Cappuccio FP, Cooper D, D’Elia L, Strazzullo P, Miller MA. Sleep dura- tion predicts cardiovascular outcomes: a systematic review and meta- analysis of prospective studies. Eur Heart J 2011;32:1484-92.
19. Nielsen LS, Danielsen KV, Sørensen TI. Short sleep duration as a pos- sible cause of obesity: critical analysis of the epidemiological evidence. Obes Rev 2011;12:78-92.
20. Morselli LL, Guyon A, Spiegel K. Sleep and metabolic function. Pflugers Arch 2012;463:139-60.
21. Faraut B, Boudjeltia KZ, Vanhamme L, Kerkhofs M. Immune, inflam- matory and cardiovascular consequences of sleep restriction and recov- ery. Sleep Med Rev 2012;16:137-49.
22. Cappuccio FP, Miller MA. Sleep and mortality: cause, consequence, or symptom? Sleep Med 2013;14:587-8.
23. Alvaro PK, Roberts RM, Harris JK. A systematic review assessing bidirectionality between sleep disturbances, anxiety, and depression. Sleep 2013;36:1059-68.
24. Zipursky RT, Press MC, Srikanthan P, Gornbein J, McClelland R, Watson K, et al. Relation of stress hormones (urinary catecholamines/cortisol) to coronary artery calcium in men versus women (from the Multi- Ethnic Study of Atherosclerosis [MESA]. Am J Cardiol 2017;119:1963- 71.
25. Forclaz MV, Moratto E, Pennisi A, Falco S, Olsen G, Rodríguez P, et al. Salivary and serum cortisol levels in newborn infants. Arch Argent Pediatr 2017;115:262-6.
26. Bathory E, Tomopoulos S. Sleep regulation, physiology and develop- ment, sleep duration and patterns, and sleep hygiene in infants, tod- dlers, and preschool-age children. Curr Probl Pediatr Adolesc Health Care 2017;47:29-42.
Figure 2. Association of cortisol concentrations with severity of clinical symptoms and PSQI scores. Both symptom scores and PSQI scores positively correlate with salivary cortisol concentrations at awakening.
Table III. Comparisons of demographic characteristics, hemodynamic parameters, PSQI scores, 7 “component” scores, and salivary cortisol between children with POTS with different response to sleep-promoting method
| Responders | Nonresponders | T | P | |||
| Cases Age, y |
24 12.5 ± 1.7 |
16 10.8 ± 2.3 |
— −2.6 |
— .013 |
||
Weight, kg 46.1 ± 6.8 40.2 ± 7.7 −2.54 .015
Supine SBP, mm Hg 103 ± 7 103 ± 11 0.113 .91
Supine DBP, mm Hg 60 ± 6 64 ± 10 1.226 .234
Upright SBP, mm Hg 107 ± 10 106 ± 14 −0.497 .662
Upright DBP, mm Hg 69 ± 8 70 ± 9 0.432 .668
Supine HR, beats/min 78 ± 9 80 ± 10 0.655 .516
Upright HR, beats/min 116 ± 15 119 ± 12 0.607 .547
DHR, beats/min 39 ± 12 39 ± 9 0.207 .837
PSQI 6.41 ± 3.11 8.37 ± 2.39 2.126 .04
SSQ 1.00 ± 0.722 1.38 ± 0.89 1.47 .15
SL 0.96 ± 0.75 1.31 ± 0.602 1.58 .123
Sleep duration 1.08 ± 0.974 1.44 ± 0.727 1.24 .223
HSE 0.96 ± 0.624 1.13 ± 0.619 0.83 .412
Sleep disturbances 0.83 ± 0.816 1.19 ± 0.655 1.45 .155
SM 0.13 ± 0.448 0.13 ± 0.342 0 1
DD 1.46 ± 0.932 1.81 ± 0.75 1.27 .21
Symptom scores 6.7 ± 2.4 5.3 ± 2.7 −1.748 .089
Awakening salivary cortisol, ng/mL 4.83 ± 0.73 4.05 ± 0.79 3.197 .003
Waking 30 min salivary cortisol, ng/mL 6.70 ± 0.76 7.00 ± 0.83 1.231 .226
Salivary cortisol at 12:00 p.m., ng/mL 3.47 ± 0.93 3.65 ± 1.07 0.558 .58
Salivary cortisol at 4:00 p.m., ng/mL 2.43 ± 0.70 2.47 ± 0.67 0.151 .881
Salivary cortisol at 8:00 p.m. ng/mL 1.75 ± 0.46 1.63 ± 0.47 0.821 .417
Salivary cortisol at bedtime, ng/mL 1.37 ± 0.38 1.29 ± 0.43 0.594 .556
(作者：万 萱1，冯建英1，严晓华1，张西嫔1，王菊燕1，李晓红1，李思琼1，成 钧2， 肖 成3，焦富勇 编辑：admin)
文章热词：川崎病，冠脉损害，干细胞
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