Efficacy of intravenous saline infusion
The main findings of our study were as follows. Our study showed that an increase in PR among participants with POTS who had a standing test early in the morning was significantly decreased after 1.5 L of intravenous saline infusion. Although increasing plasma volume is considered important for children with POTS , few reports have shown its objective efficacy. However, our finding that intravenous saline infusion was effective for improving tachycardia in children and adolescents with POTS supports this notion. We presume that this efficacy in the pathophysiology of POTS results from increases in the venous return volume, cardiac output, and total blood volume.
Regarding the treatment of POTS in children, Medow et al. reported that the effectiveness of oral rehydration was equal to or better than the effectiveness of intravenous saline infusion for POTS . Although oral rehydration is reportedly convenient, safe, and effective, many children with POTS experience difficulty during oral intake because of nausea, indigestion, and general fatigue. In our clinical experience, these manifestations are symptoms of orthostatic intolerance due to POTS; to the best of our knowledge, there are no reports regarding treatment for patients with POTS who have difficulty with respect to water and salt intake. Our findings suggest that intravenous saline infusion is a suitable, effective treatment for patients who experience difficulty during oral intake due to symptoms of POTS.
Pathophysiology of POTS
The etiology and pathophysiology of POTS are unknown, but are presumably heterogeneous. The syndrome is associated with deconditioning, recent viral illness, chronic fatigue syndrome, and limited or restricted autonomic neuropathy . Because of these various pathophysiologies, hypovolemia with reduced systemic venous return occurs, along with reduced cardiac output and reduction in total blood volume; these changes lead to orthostatic intolerance . Orthostatic intolerance is accompanied by signs and symptoms that can include loss of consciousness, cognitive deficits, loss of vision or hearing, lightheadedness, headache, fatigue, nausea, abdominal pain, sweating, and tremor .
Joyner et al. reported that cardiovascular deconditioning plays a major role in POTS because it causes orthostatic intolerance . Cardiovascular deconditioning is defined as circulatory disturbance due to hypoactivity in a microgravity environment, such as in space or during confinement in bed. This condition causes lower limb muscle atrophy and myocardial atrophy, thereby reducing cardiac output. A previous study reported that cardiovascular deconditioning due to the bed rest test, which was created by an artificial microgravity situation, caused POTS . Confinement in bed is similar to microgravity and causes orthostatic intolerance and deconditioning, which are caused by the microgravity environment in a bed rest test . We previously reported that 10 days of a bed rest test led to a decrease in orthostatic intolerance in 10 of 12 participants  and increased tachycardia when standing. Some other studies have also reported orthostatic intolerance in the bed rest test [25, 26].
The prevalence of POTS in pediatric patients has increased in recent years and is caused by changes in their lifestyle, such as a lack of physical exercise and prolonged time in bed watching television . These findings indicate that POTS is pathophysiologically heterogeneous because of autonomic dysfunction, psychosomatic stress, and cardiovascular deconditioning. Therefore, we presume that cardiovascular deconditioning has an important role, as shown by previous reports regarding bed rest tests [14, 24, 25, 26].
Efficacy of intravenous saline infusion for cardiovascular deconditioning
It is unclear whether autonomic dysfunction or cardiovascular deconditioning is improved by intravenous saline infusion. We suspect that cardiovascular deconditioning is involved. While intravenous normal saline infusion increases circulating plasma volume, cardiovascular deconditioning decreases circulating plasma volume . Therefore, we presume that patients with POTS have a chronic decrease in circulating plasma volume by cardiovascular deconditioning and an increase in plasma volume by intravenous normal saline infusion, which improves tachycardia. This possibility suggests that the cause of worsening POTS in children and adolescents in Japan is deconditioning. The mechanism by which intravenous normal saline infusion affects the autonomic nervous system remains unclear. Further research is needed regarding the response of the autonomic nervous system to intravenous normal saline infusion.
There were some limitations in this study. First, we did not measure the oral intake and plasma volumes. Water and salt intake are effective for improving POTS [10–12]. Therefore, the volume of oral intake during the previous day might have affected the degree of symptoms, postural tachycardia, and the efficacy of intravenous saline infusion. Measurement of the absolute value of plasma volume is impossible, but echocardiographic assessments and measurement of water intake should be performed in a future study. Second, this study did not investigate whether postural tachycardia is influenced by discomfort, anxiety, or previous therapy before admission to our hospital because those factors were not assessed in this study. Third, this study did not assess changes in symptoms caused by intravenous saline infusion. We cannot conclusively determine whether intravenous saline infusion is effective for children and adolescents with POTS without a clear assessment of symptom improvement following this treatment. Assessment of efficacy for specific symptoms should be also performed. We expect some improvement of the patient’s QOL because intravenous saline infusion improves the physical condition. Long-term efficacy and QOL following intravenous saline infusion therapy for POTS should be further investigated.