Keywords

1 Introduction

Orthostatic intolerance is caused by dysfunctions of the autonomic nervous system [1]. In Japan, it is well known as orthostatic dysregulation (OD) and has become a major health concern among school-aged children and adolescents. Various symptoms, including recurrent dizziness, chronic fatigue, headache, and syncope, are caused by the failure of the mechanisms that compensate for changes in cardiovascular hemodynamics due to active standing. OD is classified into four subsets according to Japanese clinical guidelines: instantaneous orthostatic hypotension (INOH), postural tachycardia syndrome (POTS), neutrally mediated syncope, and delayed orthostatic hypotension (Delayed OH).

It has recently become possible to measure oxygen metabolism in brain tissue safely and easily using near-infrared spectroscopy (NIRS). Previous studies indicate that in healthy people, cerebral blood flow remains constant even if the arterial pressure changes, which is referred to as ‘cerebral autoregulation’ [2]. In patients with OD, cerebral autoregulation is impaired as their oxygenated hemoglobin (oxy-Hb) levels significantly decrease under orthostatic load [3, 4]. Tanaka et al. studied the oxygen metabolism of chronic fatigue syndrome patients with OD under orthostatic load for each OD subset. They reported that in three subsets (INOH, Delayed OH, and POTS) of OD patients, the right prefrontal cortex showed no recovery after a transient decrease in oxy-Hb at the onset of standing, and the decrease persisted while the patients remained standing [5]. Furthermore, Kamiyama et al. reported asymmetric changes in cerebral blood oxygenation during active standing in children with POTS, with a significant decrease in the left compared with the right frontal cortex [6]. However, the laterality of the rapid recovery and cerebral oxygen metabolism during active standing in INOH patients remain unclear.

In this study, we used NIRS to measure the quantitative changes in the concentrations of cerebral oxy-Hb, deoxygenated hemoglobin (deoxy-Hb), and total hemoglobin (total-Hb) in the bilateral prefrontal cortex during an active standing test in pediatric patients with INOH.

2 Methods

The study enrolled 82 patients (mean age: 13.8 ± 2.2 years) with INOH diag-nosed in accordance with the Japanese clinical guidelines for juvenile OD [1]. INOH is classified as mild or severe according to the time taken to recover from a drop in arterial pressure. The criteria for diagnosing mild INOH are 1) recovery time for mean arterial pressure of ≥25 s or 2) recovery time of ≥20 s with an initial decrease of ≥60% in mean arterial pressure, and the severe form is diagnosed with the additional criterion of 3) a reduction in systolic arterial pressure of ≥15% during the later stage of standing (3–7 min after standing) [1]. All subjects were recruited from the outpatient clinic of the Department of Pediatrics and Child Health at Nihon University Itabashi Hospital from October 2013 to April 2018. The subjects were classified as mild (52 patients) or severe (30 patients) using the active standing test described below. We excluded patients from whom we could not obtain appropriate cerebral blood oxygenation data. Table 1 shows the clinical characteristics of the subjects according to severity. There was no significant difference between mild and severe patients.

Table 1 Clinical characteristics of all patients with INOH
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The subjects performed the active standing test between 9:00 a.m. and 11:00 a.m. After resting for 10 min in the supine position, subjects were instructed to stand up quickly by themselves and remain upright for 10 min. During the test, the subjects’ blood pressure and heart rate were monitored with the following non-invasive beat-to-beat blood pressure monitors: BP-608 Evolution II CS (Omlon Colin Co., Ltd., Tokyo, Japan; October 2013~December 2016) and Task Force monitor TFM-3040 (Nihon-Kohden, Tokyo, Japan; January 2017 ~April 2018). Cerebral blood oxygenation in the bilateral prefrontal cortex was simultaneously measured using a NIRS 2-channel miniaturized wireless tool (Pocket NIRS Duo<TM>, Hamamatsu Pho-tonics, Shizuoka, Japan). This instrument can continuously detect changes in oxy-Hb, deoxy-Hb, and total-Hb based on the modified Beer-Lambert law. The NIRS probes were symmetrically fitted on both sides of the subjects’ foreheads.

Healthy individuals usually show rapid recovery in reaction to the initial drop in oxy-Hb at the onset of active standing [5]. We evaluated the detection of rapid recovery in the NIRS parameters of the bilateral prefrontal cortices. Subjects who showed a rapid recovery followed by a reduction in oxy-Hb in the later stage of standing were included among the rapid recovery positive subjects.

The experimental time was divided into three periods, as shown in Fig. 1 b: 10 min resting time, standing time from starting to 5 min, and standing time from 5 to 10 min. The average oxy-Hb, deoxy-Hb, and total-Hb levels in each period were calculated for the selected 60-second intervals (R, S1, S2) during which the variability rates were stable and oxy-Hb levels were lower. Arterial blood pressure decreased in all cases of mild and severe forms in S1. In all mild patients, recovery of arterial blood pressure was observed in S2, but such recovery was not observed in the cases of severe patients. Therefore, I divided the standing time into two groups to investigate the influence of arterial blood pressure.

Fig. 1
figure 1

(a) The rapid recovery in NIRS parameters of a 13-year-old girl with severe INOH. The delta Hb concentration changes on the left and right sides are shown in the upper and lower box, respectively. (b). The NIRS parameter changes in a 10-year-old girl with severe INOH. Interval R represents 60 s selected during the resting period. Interval S1 represents 60 seconds selected from the start of the standing period to 5 min. Interval S2 represents 60 s selected from the standing time between 5 and 10 min. “A.u” is an abbreviation for “arbitrary unit”

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The data were analyzed using Statcel 3 software (OMS Publishing Inc., Tokorozawa, Japan). Chi-square tests were used to compare the detection of rapid recovery in the left and right prefrontal cortices. Mann-Whitney U tests were used to compare the oxy-Hb changes associated with active standing between the left and right frontal cortices. Differences were considered statistically significant when the p-values were < 0.05. The average delta oxy-Hb concentrations were analyzed among three groups using the Friedman test. Differences with p-values <0.05 were considered statistically significant. Wilcoxon signed-rank test was used in addition to the Friedman test for analysis among each group. Differences with p-values <0.017 were considered statistically significant.

This study was approved by the ethical committee of Nihon University Itabashi Hospital and was in accordance with the revised version of the Declaration of Helsinki on October 3, 2008. Informed consent was obtained from all patients and their guardians.

3 Results

The increase in heart rate during standing was not significantly different between mild and severe patients (38.2 ± 13.6 vs. 39.7 ± 12.3, p = 0.78). Among the severe INOH patients, arterial pressure remained low during the active standing test.

The rate of rapid recovery detected by the NIRS parameters on the left and right sides following the initial drop in oxy-Hb at the onset of active standing was compared according to severity. The rapid recovery in bilateral prefrontal cortex of INOH patients is shown in Fig. 1 a The mild form patients showed a more significant rapid recovery on the right than the left side (46.2% vs. 22.2%, p = 0.007). Among the severe patients, there was no significant difference between the two sides (p = 0.12).

Figure 2 shows the changes in the NIRS parameters. Using each subject’s average delta oxy-Hb concentration level in the R, S1, and S2 periods, the NIRS parameters tended to show a decrease in oxy-Hb and an increase in deoxy-Hb in the bilateral prefrontal cortex in both mild and severe INOH subjects after active standing. Furthermore, oxy-Hb showed a significant decrease (p < 0.01) in the left prefrontal cortices of both mild and severe patients after standing. Oxy-Hb also showed a significant decrease in the right prefrontal cortices of mild INOH patients, but the difference was not significant in severe INOH patients. Oxy-Hb in the right prefrontal cortices of severe patients showed a greater significant increase in S2 than in S1.

Fig. 2
figure 2

Comparison of changes in NIRS parameters. There was no significant difference between the changes in oxy-Hb concentration in severe INOH patients’ right prefrontal cortex during active standing tests. (∗∗p < 0.017) “A.u” is an abbreviation for “arbitrary unit”

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4 Discussion

The change in oxy-Hb measured by NIRS is closely correlated with local cerebral blood flow [7]. Although the absolute value of oxy-Hb measured by NIRS does not directly reflect cerebral blood flow, oxy-Hb is an important indicator of cerebral oxygen metabolism.

Our results clearly demonstrated that the detection rate of rapid recovery from the initial drop in oxy-Hb at the onset of active standing was more significant in the right than the left prefrontal cortex in mild INOH patients. Absence of rapid recovery caused by impaired cerebral autoregulation is recognized as a characteristic of OD patients. Our study is the first to reveal the asymmetry of this effect.

In addition, we revealed that the NIRS parameters tend to show a decrease in oxy-Hb and an increase in deoxy-Hb in the bilateral prefrontal cortex in mild and severe INOH patients after active standing. This change suggests that neuronal activation induces relative ischemia [8]. However, severe INOH patients did not show a significant decrease in the right prefrontal cortex. Furthermore, the delta oxy-Hb concentration in the right prefrontal cortex showed a significant increase from S1 to S2, although none of the severe patients showed any recovery of arterial pressure. Oxygen metabolism of the right prefrontal cortex was maintained only in severe INOH patients.

Recently, the central autonomic network has been revealed as the center of the autonomic nervous system [9]. The network includes the insular, prefrontal cortex, amygdala, hypothalamus, and ventrolateral medulla. Right prefrontal activity plays an important role in the autonomic nerve system, particularly in sympathetic control of the heart rate [10, 11]. In INOH patients, the decrease in cardiac output when arterial pressure drops is compensated by tachycardia, and the compensation is greater in severe than in mild INOH patients [12]. However, in this study, because we did not observe a significant difference in the increase in heart rate between mild and severe patients during active standing, we could not elucidate why right prefrontal oxygenation was maintained only in severe INOH patients during active standing. Because the arterial pressure of severe INOH patients tends to decrease in daily life, their brains might become tolerant to active standing, so that strong activation of the right prefrontal cortex can maintain the oxygen metabolism of the brain.

Comparisons with healthy controls and other subtypes are lacking in our study. In addition, handedness was not revealed in our study. Therefore, we could not clarify whether these findings were associated with a dominant hemisphere.

In conclusion, right prefrontal oxygenation tends to be maintained despite decreased arterial pressure during active standing in both mild and severe INOH patients. These findings confirm that there is asymmetrical cerebral autoregulation between the right and left prefrontal cortex.