The predictive value of low urine specic gravity in the diagnosis of vasovagal syncope in children and adolescents

Vasovagal syncope (VVS) is a kind of common neurogenic syncope in children and adolescents. Decreased blood volume is one of the pathogenesis of VVS. The study will explore the predictive value of low urine specic gravity (USG) in the diagnosis of VVS in children and adolescents.


Results
The USG of VVS group was signi cantly lower than that of the control group (P < 0.01). The sensitivity and speci city of USG prediction in the diagnosis of VVS were evaluated by ROC curve. The area under the ROC curve was 0.751, standard error was 0.035, and 95% CI (0.683, 0.819) suggested that USG was of moderate predictive value in the diagnosis of VVS. Setting USG as < 1.0185, the sensitivity and speci city and diagnostic coincidence rate of VVS were 74.39%, 66.04% and 69.68%, respectively.

Conclusion
Low USG has predictive value in the diagnosis of VVS in children and adolescents.

Background
Vasovagal syncope (VVS) is a kind of common neurogenic syncope in children and adolescents, tends to occur in the long standing, a sudden position change (eg. from the squat or sitting position suddenly to the standing position), and stuffy environment, etc. The process of syncope can lead to falling blood pressure and/or slow heart beat, characterized by transient and self-limited consciousness disorders due to transient cerebral insu ciency of blood supply, accompanied by falling down to the ground because of loss of muscle tone which maintains body posture [1]. The incidence of VVS is closely related to the low blood volume in patients [2], and low blood volume can cause vasovagal re ex. When VVS happens, volume load of left ventricular is reduced, returned blood volume is decreased and ventricle is under lling, causing hyperexcitability of sympathetic nerves, excess shrinking of cardiac ventricle, stimulation of the mechanical baroreceptor in the posterior inferior wall of the left ventricle, transmitting excitement to the brain stem, triggering diminished sympathetic activity and raised vagal activity, leading to abnormal bradycardia, decreased peripheral vascular resistance, fall of blood pressure and cerebral hypoperfusion, nally resulting in syncope. Generally, 24 h-urinary sodium of VVS patients decreased [3], and 24 h-urinary sodium is correlated with the severity of VVS. The lower the 24 h-urinary sodium is, the more severe the VVS symptoms are [4]. Therefore, measures to increase water and salt intake should be taken in treatment [5][6][7]. The diagnosis of VVS is mainly based on head-up tilt table test (HUTT), but temporary aphasia, severe arrhythmia, convulsions, psychological fear and other complications may easily occur when HUTT induces syncope [1], and thus HUTT could only be carried out in larger hospitals. To nd a simple and safe VVS diagnosis method can improve the VVS diagnosis e ciency of children and adolescents in primary hospitals.
Urine speci c gravity (USG) is under the condition of 4℃ the ratio weight of the urine to the pure water with the same volume, it depends on the concentration of the urinary solute, and is proportional to the total solids. The USG of normal people may uctuate due to differences in diet, water drinking, sweating and urination. The USG of infants is usually lower than that of adults. Under pathological conditions, urine contains more proteins, glucose, ketone bodies and various cells, which increase the USG. Clinically, the USG can be used to judge the uid status in human body [8], predict the incidence of acute ischemic stroke [9], early evaluate the hydration status of workers in extremely low humidity environment [10], identify diabetes patients with polyuria or diabetes insipidus and also as a monitoring index for the risk of urinary calculi, for example [11], the occurrence of urinary calculi can be reduced if the USG is maintained at a low level [12]. Given that the relationship between urinary speci c gravity and VVS in children and adolescents has not been reported, the objective of this study was to discuss the predictive value of USG in the diagnosis of VVS in children and adolescents.

Study population
From September 2014 to September 2018, 97 cases of children and adolescents (43 males and 54 females, aged from 4 to 16 years old, with an average age of 10.9 ± 12.18 years old, including 5 cases aged from 4 to 6 years old, 70 cases aged from 7 to 12 years old, and 22 cases aged over 13 years old), hospitalized in the Department of Pediatric Cardiovasology, The Second Xiangya Hospital, Central South University, due to unexplained premonitory syncope or syncope were selected. After detailed enquiry of medical history, physical examination, blood biochemical examination (including fasting blood glucose, myocardial enzyme, etc.), routine electrocardiogram, dynamic electrocardiogram, chest X ray lm, echocardiography, EEG and head MRI examination, etc. excluding the organic diseases of nervous system and circulatory system, and drug in uences, etc. They were diagnosed with VVS through HUTT which was carried out after adequate communication with and written informed consent from the receivers or guardians (VVS group). During the same period, 91 cases of children and adolescents were randomly examined for health in the Outpatient Department of Child Health Care in our hospital were matched as the control group, 45 males and 46 females, aged from 5 to 15 years old, among which 3 were less than 7 years old, 64 were from 7 to 12 years old, and 24 were more than 13 years old.
The informed consent was obtained from all the subjects directly or their guardians prior to enrollment.  cardioinhibitory, or mixed type. The vasoinhibitory type is characterized by a signi cant BP decrease without obvious HR reduction, the cardioinhibitory type is characterized by a marked HR decrease without marked decrease in systolic pressure, and the mixed type is characterized by both HR and BP decrease [1].

Statistical methods
The SPSS 22.0 software was used for statistical analyst, the measurement data were expressed as mean ± standard deviation (), and t test was used for comparison between groups. The receiver operating characteristic curve (ROC) was adopted to evaluate the sensitivity and speci city of urinary speci c gravity in predicting VVS and area under the curve (AUC) indicated the predictive ability of USG. AUC of 0.5 ~ 0.7 indicates low predictive ability, 0.7 ~ 0.9 is moderate predictive ability, and > 0.9 indicates high predictive ability. α = 0.05 was used as the test standard, then P < 0.05 was considered statistically signi cant in difference.

Results
3.1 There was no statistical signi cance difference in age (10.91 ± 2.18 years vs. 11.07 ± 2.02 years, t = 0.517, P > 0.05) between the VVS group and the control group, and the USG of VVS group was signi cantly lower than that of the control group (1.0159 ± 0.0067 vs. 1.0225 ± 0.0069, t = 6.747, P < 0.01), as shown in Fig. 1. 3.2 ROC curve: The receiver operating characteristic curve (ROC) was used to evaluate the sensitivity and speci city of urinary speci c gravity in predicting VVS. The area under the ROC curve was 0.751, standard error was 0.035, and 95% con dence interval (0.683, 0.819) suggested that USG had a moderate predictive value for the diagnosis of VVS. Setting USG as < 1.0185, the sensitivity and speci city and diagnostic coincidence rate of VVS were 74.39%, 66.04% and 69.68%, respectively. as shown in Fig. 2.

Discussion
USG and urine color are widely used in clinical practice [13]. USG can monitor the internal uid status of athletes. And Wilcoxson et al [8] reported that dynamic monitoring of USG had a good effect on uid retention and hydration in male runners. Osterberg et al [14] covered that USG was used to determine the pregame uid intake of American Basketball Association (NBA) athletes, when pregame USG was ≤ 1.020, athletes should be ensured to supply adequate water. Zubac et al [15] also took USG as the most commonly used biochemical index to monitor athletes' uid de ciency. And Stover et al [16] found that the USG of exercisers did not change with time and place before physical exercise. If the USG of exercisers was ≥ 1.020, it suggested that 46% of exercisers might be dehydrated.
Patients with VVS are at low blood volume status. El-sayed et al [17] conducted a double-blind randomized controlled study with oral rehydration salts (ORS) treatment on 20 VVS adult patients and found that, after more than 2 months of follow-ups, the clinical symptoms of VVS patients were signi cantly improved, especially in patients with previous salt intake < 170 mmoL/d, their blood volume increased and so did their tolerance to erectness, with more apparent symptoms improvement. Younoszai et al [18] gave oral isotonic saline intervention to 58 VVS children, and 90% (52/58) of the children had complete relief of symptoms, suggesting that oral liquid therapy was effective in treating VVS children. Li et al [19] reported that 178 cases of children with neurally-mediated syncope were followed up after nondrug treatment (health education, ORS, vertical training, etc.) as the main intervention measure, and found that subjective symptoms were signi cantly improved (100%). The rate of HUTT's conversion to negative or improvement was 72.47% (129/178 cases), and 98.88% (176/178 cases) of children had good treatment compliance. Zhu et al [20] reported 146 cases of children with orthostatic intolerance. On the basis of health education, ORS treatment was given for 14 ~ 180 days [mean (39.77 ± 31.92) days], the total clinical subjective e cacy was 78.8% (115/146 cases), and HUTT's total conversion rate was 39.0% (57/146 cases), suggesting that ORS treatment could extend the time of orthostatic intolerance in children with neurally-mediated syncope.

Conclusion
This study showed that the urinary speci c gravity of VVS children and adolescents was signi cantly lower than that of healthy control children (P < 0.01). The receiver operating characteristic curve (ROC) was used to evaluate the sensitivity and speci city of the predictive value of urinary speci c gravity in the diagnosis of VVS, and the area under the ROC curve was 0.751, indicating that the USG had a moderate predictive value in the diagnosis of VVS in children and adolescents. USG < 1.0185 was as the boundary point, the sensitivity and speci city and diagnostic coincidence rate of VVS were 74.39%, 66.04% and 69.68%, respectively. The results of this study suggested that the urine speci c gravity index could better re ect the amount of water in VVS children and adolescents, and the decrease of USG of VVS children re ected the previous research results on the pathogenesis of insu cient capacity load in the body, which guided patients to increase the intake of water and salt in clinical practice, and the effect of supplemental water and salt could be monitored by the USG [21]. Therefore, it appeared the monitoring method of USG is simple, practical and has certain predictive value for the diagnosis of VVS in children and adolescents.

Funding
The authors received no nancial support for the research, authorship, and/or publication of this article.

Availability of data and materials
There are no linked research data sets for this submission. The following reason is given: Data will be made available on request.

Ethical Approval and consent to participate
The informed consent was obtained from all the subjects directly or their guardians prior to enrollment. The study protocol was approved by the Ethics Committee of the Second Xiangya Hospital, Central South University.

Consent for publication
Participants agreed in writing to publish the data without personal privacy.

Competing interests
The authors have no con icts of interest to disclose.  ROC Curve on the Predictive Value of USG in the VVS Diagnosis in Children and Adolescents. Notes: ROC curve on the predictive value of VVS diagnosis in children and adolescents with USG as the cut-off value. The vertical axis denotes the sensitivity of USG to the predictive value of VVS diagnosis, and the horizontal axis indicates the false positive rate (1-speci city), the solid line of 45°coordinate in the gure is criterion-referenced line, indicating that the sensitivity and the false positive rate is equal, no predictive value. The farther the curve is to the upper left of the reference line, the higher the predictive value is. The area under the curve (AUC) represents the predictive value of USG in the diagnosis of VVS. The AUC value of 0.5 ~ 0.7 is low, 0.7 ~ 0.9 is medium, and > 0.9 is high.