Introduction

Vasovagal syncope (VVS) is one of the common hemodynamic types of neurally mediated syncope [1], caused by neuroreflex-mediated bradycardia and hypotension resulting in inadequate peripheral vascular and cerebral perfusion, short-lived loss of consciousness, inability to maintain the standing position of the body and collapse.VVS has a complex etiology and can occur clinically in clusters followed by prolonged asymptomatic periods [2, 3]. VVS can have syncope or pre-syncope symptoms, and although VVS is considered a benign condition, the onset of syncope can lead to syncope related somatic accidental injuries, including causing skin abrasions, lacerations, and fractures [4]. The syncope attack is commonly triggered by the patient being in a hot and stuffy environment, standing for a long time and sudden change of position (e.g., from lying or sitting or squatting position to upright position), and may be preceded by a series of pre-syncope symptoms such as dizziness, headache, chest tightness, chest pain, palpitations, sighing, blurred vision, etc. There are three hemodynamic types of VVS in children, including VVS-vasoinhibited (VVS-VI), VVS-cardioinhibited (VVS-CI) and VVS-mixed (VVS-M) [5]. VVS-VI is the most common cause of syncope in all age groups, with VVS-CI becoming more common with age and can be severe enough to produce cardiac arrest lasting several seconds followed by resumption of sinus pacing [3, 6]. The pathogenesis of VVS-VI and VVS-CI is different. The VVS-CI pathway involves an increase in parasympathetic tone, and if the cardioinhibitory effect is only on the sinus node, the heart rate (HR) is markedly reduced; if the cardioinhibitory effect involves both the sinus node and the atrioventricular node, prolonged cardiac arrest, resulting in a rapid decrease in blood pressure (BP), may occur. Syncope occurs when systemic and cerebral blood flow is completely interrupted at extremely low BP. The VVS-VI pathway efferent pathway leads to a decrease in sympathetic tone, dilatation of arteries and veins, a concomitant decrease in peripheral vascular resistance and BP, and a concentration of blood in the lower extremities and/or visceral beds, which reduces venous return and leads to a significant decrease in stroke volume, and systemic and cerebral insufficiency of perfusion, resulting in syncope [7]. There are fewer reports in the literature on the treatment of different types of VVS in children, and individualized treatment strategies should be used for different types of VVS. Li et al. reported that VVS-VI children were better treated with oral rehydration salts than VVS-CI and VVS-M [8]. Paech et al. concluded that implantation of a permanent pacemaker in children with syncope in whom VVS-CI is predominant prevents recurrent cardiac arrest during clinical syncopal events [9].

The relationship between hemodynamic types and clinical manifestations of VVS is rarely reported in the literature. Duan et al. [10] reported that the clinical manifestations of 86 children with VVS were dizziness or headache (66.3%) and syncope (65.1%). Female, age > 12 years old, with family history or flare-up of syncope were independent risk factors for head-up tilt test (HUTT) positive. Xia et al. [11] reported that ALDH2 Glu487Lys gene polymorphism did not affect the prognosis of sublingual nitroglycerin head-up tilt test (SNHUT) induced VVS patients, and there was no significant change in hemodynamic characteristics of patients with different genotypes. Pietrucha et al. [12] reported that the type of VVS was related to HUTT model. VVS-M were common after isoproterenol stimulation and VVS-CI were common after nitroglycerin stimulation. However, the above studies lack the correlation between different hemodynamic types of VVS and the clinical manifestations of syncope.

This research aims to retrospectively analyze clinical data of 2513 cases of pediatric VVS in a single center over 20 years, to explore the relationship between the hemodynamic type of VVS and the presence of syncopal symptoms, and to avoid the risk of syncopal symptoms in pediatric VVS through clinical guidance, so that pediatric VVS who are not experiencing syncopal symptoms can reduce syncopal-related physical accidents and improve their quality of life.

Materials and methods

Study population

From January 2001 to December 2021, 2513 children with unexplained syncope and pre-syncope symptoms (such as dizziness, headache, chest tightness, chest pain, palpitations, sighing, blurred vision, etc.) were visited in the Department of Pediatric Cardiovasology, The Second Xiangya Hospital, Central South University, and they were diagnosed as VVS, age 3–18 years, mean age was 11.76 ± 2.83 years, male 1124 cases, female 1389 cases.

Informed consent was signed by the subjects themselves or their legal guardians before HUTT. This research was approved by the Medical Ethics Committee, The Second Xiangya Hospital, Central South University, and conforms to the principles stated in the Declaration of Helsinki. [Ethical Audit No. Study K034 (2021), Oct 27, 2021].

Inclusion and exclusion criteria

From January 2001 to December 2021, a total of 6364 children aged 3–18 years with unexplained syncope or pre-syncope were recorded to have been visited in the Department of Pediatric Cardiovasology, The Second Xiangya Hospital, Central South University.

After detailed history questioning, physical examination, and electrocardiogram (ECG), Holter ECG, echocardiography, electroencephalogram, head MRI/CT and fasting glucose, cardiac enzymes, liver and kidney functions, 3851 children with syncope or pre-syncope caused by organic diseases such as heart, kidney and brain, immune and metabolic diseases and children who were unable to complete the HUTT were excluded.

Finally, a total of 2513 children who met the diagnostic criteria of VVS after HUTT examination were included. They were divided into syncope group (1262 cases) and pre-syncope group (1251 cases) according to whether they had syncopal symptoms.

HUTT

Subjects discontinued cardiovascular active drugs for more than 5 half-lives prior to the test [3], as well as discontinued intake of foods that may affect autonomic function. Fasting and abstaining from drinking 4 h before the test. Subjects or guardians were briefed on pre-test precautions and possible risks during the test, and written informed consent was signed by the subjects themselves or their legal guardians. HUTT was divided into basic head-up tilt test (BHUT) and SNHUT, and the test procedures were completed according to the guidelines [5].

Diagnostic criteria for VVS

The presence of syncope or pre-syncope with one of the following in HUTT is considered positive for VVS: (1) a decrease in BP: systolic blood pressure (SBP) ≤ 80 mmHg or diastolic blood pressure (DBP) ≤ 50 mmHg or a decrease in mean blood pressure ≥ 25%); (2) a decrease in HR: < 75 beats/min at 3–6 years, < 65 beats/min at 6–8 years, and < 60 beats/min at 8 years or older); (3) sinus arrest; (4) atrioventricular block and cardiac arrest of up to 3 s.

VVS hemodynamic type

(1) VVS-VI: predominantly a decrease in BP with no significant change in HR. (2) VVS-CI: predominantly a decrease in HR with no significant change in BP. (3) VVS-M: a decrease in both HR and BP.

Statistical analysis

If the continuous variable was normally distributed, it was expressed as mean ± SD. Categorical variables were expressed in frequency or as a percentage. χ2 (categorical variables), Student’s t test (normal distribution), and multiple Logistic regression were used to analyze the possible association between hemodynamic type and syncopal symptoms. We constructed two models to illustrate the stability of this relationship. All the analyses were performed with the statistical software Packages R (version 3.6.1) (http://www.R-project.org., The R Foundation) and EmpowerStats (http://www.empowerstats.com., X & Y Solutions, Inc, Boston, MA). P values < 0.05 (two-sided) were considered statistically significant.

Results

Comparison of basic characteristics between syncope group and pre-syncope group in pediatric VVS and univariate analysis for presence of syncopal symptoms

A total of 2513 children with VVS were enrolled in this research, 1124 males (44.73%). Age, height, weight, SBP, and DBP increased in the syncope group compared with the pre-syncope group; the composition ratio of females was more than that of males in the syncope group; and the composition ratio of VVS-CI and VVS-M was more in the syncope group than that of the pre-syncope group (all P < 0.05) (Table 1). Age, height, weight, SBP, DBP, female, VVS-CI, and VVS-M were potential risk factors for the presence of syncopal symptoms (all P < 0.05) (Table 2).

Table 1 Comparison of basic characteristics between syncope group and pre-syncope group in pediatric VVS [mean ± SD, n (%)]
Full size table
Table 2 Univariate analysis for presence of syncopal symptoms [mean ± SD, n (%)]
Full size table

Comparison of multiple Logistic regressions of the relationship between hemodynamic type of VVS and the presence of syncopal symptoms

We established two models to illustrate whether the effect of hemodynamic type of VVS on the presence of syncopal symptoms existed independently. By adjusting for sociodemographic factors (model I), the models showed stable effect values (OR changes < 10%) compared to the univariate results; we then added adjustments for the remaining confounding factors (model II), and the effect values remained stable (OR changes < 10%), which means VVS-CI and VVS-M were independent risk factors for the presence of syncopal symptoms, with an increased probability of 203% and 175%, respectively, compared to VVS-VI (all P < 0.01) (Table 3).

Table 3 The relationship between hemodynamic type of pediatric VVS and presence of syncopal symptoms
Full size table

Discussion

The three hemodynamic types of VVS during HUTT present as a decrease in BP alone (VVS-VI), a decrease in HR alone (VVS-CI), or a decrease in both BP and HR (VVS-M). Our research found that VVS-M and VVS-CI had a higher risk of syncopal symptoms than VVS-VI. Although the rate of VVS-CI is lower, it is a type with a higher risk of syncope in children, and once syncope occurs, patients may also suffer from malignant arrhythmias and convulsions [13, 14], which can be life-threatening in severe cases, so early identification and diagnosis of VVS subtypes are clinically significant to improve the quality of life and prognosis of children.

The prevalence of VVS-VI is high in pediatric VVS (approximately 54–67%) [15, 16], and the results of our results VVS-VI accounted for 74%, indicating that VVS-VI is a common subtype of VVS in children. However, Xu et al. [16] reported that VVS is more common in adults with VVS-M, which may be related to the fact that adults tolerate and comply better than children during HUTT and can persist until typical changes in BP and HR occur before terminating the test process. Since the development of the autonomic nervous system in children needs to be further improved and is prone to autonomic dysfunction, the HUTT process in children is not effective in observing the hemodynamic parameters as soon as clinical symptoms appear and the monitoring parameters reach the diagnostic conditions, in order to avoid the possible risks after HUTT-induced syncope, when the technician terminates the test process while paying close attention to the clinical manifestations and ECG and BP parameters of late significant changes [17].

Syncope occurs in relation to age. There are also age differences in the hemodynamic response of patients with neurally mediated syncope. Li et al. [18] reported that the young people with VVS are prone to excessive increase in HR and to stimulate the development of VVS-VI (P < 0.01); the elderly are prone to variable temporal insufficiency, impaired autonomic response and poor stability of cardiac electrical activity, and are associated with the development of VVS-M. Holmegard et al. [19] reported that patients with VVS-CI had increased BP, diminished hemodynamic responses, and reduced autonomic regulation compared to VVS-VI. In addition, VVS-CI patients also showed sympathetic predominance in the regulation of autonomic responses. Our data in this study showed an increase in the age of the syncope group and an increase in the composition ratio of VVC-CI and VVS-M compared to VVS-VI, which may be related to the inability of the developing cardiovascular system in children to provide the blood volume required for growth and development, leading to compensatory sympathetic activation, followed by parasympathetic activation, which is more persistent, and an increase in the instability of the electrical activity of the heart in patients with VVS-CI and VVS-M types of syncope, which ultimately leads to the onset of syncope [10].

The present results further suggest that in VVC-CI and VVS-M, which have a high risk of syncope, the risk of syncopal symptoms is increased by 203% and 175% in VVS-CI and VVS-M, respectively, compared with VVS-VI, but the risk of syncopal symptoms is less in VVS-M than in VVS-CI, which may be related to the fact that the two types of hemodynamic parameters are altered differently. When VVS-CI is present, the electrical activity of the heart is disturbed, the systolic function and diastolic function of the heart are reduced, the return blood volume is decreased, cardiac stroke volume is reduced, insufficient blood supply to the brain and causing syncope. In the case of VVS-M, there is an increase in cardiac inhibition and a decrease in both cardiac return and stroke volume, while there is excessive vasodilation, which “siphons” blood from the distant parts of the vessels and results in a less pronounced change in intravascular volume, thus reducing the risk of syncope due to reduced cerebral blood supply compared to VVS-CI.

VVS-CI children with increased QT dispersion (QTd) are prone to cardiac electrophysiological disturbances [20], and the optimal cutoff value of QTd at 28.5 ms has a sensitivity of 86.30% and specificity of 84.95% for the diagnosis of VVS-CI children. HUTT monitoring of catecholamines in patients with VVS-CI revealed a greater percentage increase in epinephrine levels than norepinephrine in the 4 min before syncope [21].

Correlation analysis of adenylate cyclase activity, BP, and pulse rate changes during monitored HUTT, BP, pulse rate, and adenylate cyclase activity were higher in VVS-VI patients than in healthy volunteers, SBP decreased in VVS-VI patients after 5 min of HUTT, and adenylate cyclase activity was highest and SBP lowest at 10 min. It is suggested that standing for more than 10 min in syncope patients may increase the risk of VVS-VI. It is believed that high SBP and increased adenylate cyclase activity at rest can lead to syncope in patients with VVS-VI [22]. Hermosillo et al. [23] found a 59% decrease in diastolic cerebral blood flow velocity and a 12% decrease in systolic cerebral blood flow velocity during HUTT in VVS patients with induced syncope. In addition, altered plasma human growth factor profiles in children with VVS, such as increased plasma hepatocyte growth factor (HGF) and insulin-like growth factor binding protein (IGFBP-1) plasma concentrations and decreased plasma epidermal growth factor (EGF) are also associated with clinical syncope symptoms [24].

Limitations

The associations between different hemodynamic types of VVS and syncopal symptoms investigated in this research are based on HUTT-induced, whereas syncopal symptoms in pediatric VVS clinically are often influenced by a variety of triggers, such as prolonged standing, sudden changes in body position (e.g., such as sudden changes from suping or sitting or squatting to upright position), and stuffy and hot environments. Therefore, the results of this research cannot completely simulate the hemodynamic changes of naturally occurring pediatric VVS caused by different triggers, but the relationship between different hemodynamic types and syncopal symptoms in HUTT-induced pediatric VVS may provide a reference for clinical diagnosis and treatment.

Conclusion

In this research, the hemodynamic types of VVS were strongly associated with the presence of syncopal symptoms, and the risk of syncopal symptoms was significantly increased in VVS-CI and VVS-M types of pediatric VVS. Clinical attention should be paid to patients who experience a decrease in HR or a concomitant decrease in BP during HUTT, and such children with VVS should have enhanced health management and individualized treatment plans to reduce the occurrence of syncope and its associated unintentional somatic injuries [25].