In total, 479 inpatient and outpatients with suspected clinically neuro-mediated syncope (NMS) underwent a HUTT in Ningbo Hospital, Zhejiang University from April 2016 to June 2018; 265 patients were excluded due to incomplete data, not signing the informed consent, with a negative HUTT, diagnosed with thostatic hypotension or postural orthostatic tachycardia. 214 patients with a positive HUTT were diagnosed with VVS, which performed in accordance with 2018 ESC Guidelines for the diagnosis and management of syncope . All VVS patients underwent a complete physical examination, chest X-ray, biochemical serum tests, echocardiography, and electroencephalography to exclude severe diseases related to the central nervous, cardiovascular, and metabolic systems. Then, they were followed for between 6 and 32 months. 3 patients were treated pharmacologically ( small doses of metorol or theophylline drugs, per os) , 2 patients received pacemaker treatment (just DDD pacemaker) and 34 patients were lost to follow-up during follow-up(figure 1). This study was approved by the ethics committee of ningbo first hospital and carried out in accordance with the declaration of helsinki. The data for 175 patients with a median age of 55.0 years(44.0 to 63.0 years, range from 15 to 82 years), were finally enrolled in the analysis; data from patients who were lost to follow-up or received medication or pacing were excluded from the analysis.
HUTT was strictly performed in accordance with the protocol of the European Society of Cardiology. Cardiovascular active drug treatment should be stopped using for at least 5 half-life period. Drugs and foods were avoided before the test, if not, which could affect normal autonomic nervous system function. HUTT were performed in a quiet, softly lit, temperature-controlled(20 ~ 25°C) room equipped with medical resuscitation facilities, such as defibrillation, apparatus atropine and other resuscitative drug. Ringer's solution was used to in patients who fasted for at least 4h by intravenous drip before HUTT. Clinical basic data of cerebrovascular diseases (including cerebral ischemia, cerebral infarction, epilepsy and so on), hypertension, cardiovascular disease, diabetes (including type 1 or type 2), natural course of disease and number of spells in lifetime were asked for offering.
Patients were secured to the electric st-721 head-up tilt test table with manual control board (Beijing kangjing taike medical device factory) and GE medical CASE series 12-lead synchronous ECG monitor and suntech blood pressure monitor were used for monitoring blood pressure, heart rate and rhythm. Barring a positive response or loss of consciousness, patients were tilted upritht at 70°for 20min after lying supine for at least 10 minute with record supine systolic blood pressure, supine diastolic blood pressure, and heart rate. Symptoms, blood pressure, heart rate and rhythm were recorded every 5 minute and additionally recorded every 1 minute within the begging 3 minutes to rule out orthostatic hypotension during the test. Patients were returned to a supine position as soon as the positive response occurred. The test will be terminated if HUTT is positive in basic stage and will go on with sublingual nitroglycerin HUTT.
sublingual nitroglycerin HUTT
The test process of SNHUTT was the same as that in the basic stage after the sublingual nitroglycerin administration which the baseline HUTT-negative patients received. (3/4 tablet , 0.5mg/ tablet of shandong xinyi pharmaceutical co.LTD. absorption time: usually from 2 to 5 minutes).
Syncope or pre-syncope prodrome accompanied with any of decreases in blood pressure or changers of heart rate with an electrocardiogram showing any of sinus arrest and premature junctional contractions and atrioventricular block and cardiac arrest ≥ 3 seconds was a positive HUTT response characteristic.
Positive response type for VVS(1)
- Type 1 (mixed type)
Type 1 is characterized as heart rate fall but not less than 40 beats per minute(bpm) for< 10 seconds at the time of syncope with or without asystole < 3 seconds. Bblood pressure decreases prior to the heart rate falls
- Type 2 (cardioinhibitory type) which is classified to 2 subtype.
Type 2A (without asystole)
Type 2A is characterized as a ventricular rate below 40 bpm for longer than 10 seconds and asystole<3 seconds. the blood pressure decrease occurs later than the heart rate fall.
Type 2B (with asystole)
Type 2B is characterized as that the asystole > 3 seconds occurs. The heart rate fall coincides with or precedes the blood pressure decrease.
- Type 3 (vasoinhibitory type)
Type 3 is characterized as that SBP or mean pressure decrease ≥ 20 ~ 30 mmHg or systolic BP (SBP) is ≤ 60 ~ 80 mmHg (1 mmHg = 0.133 kPa). The heart rate does not fall more than 10% from its peak value at the time of syncope.
Counseling and advice
An overview of the causes of vasovagal syncope and its overall benign outcome were informed to all patients who received advice about increasing dietary salt and fluid intake unless contraindicated. Patients were also coached on how to avoid situations that might provoke syncope such as fatigue, late night, emotional status et al. and requested for sitting down or lying to a supine position if unavoidable.
The duration of follow-up ranged from 6 to 32 months after HUTT via telephone follow-up. We one by one telephoned all patients. The patients or their parents were required to confirm recurrent syncope, which was defined as ≥ 1 syncope or typical pre-syncope prodrome that occurred during the follow-up. Patients who underwent pacing or drug therapy, such as with metoprolol during follow-up were excluded.
Recurrence of syncope is defined as the recurrence of ≥ 1 syncope or typical pre-syncope prodrome during follow-up.
All reported levels of significance are 2 sided. A P value≤0.05 was considered statistically significant. Statistical analysis was carried out with SPSS 23.0 software. Continuous variables with normal distributions are expressed as the mean ± standard deviation (SD), and comparisons of normally distributed parameters between two groups were performed with a t-test for independent samples. The nonnormally distributed parameters were reported as the median and interquartile range (25% to 75%) and compared by the Mann-Whitney U test. Categorical variables are reported as frequencies and percentages. The data were compared by the Pearson's chi-square test, and the exact probability method was used when the theoretical frequency was less than 20%. Logistics regression was used to analyze effect size and confidence interval of the individual or multiple factors with statistical significance for recurrence syncope according to the independent sample t test or the Pearson's chi-square test. The predictive performance of age was evaluated by prediction probability. The ROC curve was utilized to evaluate the predictive value of the predictors and the AUC represented the predictive value. The 95% CI of AUC did not contain 0.5 or a P value < 0.05 confirmed that the factor was a reliable predictor of recurrent syncope in VVS patients with a positive HUTT. The optimal cutoff value was determined as the maximum of the Youden index, which was defined as the sensitivity plus specificity minus 1, where sensitivity and specificity were calculated as proportions.