This prospective cohort study included only patients with pure reflex syncope, without other co-morbidities. Cases were selected among the young male candidates for military services, who were referred to a military medical care unit in Tehran, Iran. We used the census method for sampling. The aim of the TTT was differentiating the reflex syncope from delayed orthostatic hypotension [15]. However, a relatively rapid normal tilt study or a concomitant drop in heart rate can be quite suggestive of “pure” syncope. Since, neither the magnitude of bradycardia nor the definition of “rapid” drop in blood pressure have been established, we used the time frame of less than 3 minutes, thus, reducing the possibility of misdiagnosing delayed orthostatic hypotension.

Therefore, inclusion criteria included a history of abrupt syncope (loss of consciousness and postural tone). We excluded patients with associated Orthostatic Hypotension (OH), Postural Tachycardia (POTS), and diabetes, known small fibre neuropathy, Parkinson’s disease or any disorder known to be associated with a dysautonomia. We divided fainters into Group 1 (TTT with spray) and Group 2 (TTT with pearl), with simple randomization. In addition, we selected a control group from among cases with the similar complaint, but TTT was performed in these cases who were not on any provocation medications. This means that we had 3 groups ; 1- 50 cases who received TNG spray, 2- 60 cases who received TNG pearl, 3- 50 controls who did not receive any medications.

Subjects were initially asked to lie supine for a period of at least 5 minutes. Thereafter, they were tilted to an angle of 70 degrees by using a tilt table.This was then sustained for a period of 40 minutes or until a syncopal or pre–syncopal symptom occurred.Blood pressure and heart rate were recorded by a non-invasive monitor and external electrocardiograph tracing. In negative subjects, test continued with pharmacological provocation (spray or pearl TNG) according to group 1 or 2. (0.4 mg)The patients were questioned for symptoms such as feeling hot, nausea or dizziness. These symptoms were clinically correlated with a diagnosis of reflex syncope and recorded time of onset in each subject [13–17].

Subjects provided informed consents prior to all testing. Blood pressure was also monitored (in the contra lateral arm) using a standard blood pressure monitor over the arm.

SPSS for Windows 15.0 was used for statistical analysis. The descriptive statistics were presented as frequencies and percentages. Kolmogroff-Smirnov was used for checking normal distribution in quantitative variables.The differences between two groups for dichotomous variables were examined by Chi-square test and ANOVA test was used for comparing the quantitative variables in a qualitative variable with 3 or more groups. A p-value of <0.5 was accepted as statistically significant.

All cases and controls were males. This was because, our clinic, Baqiyatallah University Hospital, Tehran, IR Iran, is a referral centre for military service personnel who are referred to be screened for cardiovascular diseases. Demographic data have been arranged in [Table/Fig-1] in terms of groups. The mean age between three groups was not statistically significant (p>0.05) and it was declared that these groups were matched for this important confounding factor. In the pearl and spray groups, only 10% of subjects had fainted on not using provoking drug, while 8% of subjects had fainted on not using provoking drug among controls. After using drugs, 36.6%, 96% and 18% showed positive results in pearl, spray and control groups, respectively (p<0.05) [Table/Fig-2].

Syncope prevalence is higher in the younger age group and reflex syncope is the most common cause [7]. The term, ‘reflex syncope’ refers to a heterogeneous group of functional disturbances characterized by episodic vasodilatation and or bradycardia, leading to loss of blood pressure and cerebral hypo-perfusion [10,15].

A change in posture versus common setting, such as straining, dehydration, emotional or physical distress, etc. may be the most inciting factor [15–19]. In contrast, orthostatic hypotension (defined as reduction of systolic or diastolic blood pressure within 3 minutes of assuming the erect posture) occurs with greater frequency in the population aged 65 years and older [20,21].

It seems that a 40 minute tilt table test using sub–lingual spray form of nitrate (0.4 mg) may be associated with false positive results. This means that, if the patients of other groups are exposed to TNG spray, they may show a positive test results, although for approving this hypothesis, a cross over clinical trial study involving suspected cases divided into two groups, who both will be examined with spray and pearl, is required. This high positive result in spray group can be due to rapid absorption of TNG spray via sublingual mucosa. Thus, this form of nitroglycerin should not be used for diagnosis of neuro-cardiogenic syncope. Pearl form of this agent showed better results and it can be used for this property. Using this form of TNG seems to be not useful for distinguishing and diagnosing vasovagal shocks, especially in subjects referred for military service capacity.

“The sensitivity of passive tilt table testing had been variously reported to be 19% to 69% [22–24].” Some medications such as TNG and Isoprenaline were suggested for provocation of vasovagal symptoms in TTT [24]. TNG is recommended for TTT due to its safety and availability [25].

A TTT is routinely started with a passive phase to declare the possibility of symptoms without pharmacological interventions. Then, drugs are prescribed to accelerate the appearing symptoms. In our study, the result of this phase was similar in three groups and this can be due to similarity in properties of cases.

A higher rate of positivity of TTT has been reported with more aggressive protocols, shorter interval between the last episode and the test, younger age, increasing severity of syncopal attacks, and female sex. Most of these factors were controlled in our study and the differences in our results may have occurred because of the differences between drugs [24].

Nevertheless, there are some study limitations which restricted this research from being concluded definitely. We excluded all the patients who had known cause of dysautonomias, in an attempt to select a very pure population of patients with reflex syncope only. As a result, these findings do not apply to patients with dysautonomias who happen to faint, but only to patients who experience syncope in the absence of an underlying autonomic disorder. Finally, since we do not perform tilt table tests for longer than 40 minutes, we do not know how many additional patients would have fainted in longer time frames without use of provocation agents.We performed TTT on each group one time, although it is better to perform this test with two forms of TNG and then compare both results. This is the main limitation which restricted this research from calculating false positives for each form of TNG.