Compression Stockings to Combat Vasovagal Syncope: What Is the Rationale? M. MADALOSSO, F. GIADA, A. RAVIELE

Introduction Syncope is defined as a sudden, transient loss of consciousness and postural tone due to cerebral hypoperfusion, followed by spontaneous recovery [1]. Syncope is a common symptom that affects up to 35–50% of the general population: it is the reason for 1–3% of emergency room visits and 1–6% of hospital admissions [2]. Syncope may have different causes: cardiovascular, noncardiovascular and unexplained. The most frequent type of syncope is the vasovagal syncope, who accounts at least 35% of loss of consciousness.

Physiopathology of Vasovagal Syncope The vasovagal faint is a heterogeneous condition and may be triggered by central stimuli (pain, extreme emotions, psychic stress) and peripheral stimuli (reduction in venous return to the heart, such as in prolonged standing, hot environments, hypovolaemia, or redistribution of blood volume). In daily life vasovagal syncope is common while the subject is standing [3]. On standing, the increased gravitational forces results in pooling of 500–800 ml of blood in the distensible veins below the level of the heart, i.e., the veins of the legs and the splanchnic veins, thus reducing venous return to the heart. This leads to a decrease in arterial blood pressure and cardiac output. In normal subjects there is an autonomic compensatory reflex that keeps the arterial blood pressure and the cardiac output almost normal, through vasoconstriction and tachycardia, due to sympathetic activation and parasympa-

Division of Cardiology, Cardiovascular Department, Umberto I Hospital, MestreVenice, Italy

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thetic withdrawal, respectively. In patients who are prone to vasovagal syncope, this compensatory reflex is inadequate. Hargreaves and Muir [4] demonstrated, during orthostatic challenge, a larger increase in calf volume in patients with recurrent vasovagal syncope and a trend to greater peripheral blood pooling and reduced venous volume variability than in normal subjects. It has been postulated that, in patients with vasovagal syncope, the reduction of venous return activates an abnormal reflex, similar to the Bezold–Jarisch reflex, triggered by a vigorous contraction of an almost empty ventricular cavity. It activates intramyocardial mechanoreceptors inappropriately (the unmyelinated vagal C fibres), causing paradoxical sympathetic inhibition (peripheral vasodilation) and parasympathetic activation (bradycardia) with cerebral hypoperfusion and syncope [5]. However, the pathophysiology of vasovagal syncope is probably not so schematic, and other potential mechanisms may be responsible for this condition, such as afferent signals arising from atrial or pulmonary baroreceptors, or even from higher central nervous system centres.

Treatment of Vasovagal Syncope In the majority of subjects vasovagal syncope is a benign condition that does not represent a threat to life and does not significantly impair quality of life. Consequently, a specific treatment is usually not indicated, and recurrence may be easily prevented by reassurance and counselling of the patient. In a minority of subjects, however, the syncopal episodes are much more frequent and often occur in the absence of predictable circumstances or warning symptoms. These episodes may be accompanied by physical injury and represent the so-called ‘malignant’ or ‘atypical’ vasovagal syncope. In these cases, as also in patients with a potential occupational hazard (pilots, truck drivers, commercial painters, roofers, and so on), a specific treatment is generally recommended. Many forms of treatment are promoted for vasovagal syncope: non-pharmacological/physical, pharmacological, and electrical. None of them has been demonstrated to be surely effective in preventing syncopal recurrences. The substantial inefficacy of currently available therapeutic options for patients with recurrent or malignant vasovagal syncope justifies the search for alternative treatments.

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Compression Elastic Stockings One of the measures suggested in the past for the treatment of vasovagal syncope, but never tested with clinical studies, is the use of compression elastic stockings. The rationale for this therapy is the reduction in venous pooling and the increase in venous return that compression elastic stockings may induce. Several studies have investigated the haemodynamic and clinical effects of this therapy in different clinical settings, but to the best of our knowledge no studies have been performed to evaluate the effects of compression elastic stockings in patients with vasovagal syncope. Buhs et al. [6] studied healthy subjects during daily activity that requires nearly continuous standing and walking: under those conditions, it has been shown that graduated elastic stockings had a direct anatomic effect which can be related to the transmural pressure in the veins that preserve dilation in the deep, superficial, and perforating venous system of the lower leg. In patients with chronic venous insufficiency, compression elastic stockings have been shown to reduce the residual volume fraction, which is an indicator of improving calf muscle pump function and reflux in vein segments [7]. These favourable effects of compression elastic stockings in patients with chronic venous insufficiency seem to be a consequence of shifting blood from the superficial to the deep venous compartment of the legs [8]. This promotes venous return to the heart by means of blood milking caused by muscle contraction [9–17]. In patients with orthostatic hypotension caused by adrenergic failure, compression elastic stockings reduce the decrease in standing blood pressure by increasing total peripheral resistance and reducing venous capability [18]. In daily life this leads to a reduction of hypotension-related symptoms, such as dizziness and increased heart rhythm, and an improvement in quality of life [19].

Stic Stoc Trial On the basis of these observations, we have planned a multi-centre, randomised, placebo-controlled study, the ‘ElaSTIC STOCkings for the prevention of recurrent vasovagal syncope TRIAL’ (Stic Stoc Trial).

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Aim of the Study The aim of the study is to ascertain whether, among patients suffering from recurrent vasovagal syncope, compression elastic stockings reduce the number affected by syncope recurrences, prolong the time to the first recurrence, and improve quality of life.

Study Design Enrolled patients will be randomised to active treatment (compression elastic stockings) or placebo (non-compression stockings). The compression elastic stockings exert a pressure of 20–30 mmHg around the calves, which corresponds to class II of the European CEN classification [17]. The inactive treatment, the placebo, looks like the elastic compression stockings, but does not exert haemodynamic effects. The clinicians, nurses, and enrolled patients will be blinded to the type of stockings being worn.

Inclusion and Exclusion Criteria To be enrolled, patients will have to meet the following criteria: vasovagal syncope and positive head-up tilt testing; at least 6 syncopal events in the patient’s lifetime, the latest occurring no more than 6 months before enrolment. The following constitute exclusion criteria: non-vasovagal syncope; chronic venous and arterial insufficiency ; recent (< 6 months) acute myocardial infarction; chronic severe non-cardiac diseases (terminal neoplasia, neurological disease, etc.); pregnancy.

Other Therapies During the study period, the use of pacemakers or drugs for the prevention of vasovagal syncope, such as β-blockers, α1-agonists, fludrocortisone, serotonin uptake inhibitors, theophylline, and scopolamine, will not be allowed.

Quality of Life The patient’s quality of life will be evaluated through a questionnaire (SF-36) filled out before treatment and again after 6 and 12 months.

Follow-Up During follow-up, with a mean duration of 12 months, each enrolled patient will wear the stockings during the day time. Patients will be asked to keep a clinical diary, specifying the number, severity, and time of syncopal and presyncopal events, the circumstances in which they occur, and any associated traumas. Patients also have to report the days in which they do not wear the

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stockings, the reason why, and any adverse effects. Every 3 months, patients will be clinically assessed.

Primary Endpoint The primary clinic endpoint will be syncope, since this can be easily assessed and has been successfully used in previous studies. Patients are examined within 7 days of a fainting episode. To verify the syncopal episode, patients and witnesses are asked to describe the event and the circumstances in which it occurs, stating in particular whether there was complete loss of consciousness. Patients are also examined to evaluate any severe trauma resulting from the event. The number of patients who experience syncope during follow-up, the frequency of syncope (number of times per month), and the time to first recurrence are taken as the parameters to measure the primary clinical event.

Secondary Endpoints The secondary endpoints will be the following: (1) the number of patients with pre-syncopal recurrences, the frequency of pre-syncopal events, and time to the first pre-syncopal recurrence; (2) quality of life.

References 1.

2. 3. 4. 5.

6.

7. 8.

9.

Brignole M, Alboni P, Beneditt DG et al for the Task Force on Syncope, European Society of Cardiology (2004) Guidelines on management of syncope-up date 2004. Europace 6:467–537 Linzer M, Pontinen M, Gold GT (1991) Impairment of physical and psychosocial function in recurrent syncope. J Clin Epidemiol 44:1037–43 Baron-Esquivias G, Errazquin F, Pedrote A et al (2004) Long-term outcome of patients with vasovagal syncope. Am Heart J 147:883–889 Hargreaves AD, Muir AL (1992) Lack of variation in venous tone potentiates vasovagal syncope. Br Heart J 67:486–490 Raviele A, Brignole M, Menozzi C (1997) Development of an implantable drug delivery system for the treatment of vasovagal syncope: a dream or a real prospect? In: Raviele A (ed) Cardiac Arrhythmias 1997, Springer, Milan pp 422-427 Buhs CL, Bedick PJ, Glover JL (1999) The effect of graded compression elastic stockings on the lower leg venous system during daily activity. J Vasc Surg 30:830–835 Eberhardt RT, Raggetto JD (2005) Chronic venous insufficiency. Circulation 111:2398–2409 Gamble J, Christ F, Gartside IB (1998) Human calf precapillary resistance decreases in response to small cumulative increases in venous congestion pressure. J Physiol 507:611–617 Ibelguna V, Delis KT, Nicolaides AN et al (2003) Effect of elastic compression stockings on venous hemodynamics during walking. J Vasc Surg 37:420–425

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10.

Agu O, Backer D, Seifalian AM (2004) Effect of graduated compression stockings on limb oxygenation and venous function during exercise in patients with venous insufficiency. Vascular 12:69–76 Bellard E, Fortrat JO, Dupuis JM et al (2003) Hemodynamic response to peripheral venous congestion in patients with unexplained recurrent syncope. Clin Sci 105:331–337 Mayberry JC, Moneta GL, De Frang RD et al (1991) The influence of elastic compression stockings on deep venous hemodynamics. J Vasc Surg 13:91–100 Kierkegaard A, Norgren L (1992) Compression stockings and venous function in patients with decompensated heart failure. Phlebology 7:117–120 Belcaro G, Laurora G, Cesarone MR et al (1992) Elastic stockings in diabetic microangiopathy. Vasa 21:193–197 Evers EJ, Wuppermann Th (1999) Effect of different compression therapies on the reflux in deep veins with post-thrombotic syndrome. Vasa 28:19–23 Gamble J, Christ F, Gartside IB (1998) Human calf precapillary resistance decreases in response to small cumulative increases in venous congestion pressure. J Physiol 507:611–617 Veraart JC, Pronk G, Neumann HA (1997) Pressure differences of elastic compression stockings at the ankle region. Dermatol Surg 23:935–939 Denq JC, Opfer-Gehrking TL, Low PA (1997) Efficacy of compression of different capacitance beds in the amelioration of orthostatic hypothension. Clin Auton Res 7:321–326 Gorelik O, Fishlev G, Cohen N (2004) Lower limb compression bandaging is effective in preventing signs and symptoms of seating-induced postural hypothension. Cardiology 102:177–183

11.

12. 13. 14. 15. 16.

17. 18.

19.