It is appropriate to consider the pathophysiology of HBEs associated with vasovagal syncope in terms of afferent and efferent limbs of the reflex, the processing of the signals by the central nerve system, and finally, the role of feedback systems (Fig. 1). However, very little is known about the afferent part of the vasovagal reflex. Whereas the efferent part of the reflex is quite clear, hypotension and bradycardia are due to inhibition of the sympathetic system and to activation of the parasympathetic system, respectively. The triggers of abnormal neural reflexes are 1) fear of bodily injury; 2) painful or noxious stimuli; 3) venipuncture; 4) prolonged standing; 5) heat exposure; 6) exertion; and 7) coughing, swallowing or straining. Most vasovagal episodes seem to be associated with a number of different peripheral receptors. It is thought that the afferent neural signals are derived from organ receptors, which respond to mechanical or chemical stimuli. For example, cardiac mechanoreceptors alone were thought to be the important trigger sites in most cases of vasovagal syncope. In any event, the afferent neural signals associated with triggering vasovagal syncope ultimately converge on the nucleus tractus solitarius in the medulla as well as the hypothalamus. The former is closely related to the nuclei of the vagus nerve and the vasomotor center in the reticular formation, from which efferent neural activity is expected to initiate an appropriate circulatory response to any detected triggers [19]. Generally, three responses in vasovagal syncope are observed: 1) a mixed response with features of both cardioinhibitory and vasodepressor, 2) cardioinhibitory or 3) vasodepressor (Table 2). Among these responses, the cardioinhibitory response results from increased parasympathetic tone and may be manifested by any or all of the following ECG findings: 1) sinus bradycardia, 2) PR interval prolongation, and 3) advanced atrioventricular block.

Because HBEs are frequently observed in awake conditions under isolated ISBPB, all of the above-mentioned triggering stimuli could act as afferent neural signals of the vasovagal reflex arc in the patient undergoing shoulder surgery. Moreover, several investigators have suggested that underlying mechanisms for the occurrence of HBEs are the activation of the cardioinhibitory mechanoreceptor or the Bezold-Jarisch reflex [7,20]. Detailed discussions on the Bezold-Jarisch reflex are provided below.

Carotid sinus syndrome or CSH is an unusual type of vasovagal syncope. It rarely occurs in adults under 50 years, increases in prevalence with advancing age and in close relationship with accidental mechanical manipulation of the carotid sinuses, and can be reproduced by carotid sinus massage (CSM) [21]. This response is due to hypersensitivity of the afferent or efferent limbs of the carotid sinus reflex arc, resulting in vagal activation and/or sympathetic inhibition, which lead to bradycardia and/or vasodilation. CSH is diagnosed when CSM elicits > 3 s asystole (cardioinhibitory type), a fall in SBP (systolic blood pressure) of > 50 mmHg (vasodepressor type) or both (mixed type) [22]. In CSH, afferent neural signals arise from "peripheral" carotid artery baroreceptors. Debate has often centered on whether the peripheral receptor is indeed "hypersensitive" or whether the fault lies centrally in the manner in which the afferent signals are processed [19]. The latter argument has been supported by the findings of Tea et al. [23]. These investigators have suggested that the electromyographic analysis of the sternocleidomastoid (SCM) muscle differed significantly between the groups. Thirteen patients (76%) had pathological responses in the carotid sinus syndrome group compared with only 4 (23.5%) in the control group. The baroreceptors in the carotid sinus are considered to be stretch receptors that respond to deformation of the vessel wall in any direction [24]. During neck movements, mild stretches of both carotid receptors and SCM tension receptors occur. Therefore, it is a reasonable hypothesis that proprioceptive sensitivity of the SCM could provide important information on the mechanical origin of the baroreceptor stretching during neck movement and could modulate information coming from the carotid baroreceptors. Thus, SCM proprioceptive information could produce a strong inhibitory effect on the baroreflex arc, according to the concept of a central gating of the baroreflex as developed for cardiorespiratory interactions (Fig. 2). Therefore, these observations suggest that chronic loss of innervation of the SCM is strong evidence for a peripheral origin of CSH, with the result being an increased sensitivity of the baroreflex arc. In regard to the occurrence of HBEs during shoulder surgery, there are two possible hypotheses. The first is that HBEs occur in the prerequisite condition of CSH as mentioned above. In fact, ISBPB can block spinal nerves (C2-C4) to SCM muscles and inhibit the transmission of SCM proprioceptive information. Consequently, acute loss of innervations of the SCM may be related to the hypersensitivity of the baroreflex arc. The second possible hypothesis is that direct manipulation of the carotid sinus, during the shoulder surgery, produces HBEs. An ultrasonography study showed that there is considerable variation in the carotid artery anatomy in young subjects [25]. Location of the right and left carotid sinus bifurcation was measured from the gonion of the mandible (n = 95) and determined by Doppler ultrasound. Location of the right bifurcation was 3.2 cm (median 3.0 cm, range 0-6.5 cm), and the left bifurcation was 3.6 cm (median 3.5 cm, range 0-7.5 cm) below the angle of the mandible. Therefore, large amounts of local anesthetics in the ISBPB, which produce neck swelling, and frequent neck turning and arm traction during shoulder procedures, could be the triggering factors to produce direct mechanical stimulation of the carotid sinus. A few cases of asystolic cardiac arrest, during positional changes from supine to sitting in shoulder arthroscopic surgery, might be explained by the underlying mechanisms of CSH. In anesthesia related literature, there are two cases of asystolic cardiac arrest from CSH, triggered by positioning for head and neck surgery [26,27]. Maggi et al. [28] suggested that cardiac pacing therapy has a beneficial effect on the neutrally mediated vasovagal syncope when the cardio-inhibitory CSH can predict an asystolic mechanism at the time of spontaneous syncope. Moreover, Heusser et al. [29] suggested recently that direct electric field stimulation of the carotid sinus baroreflex afferents acutely decreases arterial blood pressure in hypertensive patients, without negative effects on physiological baroreflex regulation. This depressor response is mediated predominantly through the inhibition of the sympathetic nervous system.

HBEs seem to be related to orthostatic syncope and associated autonomic disorders. In general, with age our ability to maintain hemodynamic homeostasis during position changes becomes less effective. This predisposes elderly patients to significant changes in blood pressure upon standing and orthostatic hypotension (OH). The prevalence of OH varies according to the population being studied. A range between 5% and 60% has been reported with the lower rate in elderly individuals living in the community. OH is defined as a reduction of SBP of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 minutes of standing (Table 3). Generally, orthostatic syncope occurs when the autonomic sympathetic vasomotor system is incapacitated and fails to respond to the challenges imposed by the upright position causing hypotension (Table 4). These systems control the hemodynamic balance of blood volume, cardiac function and peripheral resistance to maintain organ perfusion during active (e.g., assuming the erect from the supine position) or passive (e.g., head-up tilt) postural changes. Normally, 30% of the blood volume is intrathoracic during the supine position. With active or passive upright positions, approximately 500 cc of volume pools into the pelvic and lower extremity circulatory system. This sudden pooling produces a transient hypotension that triggers the baroreceptors in the carotid body and the cardiopulmonary system to decrease their basal cardioinhibitory firing via the nucleus tractus solitarius of the medulla oblongata. As a result, a decrease in vagal tone and an increase in sympathetic flow ensue, leading to an increase in heart rate, peripheral vascular resistance, stroke volume and subsequently blood pressure to resume hemodynamic homeostasis. In addition, active position change, such as standing, causes muscular contraction in the pelvis and the lower extremities and leads to an increase in resistance, subsequently increasing preload. The renin-angiotensin system and vasopressin play a role in this hemodynamic homeostasis, especially in long-term maintenance (Fig. 3) [30]. Any disturbance in this model will predispose the individual to OH.

Among secondary forms, alcohol, diabetes, and amyloidosis are common causes as well as volume depletion in which the autonomic nervous system is not itself unbalanced but is unable of maintaining adequate blood pressure due to reduced circulating volume. Orthostatic syncope might also occur due to the effects of many drugs, mainly in the elderly, such as vasodilators and nitroglycerin, β- and α-adrenergic blockers, diuretics, anti-depressives, phenothiazines. In fact, because shoulder arthroscopic surgery is performed in a sitting position, it is true that there is a unique physiological change due to positional change. It is thought that preoperative NPO time or intraoperative bleeding may reduce circulating volume. ISBPB itself can affect autonomic influence by blocking the sympathetic chain. A stressful environment or a painful situation may also affect the activation of the sympathetic system. In addition, anesthesiologists frequently use antihypertensives or vasodilators in the management of high blood pressure during shoulder procedures. These factors can be associated with the occurrence of OH-like events during shoulder surgery. Although antihypertensive medications as a group are thought to be major contributors to the increased risk of OH, studies to document an association are conflicting. However, Sia et al. [8] reported that the incidence of HBEs during shoulder surgery were more frequent in the 24 patients who received antihypertensive medication (urapidil) compared to the 86 who did not (37% versus 15%; P < 0.01). These observations indicate that one of the underlying causes for HBEs during shoulder surgery may be associated with the causes of OH, especially intravenous bolus administration of antihypertensives during shoulder surgery.

HBEs during shoulder surgery in the sitting position can be associated with SGB because it is not an infrequent complication of ISBPB. In fact, the incidence of SGB with Winnie's technique of ISBPB approaches 75% [4]. In addition, cardiac sympathetic fibers originate from the stellate ganglia in conjunction with the superior and middle cervical ganglia and the first 4 or 5 thoracic sympathetic ganglia [37]. Hence, SGB after an ISBPB may affect cardiac sympathetic function. SGB itself is a common procedure for pain management. Patients in the pain clinic center occasionally experience dizziness, likely because of orthostatic hypotension, when standing after SGB. This episode of dizziness looks very similar to the occurrence of HBEs, when sitting after ISBPB. The symptoms after SGB may well be caused by impaired compensatory baroreflex integrity because SGB affects not only cardiac sympathetic nerves but also vagal afferents, including aortic depressor nerves, and these nerves play important roles in the baroreflex mechanism [38]. Interestingly, the effects of right and left SGB on heart rate and systolic blood pressure are different because of hemi-lateralization in the autonomic cardiovascular control. There is sympathetic predominance in the right hemisphere and parasympathetic predominance in the left hemisphere [39,40]. Taneyama and Goto [41] demonstrated that right SGB affected both heart rate and systolic blood pressure variability, but left SGB affected only systolic blood pressure and not heart rate variability. There is some evidence supporting these observations that stellectomy of the right-side ganglion diminished the increase in heart rate during exercise in dogs [42], whereas pharmacological right-sided SGB may attenuate not only sympathetic but also parasympathetic activity in humans [43]. In regard to HBEs, Seo et al. [10] demonstrated that 12 of 13 patients (92.3%) who had HBEs received a right side ISBPB, suggesting that the site of ISBPB may be a contributing factor to the occurrence of HBEs. They suggested that a predominance of right-sided blocks in HBEs may be associated with right SGB as a complication of ISBPB. Although D'Alessio et al. [7] did not find a predominance of right-sided blocks in HBEs, several reports and cases are supporting these hypotheses. Rogers et al. [39] demonstrated a significantly slowed heart rate after right SGB but not after a left-sided block. Fujii et al. [44] reported that right SGB induces significant increases in the QT interval and rate-corrected QT (QTc) interval for 50 minutes after the block, but left SGB induces a significant decrease in the QT interval and the QTc interval. They suggested that autonomic innervation to the sinus node is mainly through the right-sided stellate ganglion. Nakagawa et al. [45] reported that a 70° head-up tilt produced significant increases in the QT interval and QTc dispersion because the head-up tilt increased sympathetic tone and/or decreased vagal tone. Masuda and Fujiki [46] reported a case of sinus arrest that occurred after a head-up tilt in right SGB, most likely because of a vasovagal reflex. These observations indicate that right SGB, as a complication of ISBPB, may be associated with increased risks of HBEs during a shoulder procedure in the sitting position. However, Koyama et al. [47] suggested that right SGB, during the head up tilt test, suppresses cardiac sympathetic function without significantly affecting blood pressure and thus may be a safe and effective therapy for the chronic pain syndrome. In addition, up to now, there is a lack of clinical evidence that the right SGB after ISBPB in the sitting position is related to the cause of HBEs during shoulder surgery. As such, a prospective and randomized study is needed in the future to confirm whether right side ISBPB is a risk factor for HBEs.

The limbic system is concerned with emotions, and in some animal species stimulation of the limbic sympatho-inhibitory center causes hypotension and bradycardia [48]. Although episodes of bradycardia may occur during regional anesthesia in the absence of sedation, oversedation may increase the risk. Hypnotic drugs should be given to obtain anxiolysis, rather than deep sedation [20]. In addition, there is some evidence that endogenous opioids, which are important neurotransmitters in the nucleus tractus solitarius, are involved in syncopal reactions in animals [49]. Griffioen et al. [50] demonstrated that fentanyl inhibits GABAergic transmission to cardiac vagal neurons in the nucleus ambiguus, providing one mechanism for opioid-induced bradycardia.

It is not well known whether intravenous administration of sedatives would be a triggering factor for the occurrence of HBEs during shoulder surgery. Previous studies have suggested that intraoperative sedation is not a major triggering factor for HBEs [8,9]. Souron et al. [51] demonstrated that in a single observation group, with 140 patients, target-controlled propofol infusion (0.8-0.9 µg/ml) following hydroxyzine premedication is a safe and effective technique for sedation when combined with ISBPB during shoulder surgery in the sitting position. The incidence of HBEs in their study was 5.7% (8 patients). With supplementation during regional anesthesia, an intravenous bolus of fentanyl (1-3 µg/kg) is frequently chosen because of its potent, short-lasting analgesia. However, Seo et al. [10] demonstrated that there is a higher incidence of fentanyl supplementation in the HBEs group (53.8%) compared to the non-HBEs group (4%). In addition, Song et al. [52] demonstrated that the incidence of HBEs is increased in the group receiving an intravenous bolus administration with 100 mcg of fentanyl (27.5%) compared with the saline group (10%). Although 100 µg of fentanyl is a reasonable dose, it can produce a marked decrease in arterial blood pressure, with a mean percent of change of approximately 20%. This finding suggests that intravenous administration of fentanyl for incomplete ISBPB is a triggering factor for the occurrence of HBEs during shoulder arthroscopic surgery. Therefore, it is reasonable that the effective dose of fentanyl must be reduced by 50%.

To prevent major complications related with ISBPB, including HBEs, anesthesiologist should consider the technical aspects of ISBPB. First, anatomical structures related with major complications are located on the medial side from anterior scalene muscles. Therefore, a medially directed needle could increase the possibility of complications such as intravascular injections (the internal jugular vein or even the carotid artery), phrenic nerve block, epidural and spinal anesthesia, Horner's syndrome, hoarseness, and dysphagia. The symptoms from these complications might be associated with psychological factors to the vasovagal reflex reaction. Feigl et al. [53] demonstrated in their cadaveric study that the group of interscalene blocks by the Winnie technique, with the use of 30 ml, showed spread in a lateral direction in all cases and the dye additionally distributed medial to the anterior scalene and disseminated ventrally and dorsally to the anterior scalene muscle. It reached the phrenic nerve, the vagus nerve, the sympathetic trunk, and the great vessels of the superior mediastinum. In contrast, when they developed and used the supraomohyoidal block, which is an approach that avoids medially directed needle advancement and favors spread to lateral regions only, the phrenic nerve, stellate ganglion, laryngeal nerve and the vertebral artery were not exposed to the injected solution. Second, major complications of ISBPB often occur when the needle insertion is deeper than required because the interscalene block is a relatively "superficial" block. Third, the volume of local anesthetic for ISBPB should be considered to prevent the complications. Recent reports have suggested that ultrasonography-guided ISBPB can reduce the minimal effective volume of ISBPB [54], although it is unknown whether lower volumes of ISBPB can reduce the incidence of HBEs during shoulder surgery or not.