Hypotensive and bradycardic events (HBEs) in patients who underwent shoulder arthroscopic surgery in the sitting position under interscalene block (ISB), while usually not serious, are very challenging complications for anesthesiologists [1,2]. The position of the patient in shoulder arthroscopy largely depends on the choice of the surgeon. The sitting position has benefits, such as easier airway access, easier conversion to open surgery, less bleeding, a familiar anatomical orientation, and low risk of brachial plexus injury. Despite these benefits, the sitting position can cause adverse cardiovascular events, such as hypotensive bradycardic events and cerebrovascular desaturation events (CDEs), as reported in many articles [2-7]. The incidence rate of HBEs in patients undergoing shoulder arthroscopic surgery ranges from 13% to 21% [1,3,4]. Severe asystolic cardiac arrests can be caused by HBEs, and can be life-threatening without immediate correct treatment [5]. Several previous studies have suggested that HBEs may be related to intravenous (IV) drugs administrated intraoperatively [3,6,7]. Although antihypertensives, sedatives, and analgesics such as propofol, dexmedetomidine, and fentanyl may be involved in the development of HBEs, it has not yet been investigated which of these drugs are independent risk factors. In addition to these drugs, HBEs may be associated with the underlying mechanisms responsible for neurally mediated syncope, carotid sinus hypersensitivity (CSH), orthostatic hypotension, and other types of syncope [1,8,9]. Thus, HBEs may be associated with the patient’s age, sex, body mass index, past medical history, and the technical aspects of ISB, but the relationships between patient or anesthesia factors and HBEs in the clinical setting of shoulder arthroscopic surgery have not been studied. In this study, we retrospectively analyzed the records of 2549 patients who underwent shoulder arthroscopic surgery in the sitting position to explore the independent risk factors of HBEs by logistic regression analysis.

The incidence of HBEs was 14.0% (357/2549). HBE incidence during shoulder arthroscopic surgery under ISB was examined using univariable analysis. The results revealed that demographic data, such as American Society of Anesthesiologists (ASA) physical status, age, sex, height, weight, and BMI were related to HBE incidence (P < 0.05, Table 1). However, preoperative diagnosis and the site of operation (right versus left) were not significantly correlated with the occurrence of HBEs (P > 0.05). The univariable analysis of the relationships between past medical history and preoperative medications and HBEs revealed that a history of hypertension and antihypertensive medication were risk factors for HBEs (P < 0.05, Table 2). However, history of DM, liver disease, heart disease, pulmonary disease, brain disease, and DM medication were not risk factors (P > 0.05). Regarding the anesthetic characteristics of ISB, univariable analysis revealed that a guided ISB device (sonography versus nerve stimulator), operation time, and total amount of LA (ropivacaine, mepivacaine, and lidocaine) were not related with HBEs (P > 0.05, Table 3). Table 4 shows the analysis of perioperative vital signs and intraoperative use of vasoactive drugs as risk factors for HBEs. Univariable analysis of the relationships between baseline vital signs and HBEs revealed that baseline SBP and DBP were significantly associated to HBEs (P < 0.05), while among intraoperative medications, the intraoperative use of IV hydralazine, propofol, midazolam and dexmedetomidine were significantly correlated with the occurrence of HBEs (P < 0.05, Table 5). However, the intraoperative use of nicardipine was not a risk factor for HBEs: Indeed the use of nicardipine in the HBEs group was significantly lower (P < 0.05, Table 5) than in the non-HBEs group. Furthermore, the intraoperative use of fentanyl was not significantly correlated with the occurrence of HBEs (P > 0.05).

The variables described above were examined through logistic regression analysis with the forward conditional method for variable selection, and the results indicated that the intraoperative use of IV hydralazine, propofol, and dexmedetomidine were independent risk factors for developing HBEs during shoulder arthroscopic surgery under ISB (P < 0.05, Table 6). The results of the logistic regression analysis adjusted by age, sex, BMI, preoperative medical history, perioperative medication, and vital signs are shown in Table 7. The intraoperative use of hydralazine (OR 4.2; 95% CI 2.9–6.3), propofol (OR 2.1; 95% CI 1.3–3.6), and dexmedetomidine (OR 3.9; 95% CI 1.9–7.8) were identified as independent risk factors for the occurrence of HBEs during shoulder arthroscopic surgery (Table 7).

Shoulder arthroscopic surgery is commonly performed in the sitting position under ISB, and the anesthesiologist should focus on monitoring the patient vital signs, so as to allow early detection and treatment of HBEs occurring during surgery. We retrospectively analyzed the data of 2549 patients who underwent shoulder arthroscopic surgery under ISB, and found that the incidence rate of HBEs was 14.0%. In addition, our results indicated that the use of hydralazine, propofol, and dexmedetomidine before HBE occurrence were independent risk factors for developing HBEs.

The use of intraoperative antihypertensives during shoulder arthroscopic surgery can be increased by the operator’s demand for blood pressure control, because high blood pressure can increase bleeding and blur the operation field. For the anesthesiologist, it is very challenging to use IV antihypertensive drugs in conscious sitting patients under ISB. Our results show that vasodilators such as hydralazine were strong risk factors for HBEs, but calcium channel blockers (CCBs) such as nicardipine and diltiazem were not. Especially the use of nicardipine in the HBEs group was significantly lower than in the non-HBEs group in our results. Therefore, the intraoperative use of nicardipine was not a risk factor for HBEs despite of statistical significance. In a previous study [6], another antihypertensive drug, namely urapidil, was identified as a risk factor for HBEs in shoulder arthroscopic surgery. Urapidil [10], which is currently not approved by the U.S. Food and Drug Administration, acts as an α1-adrenoreceptor antagonist and as a 5-HT1A receptor agonist. These findings suggest that the anesthesiologist should pay attention to the selection of antihypertensive agents during shoulder arthroscopic surgery under ISB.

Hydralazine is known to act directly on the vascular smooth muscle causing strong vasorelaxation and primary artery relaxation [11]. However, the action time of hydralazine is unpredictable, compared with other intravenous antihypertensives used for the treatment of malignant hypertension, and can be as long as 8 h in some cases [12]. The cause of such longer action time of hydrazine is not well known, but animal experiments confirmed that the active metabolite of hydralazine adheres to tissues in the vascular wall for a certain period of time, and that the hydralazine metabolites deposited on the vascular endothelial cells can continuously produce endothelial-dependent NO [12]. In contrast, CCBs block the L-type voltage-dependent calcium channels of the vascular smooth muscle, inhibiting calcium influx, thereby relaxing the vascular smooth muscle. The production of nitric oxide in vascular endothelial cells is usually caused by calcium-dependent nitric oxide synthase, and CCBs do not directly affect NO production [13]. Considering these aspects, when the need arises to use IV anti-hypertensive drugs during shoulder arthroscopy under ISB, it is safer to choose CCBs rather than hydralazine that alters NO production and has long-lasting effects.

A previous study [7] reported that a large single IV bolus dose of fentanyl (100 ug) was associated with the development of HBEs. However, the use of fentanyl in this study was not a risk factor for HBEs, possibly because we use fentanyl in a single bolus dose generally smaller than 50 ug. On the contrary, propofol was identified in this study as an independent risk factor for HBEs. However, Souron et al. [14] performed target-controlled propofol infusion (0.8–0.9 μg/ml) in 140 patients during shoulder arthroscopic surgery under ISB and found that the propofol infusion group had a low incidence of HBEs (5.7%). This discrepancy may be caused by the different purpose and protocol of propofol administration compared with this study. In our center, we do not routinely use patient sedation during shoulder arthroscopic surgery, and propofol is not used for patient sedation itself. In cases of insufficient block or strong patient’s demand, if analgesics or sedatives such as fentanyl or midazolam are not effective, an IV bolus injection and/or IV infusion of propofol are used. Therefore, the effect of propofol in this study should be interpreted as a combination effect of propofol with fentanyl and midazolam. Although dexmedetomidine was used for sedation in a small number of patients, we found it to be an independent risk factor for HBEs. Since the stability of dexmedetomidine during shoulder surgery in the sitting position has not yet been established, the use of IV dexmedetomidine requires caution, and further studies are needed.

Various syncopal reactions, including HBEs, may be triggered by similar mechanisms and use the same efferent limb of the reflex [1,8]. HBEs often occur in response to an orthostatic stimulus (prolonged sitting position), other non-orthostatic stimuli (fear, emotional stress, pain), and a variety of activities (coughing, swallowing, and pressure on the carotid sinus) [15]. These stimuli cause a sudden transient failure of the autonomic nervous system, resulting in hypotension and bradycardia. This study revealed that lower baseline SBP and DBP (Table 4) were associated with the development of HBEs. We also found that older age, lower BMI, and the female sex were associated with the development of HBEs in univariable analysis. Sex differences in patients with HBEs in this study may be closely related with female predominance in neurally mediated syncope [9,16]. Women are more susceptible to orthostatic intolerance in warm environments. Recently, Meendering et al. [17] evaluated the influence of menstrual cycle and sex on the hemodynamic responses to combined orthostatic and heat stress, and found that men had greater orthostatic tolerance than women during combined upright tilting and passive heating. Neurally mediated syncope is more common in younger people [9], but in this study, HBEs tended to occur more frequently in older people. In addition, this study showed that higher ASA physical status (Table 1) and a history of hypertension (Table 2) were risk factors for HBEs. Although syncope in the elderly is usually multifactorial, and often associated with orthostatic hypotension and carotid hypersensitivity [18-20], further research is needed to clarify the association between HBEs and these factors.

Recent studies have reported the effects of ISB on sympathetic activity, possibly by the extension of ISB to the stellate ganglions [21,22], and some studies have reported the possibility of a difference between the left and right sides [4,21]. A previous retrospective study [4] has reported that the ISB site (right versus left) may be considered a risk factor of HBEs, but this result may be underpowered owing to the small sample size.

However, our results did not identify the ISB site as a risk factor of HBEs (Table 1), and we consider them to be more reliable, because our study had a much larger sample size than the previous one. Additionally, we also examined the association between the total amount of local anesthetics and HBEs, without finding a significant result. Our results may suggest that HBEs cannot be separated from various other types of syncopal reaction. However, preoperative ISB was reported as one of the risk factors associated with HBEs in a recent study of open shoulder surgery [23]. Further studies are thus needed before a definite conclusion can be drawn about the impact of the ISB on HBEs.

The definition of HBEs may differ somewhat from that of neurally mediated syncope that is defined using the tilting test [9,24]. The definition of HBEs used in this study was based on the general guidelines for the administration of ephedrine or atropine upon changes in patient blood pressure or heart rate during shoulder arthroplasty. This specific definition might explain the high prevalence of HBEs assessed in this study. In addition, as a retrospective analysis of data from a single research center, this study inevitably has some limitations. One of the potential limitations is the long study period, chosen so as to include all cases operated in our institution without selection; in particular, regarding nerve stimulator-guided ISB, the period included in the study was 16 years long. Owing to such a long period, there were some changes in anesthesia and surgical procedures that could affect the results of the study. However, as previously described, only one surgeon and three anesthesiologists were involved in the surgeries in this study, and we tried to standardize the anesthesia process, so that the changes occurred during the study period might not present a major concern. Unfortunately, a large part of the data was taken before our institution adopted an electronic medical record system; thus, a significant portion of data about the amount and type of perioperative drugs was missing. This made it difficult to analyze the role of the amount and type of perioperative drugs. However, all patients were analyzed simultaneously, without selectivity. Therefore, our results are more reliable than those of other retrospective studies, thanks also to the comparatively large sample size and the controlled ISB procedure.

In conclusion, our findings indicate that the use of hydralazine, propofol, and dexmedetomidine before HBEs increases the susceptibility to HBEs during shoulder arthroscopic surgery in the sitting position under ISB.