The prevalence of coexisting coronary artery disease in patients undergoing carotid endarterectomy (CEA) is frequent. As a result, evidence of perioperative myocardial ischemia is found in more than half of high-risk patients, even when CEA is performed under regional anesthesia (1,2). Patients with intraoperative myocardial ischemia seem to be at an increased risk for postoperative cardiac events (1). Although combined (deep plus superficial) cervical plexus (CP) blockade is a regional anesthesia technique often used for CEA (3), it can lead to increased systolic blood pressure (SBP) and heart rate (HR) before surgery (4–6). Such responses may be caused by patient anxiety, discomfort, the effect of systemic absorption of local anesthetics, or epinephrine use as a vasoconstrictor (4–6). However, it is unclear if regional anesthesia blockade of the deep and superficial CP causes alterations in cardiovascular (CV) autonomic control, including activation of the sympathetic nervous system, and thereby eliciting changes in SBP and HR (6).
Estimation of autonomic dysfunction, characterized by reduced vagal modulation, decreased baroreflex sensitivity (BRS), and increased sympathetic activity, is receiving increased attention because of reports that these changes are important prognostic variables predicting mortality rates and arrhythmias in heart disease patients (7–9). In addition, the baroreflex is a powerful negative feedback reflex that attempts to correct perturbations in arterial blood pressure (BP). The primary mechanism by which baroreflexes contribute to BP regulation is through effects on both the parasympathetic and sympathetic branches of the autonomic nervous system (7,10).
The advancing needle used during deep CP blockade for CEA runs immediately adjacent to several major anatomical structures and autonomic nerves, including the carotid sinus and the glossopharyngeal and vagus nerves to the cardiopulmonary and arterial baroreceptors (3,11) in the vicinity of cervical nerve roots C2, C3, and C4 (12). Thus, given the possibility of baroreceptor and autonomic nerve blockade during this procedure, it is feasible that CV autonomic function and baroreflex reserve may be affected, thereby causing changes in SBP and HR. However, the hemodynamic and reflex consequences of combined CP blockade for CEA on CV autonomic control per se are poorly understood.
The purpose of the present observational study was to examine whether combined CP blockade for CEA alters the basal autonomic indices of resting cardiac and vascular regulations. Such information may also provide additional insight into mechanisms of hypertension and tachycardia after combined CP blockade. To determine these relationships, HR variability (HRV), SBP variability (SBPV), and spontaneous BRS were assessed before and after combined CP blockade.
Twenty-eight patients received written explanations of the experimental protocol and signed a consent form that was approved by the IRB for Protection of Human Subjects. Twenty-two of the 28 patients scheduled for CEA under combined CP blockade were included in this study, with 6 patients excluded because they showed abnormal heart rhythm before or after CP blockade, such as atrial fibrillation, atrioventricular conduction defects, or atrial and ventricular premature contraction. No premedication was given, and patients taking antianginal and antihypertensive medication continued these therapies until the day of surgery because it was considered unethical to discontinue such interventions.
Patients were allowed to acclimatize for at least 10 min in the supine position in a quiet operating room with an ambient temperature ranging from 24°C–26°C. The radial artery was then cannulated with a 20-gauge catheter, and 20 min later, baseline beat-by-beat electrocardiography (ECG) and arterial BP signals were recorded continuously for 5 min. The deep CP blockade was achieved by injecting 7 mL of 0.75% ropivacaine with epinephrine 1:200,000 approximately 2 mm lateral to each ipsilateral transverse cervical process of C2, C3, and C4. Sensory loss to pinprick in the C2–4 dermatome distribution was confirmed. The superficial CP blockade was then performed using 9 mL of the same solution injected subcutaneously along the posterior border of the sternocleidomastoid muscle. Twenty minutes after CP blockade, ECG and arterial BP signals were continuously recorded for 5 min during quiet rest before skin preparation for CEA.
Beat-by-beat ECG and arterial BP signals (VSM 5, Physio-Control, Redmond, WA) were digitized and collected at 500 samples per second using an online personal computer that interfaced with an analog-to-digital converter (DI-720U, DATAQ instruments, Akron, OH). Offline analysis was performed using signal processing software (CODAS, DATAQ; DADiSP/Adv DSP, DSP Development, Cambridge, MA) and custom-written MATLAB (The MathWorks, Inc., Natick, MA) scripts.
R-R intervals (RRI) were derived from the time difference between marks placed on the peaks of the R waves, and SBPs were derived from the maxima of beat-by-beat arterial BP waveforms. Time-domain analysis of HRV was calculated from the root mean squared successive difference of RRI (RMSSD). This time-domain parameter is the most frequently used HRV variable and is thought to be related primarily to parasympathetic control of the HR (13). For frequency-domain analysis of variability, 5-min time series data of beat-by-beat RRI and SBP were interpolated to 5 Hz to provide equidistant samples. The fast-Fourier-transformed power spectrum density, based on Welch’s algorithm of averaging periodograms, was calculated for the filtered signals using a sliding window with a width of 500 points and an overlap of 250 points after detrending and application of a Hanning filter. The resulting five periodograms were averaged to produce the estimated spectrum. This method yields a frequency resolution of 0.01 Hz. The areas under the power spectra in the low-frequency (LF) and high-frequency (HF) regions (defined as 0.04–0.15 Hz and 0.15–0.40 Hz, respectively) of HRV and SBPV were integrated (13). In addition, the LF and HF components of HRV were measured in normalized units, which represent the relative value of each power component in proportion to the total power of the HF and LF bands (13). The HF power of HRV was used as a valid marker of vagal tone (7,13), and the LF power of SBPV was used as an index of vascular sympathetic outflow because this has been shown to be closely linked to vascular sympathetic activity (7,14,15).
Cardiac BRS was estimated from spontaneous beat-by-beat fluctuations in SBP and RRI. Because baroreflex function cannot be accurately assessed using only one technique (16), this study engaged two distinct techniques for quantifying BRS, namely frequency-domain transfer function analysis and time-domain sequence analysis. Details of the transfer function analysis are provided in our previous study (17). Briefly, the transfer function magnitude and coherence (the squared coherence function) between SBP and RRI were estimated using the cross-spectral method (18,19). We calculated the transfer function magnitude between HRV and SBPV separately as an index of BRS in the LF (BRSLF) and HF (BRSHF) regions, where coherence is more than 0.5. In contrast, the sequence method identifies sequences of 3 or more consecutive heartbeats in which both SBP and subsequent RRI either increase or decrease. The minimum criteria for changes in SBP and RRI were 1 mm Hg and 4 ms, respectively (20). The linear correlation between RRI and SBP was computed for each sequence. The regression slope was calculated for those sequences with correlation coefficients exceeding 0.85, and the mean value of all individual slopes occurring within the 5-min data collection was taken as an estimate of sequence BRS (BRSSEQ).
All data are presented as mean ± sd. The effects of the combined CP blockade were compared using Student’s paired t-test after examining the normality of data using the Kolmogorov-Smirnov test. Logarithmic transformations of the HF and LF powers of HRV are provided because their absolute values were not normally distributed. Pearson product-moment correlation analysis was used to test for correlations between variables. A P value < 0.05 was considered to indicate a significant difference.
No serious complications relating to blockades were observed, with transient dysphonia being the most frequent side effect (7 of 22 patients). Patient medical characteristics and preoperative CV medications are listed in Table 1. We found that SBP and HR increased after combined CP blockade, as previously reported (4,5) (Table 2).
Representative power spectral density curves for HRV and SBPV and magnitude and coherence according to transfer function analysis of data from one patient before and after combined CP blockade are shown in Figure 1. The LF and HF power of HRV and transfer function magnitude, which can assess baroreflex function between SBP and HR spectral variability, all decreased after combined CP blockade. In contrast, the LF and HF power of SBPV increased. RMSSD and the HF power of HRV decreased after combined CP blockade, indicating reduced cardiac vagal modulation of HR. Conversely, the LF component of SBPV, which is closely associated with vascular sympathetic activity, increased after combined CP blockade (Table 2).
Representative BRSSEQ slopes of linear regression lines created using sequence method analysis of data from one patient are shown in Figure 2. We found that BRSSEQ, BRSLF, and BRSHF all decreased after combined CP blockade (Table 2). The individual changes in BRSSEQ, BRSLF, and BRSHF before and after combined CP blockade are shown in Figure 3. Reduced transfer function magnitude within the breathing frequency (BRSHF) suggest the combined CP blockade reduced the gain of vagal modulation of HR. BRSLF could not be calculated in 7 of 22 patients, or BRSHF in 1 of 22 patients, because the coherence between RRI and SBP was <0.5. In addition, BRSSEQ could not be measured in 4 of 22 patients because of a lack of spontaneous sequences. Changes in SBP correlated negatively with changes in BRSHF before and after combined CP blockade (r = −0.455; P = 0.038), but not between changes in SBP and changes in either BRSSEQ or BRSLF. This selective correlation with BRSHF speaks to a potential role for reduced vagal activity, as also suggested by the decrease of the HF component of the HRV.
The major findings of this study were that combined deep and superficial CP blockade using ropivacaine with 1:200,000 epinephrine resulted in decreased cardiac vagal modulation, increased vascular sympathetic outflow, and decreased BRS that correlated with increased SBP. There are little data to demonstrate that vagal function and the physiological baroreflex reserve are concomitantly affected in addition to the increased vascular sympathetic outflow that occurs after combined CP blockade for CEA. Although the indirect nature of spectral analysis calls for caution in inferring autonomic regulation (15), the simultaneous increases in SBP and HR, together with an overall alteration in autonomic CV regulation, indicate a major shift of resting autonomic state towards sympathetic dominance, vagal withdrawal, and decline in baroreflex reserve after combined CP blockade for CEA.
There is strong clinical evidence that autonomic balance and vagal reflexes influence morbidity and mortality rates after myocardial injury (9,21). For instance, a multicenter study demonstrated that both resting cardiovagal tone and BRS have a prognostic value for long-term survival after myocardial infarction (9). Specifically, patients surviving myocardial infarction who had either low HRV or low BRS had an increased risk of malignant arrhythmia and subsequent sudden cardiac death. Likewise, in patients undergoing CEA, occurrence of postoperative baroreflex dysfunction and arterial BP instability was associated with a 3.3 times higher risk of developing major CV complications and an eight-fold increased risk of CV mortality in the five years after the operation (22). It is therefore likely that impairment of cardiovagal, BRS, and sympathetic function after combined CP blockade for CEA may play an important role in increasing cardiac risk, especially in high-risk patients with ischemic heart disease and congestive heart failure. Given the prevalence of coexisting coronary artery disease and perioperative myocardial ischemia in patients undergoing CEA with combined CP blockade (1,3), this intriguing hypothesis merits further investigation because it may lead to a better understanding of specific factors involved in perioperative CV morbidity and mortality rates.
Although the present study does not provide definitive information on the mechanisms underlying changes in autonomic CV regulation and increases in SBP and HR, we hypothesize that these changes might be due, at least in part, to local anesthetic blockade of impulses from arterial and cardiopulmonary baroreceptors. Fagius et al. (23) performed lidocaine blockade of the glossopharyngeal and vagal nerves that transmit impulses from baroreceptors, and showed that anesthetic blockade of these nerves resulted in a strong increase in sympathetic outflow accompanied by hypertension and tachycardia. Likewise, Ikeda et al. (24) observed that sympathetic outflow increased after injecting mepivacaine into the stellate ganglion, which was associated with increased HR, suggesting that these changes might be caused by simultaneous blockade of vagal fibers from arterial baroreceptors in the aortic arch. In addition, severe hypertension after stellate ganglion blockade has also been reported by Kimura et al. (25), who postulated that diffusion of the local anesthetic along the carotid sheath may produce vagal blockade causing unopposed sympathetic activity as a result of attenuation of the baroreceptor reflex. Therefore, our observation of sympathetic dominance, vagal withdrawal, and decline in baroreflex reserve may be caused, at least in part, by suppression or blockade of autonomic nerves from carotid arterial and cardiopulmonary baroreceptors caused by ropivacaine spreading into adjacent barosensitive areas, resulting in autonomic imbalance and increases in SBP and HR.
It should be considered that factors other than local anesthetic blockade of impulses from baroreceptors may have contributed to the findings of this study. First, mental stress leads to an increase in BP and HR by way of altered neural CV regulation, often consisting of increased sympathetic activity and reduced BRS (26). Thus, preoperative anxiety, pain, and discomfort during the performance of the blockade could potentially have contributed to the development of autonomic CV alterations and increases in SBP and HR. Second, the addition of epinephrine to the ropivacaine solution may confound the tachycardia and hypertensive effect of the CP blockade, enabling a larger dose of local anesthetic to be administered with less toxicity. As another cause of tachycardia, systemic absorption of epinephrine has been associated with increased HR (27), although no changes in HR with superficial CP blockade alone using epinephrine in the blockade solution have been reported (28) Thus, it is also possible that systemic absorption of local anesthetic or epinephrine may affect autonomic CV regulation (29).
The present study also found that CP blockade-induced attenuation of BRSHF correlated with increased SBP amplitude, indicating the importance of the physiological baroreflex reserve in the regulation of BP homeostasis in patients receiving CP blockade for CEA. However, our results also showed that SBP changes did not correlate with changes in either BRSSEQ or BRSLF. Although the present data do not allow us to identify the precise reason for this inconsistency, it should be noted that BRSSEQ or BRSLF, in contrast to BRSHF, could not be measured in several patients because of a lack of coherence or lack of sequences between RRI and SBP and that the antihypertensive and antianginal medications that were administered until the day of surgery might have affected CV autonomic activity. We suggest that those factors may have contributed to the inconsistent correlation analysis of BRS in the present study.
Several potential limitations are associated with the present study. First, premedication sedatives were not administered because they may have interfered with neurological monitoring during CEA. Thus, withholding such medication may have allowed anxiety to contribute to tachycardia. Second, underlying diseases such as diabetes and CV medications such as β adrenergic antagonists may have affected changes in autonomic CV control (7,13). However, either exclusion of diabetic patients or exclusion of β adrenergic antagonists did not significantly affect the results (data not shown). Moreover, discontinuing CV drug treatment may be unethical in patients with underlying diseases, particularly considering the frequent increases of SBP and HR after CP blockade for CEA. Nevertheless, our data showed that combined CP blockade elicited an autonomic imbalance and reduced cardiac baroreceptor function significantly and that these alterations occurred even when the data were adjusted for confounding factors, such as the concomitant presence of other CV diseases and exposure to CV drugs. Third, we used an epinephrine-containing ropivacaine solution for combined CP blockade. Thus, further study without adding epinephrine to the local anesthetic solution will be required to exclude confounding factors and to provide additional information regarding the mechanisms underlying SBP and HR increases after combined CP blockade. Fourth, we did not demonstrate the duration of impaired autonomic homeostasis after combined CP blockade. Thus, further study will be required to determine whether the duration of autonomic impairment and the perioperative risks are associated. Finally, we did not control patient tidal volumes and respiratory rates throughout the study period. However, a recent study has shown that neither HRV nor up-and-down baroreflex sequences were affected by the mode of breathing (30).
In summary, before CEA surgery commencement, we observed that increases in SBP and HR after combined CP blockade were accompanied by decreased vagal cardiac function, as well as increased vascular sympathetic outflow and a reduced baroreflex reserve. These findings suggest an overall alteration in autonomic CV regulation after combined CP blockade. Additionally, this altered cardiac autonomic control could play a role in increasing cardiac risk by enhancing the incidence of CV disturbances such as arrhythmias, especially in patients with coronary artery disease. Further studies are required to assess whether these autonomic homeostasis alterations have independent prognostic significance during or after surgery in patients undergoing CEA under combined CP blockade, as is the case in postmyocardial infarction and congestive heart failure patients. Thereby, our results might be able to serve as a stimulus for debate concerning whether superficial CP blockade alone would be required, specifically in high-risk patients.
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