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Changes in baroreceptor sensitivity after eversion carotid endarterectomy
Changes in baroreceptor sensitivity after eversion carotid endarterectomy Serdar Demirel, MD,a Nicolas Attigah, MD,a Hans Bruijnen, MD,b Laura Macek, MD,a Maani Hakimi, MD,a Thomas Able, MD,a and Dittmar Böckler, PhD,a Heidelberg and Munich, Germany Objective: Posteversion carotid endarterectomy hypertension has been suggested to be associated with impaired baroreceptor sensitivity (BRS), which has been identified as a factor of prognostic relevance in patients with cardiovascular disease. The aim of this prospective single-center nonrandomized study was to describe the changes of BRS in the early postoperative period after eversion carotid endarterectomy (E-CEA). Methods: Spontaneous BRS and hemodynamic parameters such as blood pressure (BP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were evaluated preoperatively as well as postoperatively after 1 and 3 days using a noninvasive sequential cross-correlation method. Additionally, any modification in vasoactive medication due to BP derangement in the postoperative period was noted. Due to non-normal distribution of BRS, HR, and TPR samples, all measured values were expressed as medians with interquartile range (IQR), and a nonparametric test (Friedman) was performed. After adjustment for multiple testing, differences were considered statistically significant when the two-tailed P value was less than .0036. Results: Thirty-five patients (mean age, 71 years) with symptomatic or asymptomatic internal carotid artery stenosis were included. The BRS significantly decreased to a lower level 24 hours after surgery (4.71 ms/mm Hg [3.02-6.1]) than preoperatively (5.95 ms/mm Hg [4.68-10.86]; P < .0001), resulting in a within-patient difference of –2.46 ms/mm Hg (95% confidence interval [CI], – 8.38 - –1.52). This difference (95% CI, [– 1.58 (– 8.24 - – 0.80)]) persisted at the 72-hour measurements (5.63 ms/mm Hg [3.23-7.69]; P ⴝ .0005). The HR, reflecting the sympathetic activity, increased 24 hours after the operation (69 bpm [61.3-77.7]) compared with preoperative values (63 bpm [57.9-73.2]; P ⴝ .005) (within-patient difference [95% CI] 3.7 [1.5-8.5]), and this increase reached significance at 72 hours (69 bpm [65.4-77.5]; P ⴝ .001) (within-patient difference [95% CI] 5.5 [2.3-8.8]). Values of systolic pressure, diastolic pressure, mean arterial pressure, CO, and TPR were not significantly different between pre- and postoperative measurements. Overall, 23 (66%) patients developed significant postoperative hypertension requiring aggressive management with additional medications. Conclusions: E-CEA might have a decreasing influence on BRS, leading to increased sympathetic activity. Investigations of the longer-term effects of impaired BRS are warranted. These findings should be interpreted with caution, noting the limitation of an absent control group. ( J Vasc Surg 2012;55:1322-8.)
Carotid artery stenosis typically involves accumulation of rigid atheroma at the common carotid artery bifurcation, progressing into the ostium of the internal carotid artery and beyond. Anatomically, this location is in close proximity to the carotid baroreceptors and comprises an apparatus essential to the autoregulation of cerebral blood flow. Baroreceptors are activated by increases in wall tension occurring with increased arterial pressure and modulate both heart rate (HR) and peripheral vascular tone through the medullary baroreflex system. With an acute increase in From the Department of Vascular and Endovascular Surgery, University Hospital of Ruprecht-Karls, Heidelberga; and the Department of Vascular and Thoracic Surgery, Augsburg City Hospital, University of LudwigMaximillians, Munich.b Author conflict of interest: Maquet Getinge Group Cardiovascular sponsored the leasing rates of the device needed for BRS measurements. Maquet was not involved in study design, data acquisition, statistical analysis of the data, or in writing the manuscript. Reprint requests: Serdar Demirel, MD, Department of Vascular and Endovascular Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest. 0741-5214/$36.00 Copyright © 2012 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2011.11.134
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blood pressure (BP), impulses are propagated through the glossopharyngeal and vagal nerves to the nucleus tractus solitarii of the medulla, with resultant activation of parasympathetic nuclei and inhibition of sympathetic nuclei.1 Thus, the consequences of baroreceptor activation include reduction in HR, cardiac output (CO), and total peripheral resistance (TPR); changes that buffer the increase in BP. As such, baroreceptor sensitivity (BRS) can be quantified by the HR response to changes in BP (ms/mm Hg). Clinically, chronic impairment of the baroreceptor sensitivity results in sustained increases in sympathetic nerve activity. This augmented sympathetic activity increases the risk of serious pathologic and morbid consequences, especially in the presence of cardiovascular disease states such as hypertension, heart failure and myocardial infarction, and stroke.2-5 Further, it is associated with increased long-term mortality after acute ischemic stroke, irrespective of age, gender, BP, or the etiologic mechanism of the stroke.5 Traditional carotid endarterectomy (C-CEA) was first reported by DeBakey 6 decades ago6 and involves a longitudinal arteriotomy at the carotid bifurcation with removal of the atheroma and closure of the artery, most commonly with a patch. Eversional carotid endarterectomy (E-CEA) was subsequently reported by DeBakey and popularized by
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Etheredge and Raithel et al as an alternative to C-CEA.7,8 E-CEA requires an oblique circumferential transection of the internal carotid artery (ICA) at the carotid bulb. This maneuver has the potential advantage that patch closures may not be necessary, but it is often accompanied by transection of the longitudinal nerve fibers of the carotid sinus nerve, which in prior studies has been associated with the loss of the baroreceptor reflex and postoperative hypertension.9-13 We hypothesize that eversion endarterectomy is associated with a depressed postoperative BRS, resulting in hemodynamic aberrations. While previous studies have examined changes in BRS after C-CEA,14-18 there are currently no reports that describe the changes that follow E-CEA. Herein, we describe the BRS changes, analyzing hemodynamic parameters such as BP, HR, CO, and TPR preoperatively and in the early postoperative period following E-CEA. METHODS The study protocol was approved by the local ethics committee, and informed written consent was obtained from all patients. Thirty-five consecutive patients, admitted with symptomatic or asymptomatic internal carotid artery stenosis, were included in an open, prospective study. Symptomatic stenosis was defined as transient ischemic attack (TIA) or minor stroke (modified Rankin Scale [mRS] of 0-2). Patients who had experienced a severe stroke causing major disability (mRS of 3-5) as well as patients with prior contralateral carotid surgery and ipsilateral restenosis were excluded from the study. The diagnosis of ICA stenosis was confirmed by color duplex ultrasonography. The postoperative period was defined as the time from the patient’s arrival in the recovery room until discharge from hospital, which usually was the 5th postoperative day, a length of stay that is currently standard in most German hospitals. Postoperative hypertension (HTN) was defined as an elevation in systolic pressures of ⬎180 mm Hg or a ⬎40% rise above normal requiring pharmacologic treatment. Hemodynamic measurements. Noninvasively estimates of BRS were obtained in the time-domain (BRSTD) by the sequence method (cross-correlation BRS), using the Finometer device (Finapres Medical Systems BV, Amsterdam, The Netherlands). This device consists of a strain gauge attached to a finger cuff and connected to a portable recording unit. All patients were placed in the supine position for at least 10 minutes before measurement. A cuff of appropriate size was attached to the middle finger of the nondominant hand, maintained at heart level. Continuous BP (mm Hg) and HR (beats/min) were measured preoperatively on the day of admission and again at 24 and 72 hours after operation. At each time point, CO (L/min) was calculated as the product of stroke volume, and HR and TPR (mm Hg - min/L) were computed as the ratio of mean arterial pressure to CO. The Finometer device computes the cross-correlation in time-domain between beat-to-beat systolic BP and RR
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interval, resampled at 1 Hz, in a sliding 10-second window, with delays of 0 to 5 seconds for interval. The delay with the greatest positive correlation is selected and, when significant at P ⫽ .01, slope and delay are recorded as 1 ⫻ BRS value. Each 1 second of the recording is the start of a new computation. Beat-to-beat averages of all parameters were obtained over 10-minute periods. The potential advantages of this method over common sequential methods include a much larger number of estimates more regularly distributed over time, a halving of the estimation variance as validated in the European Society of Hypertension Working Group on Baroreflex and Cardiovascular Variability (EUROBAVAR) database, and the availability of the best delay as an extra BRS parameter.19 In an effort to limit the effect of antihypertensive agents on BRS, each measurement was performed 1 hour after the administration of routine antihypertensive agents. To address the possible influence of cervical plexus anesthesia on BRS as considered as a confounder, the first postoperative measurement was carried out 24 hours after surgery. If patients had received vasoactive drugs preoperatively, the type of medication was noted, as was any modification in medication made as a result of postoperative BP aberrations. Operative technique and postoperative management. Endarterectomy procedures were performed by an experienced board certified vascular surgeon under cervical plexus block by means of the eversion technique. All patients received 150 g of clonidine for its sedative, analgesic, and hemodynamic stabilizing effects.20 In brief, the E-CEA technique was performed by approaching the carotid bifurcation anterior to the internal jugular vein.21 After dividing the platysma muscle, the jugular vein was identified, and all tributaries were ligated up to the digastric muscle cranially. Next, the carotid artery was mobilized with isolation of the superior thyroid artery, external carotid artery, and the hypoglossal nerve. Complete circumferential mobilization of the carotid bifurcation with transection of the carotid sinus nerve was performed after systemic anticoagulation and clamping of the internal carotid artery. All postoperative antihypertensive medications decisions were coordinated by the two study physicians (S.D., N.A.). In the recovery room, hypertension was managed as necessary with intravenous (IV) clonidine at a dose of 75 g. Similarly, hypertension developing on the ward was treated with subcutaneous clonidine (75 g) or oral nifedipine (10 mg). With n ⫽ 35 patients, we had 80% power at the overall 0.05 significance level to detect a mean population difference between preoperative and 24 hours postoperative BRS values of 5.4 ms/mm Hg or greater with a two-tailed paired t test, assuming a standard deviation of 11 ms/mm Hg and adjusting for multiple testing (two time points and seven variables of interest). Statistics. The Shapiro–Wilk W test was used to quantify the normality of distribution for BRS and the hemodynamic parameters (systolic pressure [SP], diastolic pressure
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Table I. Demographics and indication for surgery of patients undergoing E-CEA Patients Male Female Age (years) (SD) Symptomatic stenosis Modified Rankin scale 0 1 Asymptomatic stenosis Hypertension Coronary artery disease Diabetes mellitus Hyperlipoproteinemia Symptomatic peripheral arterial disease Arrhythmia Nicotine use Body mass index (mean ⫾ SD) American Society of Anesthesiology scale 1 2 3 4 Stenosis ipsilateral (%) (SD) Severe contralateral stenosis (ⱖ70%) On antihypertensive medication
E-CEA (n ⫽ 35) 32 (91%) 3 (9%) 71 (8.86) 11 (31%) 33 (94%) 2 (6%) 24 (69%) 34 (97%) 12 (34%) 12 (34%) 32 (91%) 15 (43%) 11 (31%) 15 (43%) 26 ⫾ 2.8 0 10 (29%) 25 (71%) 0 84.4 (7%) 2 (5.7%) 33 (94%)
E-CEA, Eversion carotid endarterectomy; SD, standard deviation.
[DP], mean arterial pressure [MAP], CO, and TPR). BRS (P ⬍ .0001), HR (P ⫽ .02), and TPR (P ⬍ .0001) were unlikely to be from a normal distribution, as were the preto postoperative changes for all variables except HR. Therefore, for the purpose of uniformity of statistical testing and because the standard deviation is a poor measure of spread for skewed distributions, values were expressed as median and interquartile range (IQR). Nonparametric tests (Friedman test) for paired samples were performed. To maintain an overall significance level of 0.05 when conducting multiple tests (14 tests: baroreceptor sensitivity and six other hemodynamic parameters, each at 24 and 72 hours), the criterion for significance for each two-tailed test was P ⬍ .0036, applying the Bonferroni correction. The MannWhitney U test was performed to evaluate any association between the changes and baseline variables. Statsdirect software (Version 2.7.3, Statsdirect Ltd, Cheshire, UK) was used for all statistical analyses. RESULTS History of hypertension. Among the 35 patients in the final cohort, 34 (97%) had a history of hypertension, and 33 (97%) of these were receiving antihypertensive therapy at the time of enrollment (Table I). Among those patients receiving antihypertensive therapy, 22 (67%) had normal preoperative baseline BP (systolic BP ⬍140 mm Hg and diastolic BP ⬍90 mm Hg), and 11 (33%) had high BP (systolic BP ⬎140 mm Hg or diastolic BP ⬎90 mm Hg) despite antihypertensive medication. Neither of the remaining two patients (one with and one without a history
of hypertension) had elevated BP, and neither was on antihypertensive medication. Baroreceptor sensitivity. The median baseline BRS was 5.95 with an IQR of 4.68 to 10.86. Postoperatively, the median BRS fell to 4.71 (IQR 3.02-6.10) at 24 hours (P ⬍ .0001; Table II) and to 5.63 (IQR 3.23-7.69) at 72 hours (P ⫽ .0005; Table III). No baseline variable (age, gender, hyperlipidemia, hypertension, smoking, diabetes mellitus, coronary artery disease, arrhythmia, and peripheral artery disease) was associated with the pre- to postoperative change in BRS. The lowest preoperative BRS value was 2.06 ms/mm Hg, observed in a symptomatic patient with an acute stroke (mRS 1) and positive computed tomography findings in the insular region. BRS did not increase after E-CEA in this patient, with BRS values of 2.39 and 2.08 at 24 and 72 hours following operation, respectively. There was some restoration of BRS between the earlier (24-hour) and later (72-hour) time points (Fig 1). Overall, 29 (83%) patients had a reduction in BRS (Fig 2). There were four patients who were considered outliers on the basis of preoperative BRS, and their responses are illustrated in Fig 3. The postoperative increase of HR, reflecting the sympathetic activity, was significant at 72 hours (P ⫽ .001) after operation (Table III, Fig 4). Values of SP, DP, MAP, CO, and TPR were not significantly different from baseline at either the 24- or 72-hour time point (Tables II and III). The negative correlation between preoperative to postoperative BRS and HR did not achieve statistical significance (Spearman’s rank correlation coefficient ⫽ 0.25; 95% CI, 0.54-0.09; one-sided P ⫽ .07), nor were there any significant correlations between BRS and the other hemodynamic parameters (SP, DP, MAP, CO, and TPR). Requirements for antihypertensive therapy. Administration of at least one vasodilator for systolic BP of ⬎180 mm Hg or a ⬎40% rise above normal was required in 23 (66%) patients overall, including nine (26%) patients during the first 6 hours in the recovery room and 19 (54%) cases after transfer to the surgical ward. Among patients requiring acute administration of vasodilator, 14 belonged to the group with preoperatively normal BP (14/24 [58%]) and the remaining nine patients to the group with preoperatively high BP despite antihypertensive medication (9/11 [82%]). The dosage of existing antihypertensive medications during hospitalization was increased and/or additional antihypertensive medication was prescribed in seven (20%) patients. Among the 23 (66%) patients requiring supplemental antihypertensive medication, one (3%) experienced prolonged hypertension and required 2 additional hospital days. No patient experienced stroke, myocardial infarction, or death following operation. DISCUSSION Baroreceptor sensitivity falls following eversional carotid endarterectomy and denervation of the carotid sinus nerve. As well, HR and BP rise, indicative of increased sympathetic activity in the immediate and short-term pe-
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Table II. Baroreceptor sensitivity and other hemodynamic parameters n ⫽ 35 Baroreceptor sensitivityTD (ms/mm Hg) Systolic pressure Diastolic pressure Mean arterial pressure Heart rate (beats/min) Cardiac output (L/min) Total peripheral resistance (mm Hg.min/L)
Preoperative (median [IQR])
24 hours postoperative (median [IQR])
5.95 (4.68-10.86)
4.71 (3.02-6.10)
130 (115.9-145.1) 65 (56.6-72.7) 87 (79.7-97.2) 63 (57.9-73.2) 5.99 (4.8-7.4) 1150 (913-1664)
121 (108.8-138.6) 64 (55.8-73.5) 86 (76.3-96.3) 69 (61.3-77.7) 6.05 (5.0-7.6) 1144 (877-1487)
P valuea
Within-patient differences (median [99.64% CI])b
⬍.0001
⫺2.46 (–11.25 - ⫺1.06)
.63 .91 .81 .005 .91 .81
⫺4.3 (⫺24.6-5.4) ⫺2.1 (⫺9.1-5.0) ⫺1.7 (⫺13.3-4.7) 3.7 (0.4-10.8) ⫺0.2 (⫺0.7-1.2) ⫺27.6 (⫺2503.5-996.1)
CI, Confidence interval; IQR, interquartile range. Values represent the beat-to-beat averages over 10-minute recording periods; preoperative versus 24-hour postoperative values. Comparison of non-normally distributed values with Friedman test (nonparametric test). a Significance criterion for each test: P ⬍ .0036, adjusting for multiple testing. b Instead of the usual 95% CI, the 99.64% CI was calculated according to the P value .0036, which was obtained in the analysis.
Table III. Baroreceptor sensitivity and other hemodynamic parameters n ⫽ 35 Barorecepter sensitivityTD (ms/mm Hg) Systolic pressure Diastolic pressure Mean arterial pressure Heart rate (beats/min) Cardiac output (L/min) Total peripheral resistance (mm Hg.min/L)
Preoperative (median [IQR])
72 hour postoperative (median [IQR])
P valuea
Within-patient differences (median [96.64% CI])b
5.95 (4.68-10.86)
5.63 (3.23-7.69)
.0005
⫺1.58 (⫺11.47 - –0.63)
130 (115.9-145.1) 65 (56.6-72.7) 87 (79.7-97.2) 63 (57.9-73.2) 6.0 (4.8-7.4) 1150 (913-1664)
135 (111.6-154.5) 67 (56.2-75.0) 90 (77.8-101.0) 69 (65.4-77.5) 6.2 (4.6-7.9) 1132 (920-1636)
.81 .55 .91 .001 .91 .4
⫺1.4 (⫺17.7-12.7) 1.3 (⫺8.1-8.0) ⫺0.3 (⫺9.2-9.2) 5.5 (0.8-10.4) ⫺0.1 (⫺0.6-1.4) ⫺45.0 (⫺2505.4-1017.7)
CI, Confidence interval; IQR, interquartile range. Values represent the beat-to-beat averages over 10-minute recording periods; preoperative versus 72-hour postoperative values. Comparison of non-normally distributed values with Friedman test (nonparametric test). a Significance criterion for each test: P ⬍ .0036, adjusting for multiple testing. b Instead of the usual 95% CI, the 99.64% CI was calculated according to the P value .0036, which was obtained in the analysis.
riod after operation. While no significant differences in other hemodynamic parameters, including SP, DP, MAP, CO, and TPR were detected at the 24- and 72-hour time points, this observation was a likely result of recording of these parameters at just two discrete time points; hypertension was detected and treated rapidly such that a normotensive state was quickly achieved. Further, patients in the current study were routinely treated with clonidine, an agent known to decrease peripheral norepinephrine release. Through stimulation of prejunctional inhibitory ␣2 adrenoceptors and inhibition of neural transmission in different brainstem areas such as the nucleus-tractus solitarius and the lateral reticular nucleus in the ventrolateral medulla, clonidine may have attenuated the BRS effects on the hemodynamic parameters.20 Miyamoto et al examined the effects of clonidine on the HR response to dynamic cardiac sympathetic nerve stimulation in a rabbit model.22 Clonidine attenuated the dynamic HR response to sympathetic nerve stimulation. A decrease in mean HR was observed, but a residual increase in HR persisted. Other antihypertensives, includ-
ing -blockers, diuretics, calcium-channel blockers, angiotensin receptor-1 blockers, nitro-glycerin (in acute administration), and clonidine, increase BRS. Diuretics and other antihypertensives decrease BP and BP-variability, resulting in an increased BRS. Clonidine improves spontaneous BRS through parasympathetic activation.23-27 For ethical reasons, we were not able to withdraw antihypertensive drugs, agents that represent potential confounders of BRS and hemodynamic measurements. However, despite the fact that these drugs enhance BRS, the postoperative BRS values decreased significantly. The failure to detect significant changes in BP values such as SP, DP, and MAP, as well as TPR, suggests that medical interventions successfully controlled BP despite impaired BRS. Our results support the hypothesis that unilateral carotid sinus nerve denervation is sufficient to generate significant physiological changes, in parallel with the clinical findings of a previous study that demonstrated a rise in systolic BP through the 4th day following E-CEA.11 Speculatively, the explanation for the transience of this phenom-
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Fig 1. Notched box and whisker plots displaying postoperative change in baroreceptor sensitivity (BRS). A, The change in absolute values of the BRS. B, The preoperative-to-postoperative change in BRS. The length of each box represents the interquartile range, defined as the distance between the 25th and the 75th percentiles. The three horizontal lines running through the box represent the median (middle line) and the upper and lower bounds of the 95% confidence interval around the median (median ⫾ 1.58 ⫻ the quartile range.) The length of the whiskers above each box depicts 1.5 times the interquartile distance and the length of the whiskers below each box represents the interquartile distance times 1.5 as measured down from the top of the box. Outside values are defined as those data points that are 1.5 to 3.0 times the interquartile distance, while far outside values are defined as those that exceed three times the interquartile distance.
Fig 3. Baroreceptor sensitivity (BRS) of the four preoperative outliers at baseline, 24 hours, and 72 hours after surgery.
Fig 2. Baroreceptor sensitivity (BRS) change from baseline at 24 and 72 hours following operation.
enon may relate to recovery of BRS function through the baroreflex apparatus located on the contralateral side and the aortic arch; compensatory mechanisms that may require several days to adapt. Scher et al demonstrated a rise in mean BP lasting for 1 week in a large animal model of bilateral carotid sinus nerve denervation.28 However, to our knowledge, no experimental data exists on unilateral carotid sinus nerve denervation. Preoperative neurologic deficits have been reported to be an independent predictor of hypertension after CEA.29,30 This phenomenon could be contributed to impairment of the central component of the baroreflex.5 Patients with prior contralateral or ipsilateral carotid sur-
gery might have altered baroreflex function from damage to the carotid sinus nerve and the carotid sinus baroreceptors.13 Therefore, patients who had experienced a severe stroke causing major disability (mRS of 3-5) as well as patients with prior contralateral carotid surgery and ipsilateral restenosis were excluded from the current study. Seagard et al identified two types of carotid sinus baroreceptors with distinct contributions to the regulation of BP. Selective elimination of type one receptors, mainly large myelinated A-fibers, produced a decrease in BRS or attenuation of control of dynamic changes in BP, without an associated change in the tonic resting BP. Subsequent elimination of type-two receptors, mainly small A-fibers and nonmyelinated C-fibers, produced additional attenuation of BRS and significant increases in resting baseline BP.31 These observations are relevant to the observations of the present study. It appears that dissection of the carotid
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Fig 4. Notched box and whisker plots displaying postoperative change in heart rate (HR).
bulb and transection of the carotid sinus nerve during E-CEA at least impair the sensitivity of type two baroreceptors. Chronic impairment of the baroreflex results in sustained increases in sympathetic nerve activity with potentially serious pathologic and morbid consequences in cardiovascular disease states, such as hypertension, heart failure, myocardial infarction, and stroke.2-5 BRS lower than 3 ms/mm Hg is a powerful independent prognostic risk factor for sudden cardiac death.32,33 An enhanced BRS had beneficial effects on the outcome of patients with cardiovascular disease, possibly by preventing ventricular arrhythmias.34 Chao et al found that patients with carotid artery stenosis exhibited a significant reduction in BRS compared with controls.35 Sykora et al demonstrated that acute stroke with insular involvement was associated with significantly greater BRS impairment compared with BRS in stroke patients without insular involvement.36 Interestingly, the lowest initial BRS value in the current series (2.06) belonged to a patient with an acute insular stroke. In a sense, C-CEA might be protective against postoperative cardiovascular events, since the procedure may be associated with increased BRS. A longitudinal arteriotomy is generally employed during C-CEA, and unlike E-CEA, complete mobilization of the carotid bifurcation and division of the carotid sinus nerve is not necessary.13 As far back as 1974, Angell-James and colleagues demonstrated that removal of rigid atheroma at C-CEA improved carotid baroreflex sensitivity.9 The pathophysiological explanation of this phenomenon relates to a reduction pressure wave dampening after removal of the atherosclerotic plaque, increasing baroreceptor stimulation from increased vessel compliance.12 We previously reported an association between C-CEA and decreased BP in the immediate and short-term postoperative period.11 There exist clinical observations to support these hypotheses; Hirschl et al found BRS to be a predictor of cardiovascular morbidity and
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mortality in patients after C-CEA.15 Failure of BRS to increase postoperatively was associated with a significantly higher risk of major vascular events over 5-year follow-up. The main limitation of the current study is the fact that there is no control group. While the study size was sufficient to demonstrate significant impairment in BRS following E-CEA, it was not large enough to reliably detect a clinically prognostic association between impaired BRS and postoperative adverse events such as cardiovascular, neurologic, and other complications. As well, the potential masking of hemodynamic changes by the use of antihypertensive agents may have blunted the effect of baroreceptor disruption on hemodynamic parameters. In conjunction with the small sample size, such an effect may account for the failure to achieve statistically significant differences in the pre- to postoperative hemodynamic changes or in the correlations between BRS and hemodynamic variables. Further, the study protocol mandated recording of hemodynamic parameters at just two discrete time points, 24 and 72 hours, for purposes of data collection. This may explain the failure to detect a significant difference between the pre- and postoperative hemodynamic values; for instance, postoperative hypertension was relatively quickly identified and treated with normalization of hemodynamic variables by the time of the recordings. Lastly, the lack of a control group of patients treated without carotid sinus nerve denervation, for example, patients undergoing conventional carotid endarterectomy with preservation of the nerve, is a shortcoming of our study design. Inclusion of such a group might have allowed the detection of hemodynamic differences directly attributable to BRS and provided some evidence of causality. In conclusion, E-CEA might have a decreasing influence on BRS leading to higher sympathetic tone during the early postoperative period. Clearly, however, subsequent longer-term, larger-scale studies with inclusion of a group of patients undergoing C-CEA are warranted to discover whether the BRS impairment is chronic and if it is associated with long-term adverse outcomes. These findings should be interpreted with caution, noting the limitation of an absent control group. AUTHOR CONTRIBUTIONS Conception and design: SD Analysis and interpretation: SD, NA Data collection: LM Writing the article: SD, NA Critical revision of the article: DB, MH, TA Final approval of the article: SD Statistical analysis: HB Obtained funding: SD Overall responsibility: SD SD and NA contributed equally to this work. REFERENCES 1. Filippone JD, Bisognano JD. Baroreflex stimulation in the treatment of hypertension. Curr Opin Nephrol Hypertens 2007;16:403-8.
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2. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (autonomic tone and reflexes after myocardial infarction) investigators. Lancet 1998;351:478-84. 3. Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 1997;96:3450-8. 4. Piccirillo G, Di Giuseppe V, Nocco M, Lionetti M, Moisè A, Naso C, et al. Influence of aging and other cardiovascular risk factors on baroreflex sensitivity. J Am Geriatr Soc 2001;49:1059-65. 5. Robinson TG, Dawson SL, Eames PJ, Panerai RB, Potter JF. Cardiac baroreceptor sensitivity predicts long-term outcome after acute ischemic stroke. Stroke 2003;34:705-12. 6. Fields WS, Crawford ES, Debakey ME. Surgical considerations in cerebral arterial insufficiency. Neurology 1958;8:801-8. 7. Etheredge SN. A simple technic for carotid endarterectomy. Am J Surg 1970;120:275-8. 8. Kasprzak P, Raithel D. [Eversion endarterectomy of the internal carotid artery]. Vasa Suppl 1992;37:83-4. 9. Angell-James JE, Lumley JS. The effects of carotid endarterectomy on the mechanical properties of the carotid sinus and carotid sinus nerve activity in atherosclerotic patients. Br J Surg 1974;61:805-10. 10. Bove EL, Fry WJ, Gross WS, Stanley JC. Hypotension and hypertension as consequences of baroreceptor dysfunction following carotid endarterectomy. Surgery 1979;85:633-7. 11. Demirel S, Bruijnen H, Attigah N, Hakimi M, Bockler D. The effect of eversion and conventional-patch technique in carotid surgery on postoperative hypertension. J Vasc Surg 2011;54:80-6. 12. Lehv MS, Salzman EW, Silen W. Hypertension complicating carotid endarterectomy. Stroke 1970;1:307-13. 13. Mehta M, Rahmani O, Dietzek AM, Mecenas J, Scher LA, Friedman SG, et al. Eversion technique increases the risk for post-carotid endarterectomy hypertension. J Vasc Surg 2001;34:839-45. 14. Dehn TC, Angell-James JE. Long-term effect of carotid endarterectomy on carotid sinus baroreceptor function and blood pressure control. Br J Surg 1987;74:997-1000. 15. Hirschl M, Kundi M, Blazek G. Five-year follow-up of patients after thromboendarterectomy of the internal carotid artery: relevance of baroreceptor sensitivity. Stroke 1996;27:1167-72. 16. Sigaudo-Roussel D, Evans DH, Naylor AR, Panerai RB, London NL, Bell P, et al. Deterioration in carotid baroreflex during carotid endarterectomy. J Vasc Surg 2002;36:793-8. 17. Tydén G, Samnegård H, Thulin L. Rational treatment of hypotension after carotid endarterectomy by carotid sinus nerve blockade. Acta Chir Scand Suppl 1980;500:61-4. 18. Wade JG, Larson CP, Jr, Hickey RF, Ehrenfeld WK, Severinghaus JW. Effect of carotid endarterectomy on carotid chemoreceptor and baroreceptor function in man. N Engl J Med 1970;282:823-9. 19. Westerhof BE, Gisolf J, Stok WJ, Wesseling KH, Karemaker JM. Time-domain cross-correlation baroreflex sensitivity: performance on the EUROBAVAR data set. J Hypertens 2004;22:1371-80. 20. Schneemilch CE, Bachmann H, Ulrich A, Elwert R, Halloul Z, Hachenberg T. Clonidine decreases stress response in patients undergoing carotid endarterectomy under regional anesthesia: a prospective, randomized, double-blinded, placebo-controlled study. Anesth Analg 2006;103:297-302, table of contents.
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21. Zarins CK, Gewertz BL. Atlas of vascular surgery. New York: Churchill Livingstone; 2005. 22. Miyamoto T, Kawada T, Yanagiya Y, Akiyama T, Kamiya A, Mizuno M, et al. Contrasting effects of presynaptic alpha2-adrenergic autoinhibition and pharmacologic augmentation of presynaptic inhibition on sympathetic heart rate control. Am J Physiol Heart Circ Physiol 2008; 295:H1855-66. 23. Gori T, Floras JS, Parker JD. Effects of nitroglycerin treatment on baroreflex sensitivity and short-term heart rate variability in humans. J Am Coll Cardiol 2002;40:2000-5. 24. Shaltout HA, Rose JC, Figueroa JP, Chappell MC, Diz DI, Averill DB. Acute AT(1)-receptor blockade reverses the hemodynamic and baroreflex impairment in adult sheep exposed to antenatal betamethasone. Am J Physiol Heart Circ Physiol 2011;299:H541-7. 25. Tank J, Jordan J, Diedrich A, Obst M, Plehm R, Luft FC, et al. Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation. Hypertension 2004;43: 1042-7. 26. Truijen J, Davis SC, Stok WJ, Kim YS, van Westerloo DJ, Levi M, et al. Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under beta-adrenergic blockade. Clin Sci (Lond) 2011; 120:161-7. 27. Xie HH, Zhang XF, Chen YY, Shen FM, Su DF. Synergism of hydrochlorothiazide and nifedipine on blood pressure variability reduction and organ protection in spontaneously hypertensive rats. Hypertens Res 2008;31:685-91. 28. Scher AM. Carotid and aortic regulation or arterial blood pressure. George A. Brown memorial lecture. Circulation 1977;56:521-8. 29. Towne JB, Bernhard VM. The relationship of postoperative hypertension to complications following carotid endarterectomy. Surgery 1980; 88:575-80. 30. Wong JH, Findlay JM, Suarez-Almazor ME. Hemodynamic instability after carotid endarterectomy: risk factors and associations with operative complications. Neurosurgery 1997;41:35-41; Discussion 41-3. 31. Seagard JL, Hopp FA, Drummond HA, Van Wynsberghe DM. Selective contribution of two types of carotid sinus baroreceptors to the control of blood pressure. Circ Res 1993;72:1011-22. 32. Honzikova N, Fiser B, Semrad B. Critical value of baroreflex sensitivity determined by spectral analysis in risk stratification after myocardial infarction. Pacing Clin Electrophysiol 2000;23:1965-7. 33. Honzíková N, Semrád B, Fiser B, Lábrová R. Baroreflex sensitivity determined by spectral method and heart rate variability, and two-years mortality in patients after myocardial infarction. Physiol Res 2000;49: 643-50. 34. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730-7. 35. Chao AC, Chern CM, Kuo TB, Chou CH, Chuang YM, Wong WJ, et al. Noninvasive assessment of spontaneous baroreflex sensitivity and heart rate variability in patients with carotid stenosis. Cerebrovasc Dis 2003;16:151-7. 36. Sykora M, Diedler J, Rupp A, Turcani P, Steiner T. Impaired baroreceptor reflex sensitivity in acute stroke is associated with insular involvement, but not with carotid atherosclerosis. Stroke 2009;40:737-42.
Submitted Sep 6, 2011; accepted Nov 28, 2011.
Carotid artery stenosis typically involves accumulation of rigid atheroma at the common carotid artery bifurcation, progressing into the ostium of the internal carotid artery and beyond. Anatomically, this location is in close proximity to the carotid baroreceptors and comprises an apparatus essential to the autoregulation of cerebral blood flow. Baroreceptors are activated by increases in wall tension occurring with increased arterial pressure and modulate both heart rate (HR) and peripheral vascular tone through the medullary baroreflex system. With an acute increase in From the Department of Vascular and Endovascular Surgery, University Hospital of Ruprecht-Karls, Heidelberga; and the Department of Vascular and Thoracic Surgery, Augsburg City Hospital, University of LudwigMaximillians, Munich.b Author conflict of interest: Maquet Getinge Group Cardiovascular sponsored the leasing rates of the device needed for BRS measurements. Maquet was not involved in study design, data acquisition, statistical analysis of the data, or in writing the manuscript. Reprint requests: Serdar Demirel, MD, Department of Vascular and Endovascular Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest. 0741-5214/$36.00 Copyright © 2012 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2011.11.134
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blood pressure (BP), impulses are propagated through the glossopharyngeal and vagal nerves to the nucleus tractus solitarii of the medulla, with resultant activation of parasympathetic nuclei and inhibition of sympathetic nuclei.1 Thus, the consequences of baroreceptor activation include reduction in HR, cardiac output (CO), and total peripheral resistance (TPR); changes that buffer the increase in BP. As such, baroreceptor sensitivity (BRS) can be quantified by the HR response to changes in BP (ms/mm Hg). Clinically, chronic impairment of the baroreceptor sensitivity results in sustained increases in sympathetic nerve activity. This augmented sympathetic activity increases the risk of serious pathologic and morbid consequences, especially in the presence of cardiovascular disease states such as hypertension, heart failure and myocardial infarction, and stroke.2-5 Further, it is associated with increased long-term mortality after acute ischemic stroke, irrespective of age, gender, BP, or the etiologic mechanism of the stroke.5 Traditional carotid endarterectomy (C-CEA) was first reported by DeBakey 6 decades ago6 and involves a longitudinal arteriotomy at the carotid bifurcation with removal of the atheroma and closure of the artery, most commonly with a patch. Eversional carotid endarterectomy (E-CEA) was subsequently reported by DeBakey and popularized by
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Etheredge and Raithel et al as an alternative to C-CEA.7,8 E-CEA requires an oblique circumferential transection of the internal carotid artery (ICA) at the carotid bulb. This maneuver has the potential advantage that patch closures may not be necessary, but it is often accompanied by transection of the longitudinal nerve fibers of the carotid sinus nerve, which in prior studies has been associated with the loss of the baroreceptor reflex and postoperative hypertension.9-13 We hypothesize that eversion endarterectomy is associated with a depressed postoperative BRS, resulting in hemodynamic aberrations. While previous studies have examined changes in BRS after C-CEA,14-18 there are currently no reports that describe the changes that follow E-CEA. Herein, we describe the BRS changes, analyzing hemodynamic parameters such as BP, HR, CO, and TPR preoperatively and in the early postoperative period following E-CEA. METHODS The study protocol was approved by the local ethics committee, and informed written consent was obtained from all patients. Thirty-five consecutive patients, admitted with symptomatic or asymptomatic internal carotid artery stenosis, were included in an open, prospective study. Symptomatic stenosis was defined as transient ischemic attack (TIA) or minor stroke (modified Rankin Scale [mRS] of 0-2). Patients who had experienced a severe stroke causing major disability (mRS of 3-5) as well as patients with prior contralateral carotid surgery and ipsilateral restenosis were excluded from the study. The diagnosis of ICA stenosis was confirmed by color duplex ultrasonography. The postoperative period was defined as the time from the patient’s arrival in the recovery room until discharge from hospital, which usually was the 5th postoperative day, a length of stay that is currently standard in most German hospitals. Postoperative hypertension (HTN) was defined as an elevation in systolic pressures of ⬎180 mm Hg or a ⬎40% rise above normal requiring pharmacologic treatment. Hemodynamic measurements. Noninvasively estimates of BRS were obtained in the time-domain (BRSTD) by the sequence method (cross-correlation BRS), using the Finometer device (Finapres Medical Systems BV, Amsterdam, The Netherlands). This device consists of a strain gauge attached to a finger cuff and connected to a portable recording unit. All patients were placed in the supine position for at least 10 minutes before measurement. A cuff of appropriate size was attached to the middle finger of the nondominant hand, maintained at heart level. Continuous BP (mm Hg) and HR (beats/min) were measured preoperatively on the day of admission and again at 24 and 72 hours after operation. At each time point, CO (L/min) was calculated as the product of stroke volume, and HR and TPR (mm Hg - min/L) were computed as the ratio of mean arterial pressure to CO. The Finometer device computes the cross-correlation in time-domain between beat-to-beat systolic BP and RR
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interval, resampled at 1 Hz, in a sliding 10-second window, with delays of 0 to 5 seconds for interval. The delay with the greatest positive correlation is selected and, when significant at P ⫽ .01, slope and delay are recorded as 1 ⫻ BRS value. Each 1 second of the recording is the start of a new computation. Beat-to-beat averages of all parameters were obtained over 10-minute periods. The potential advantages of this method over common sequential methods include a much larger number of estimates more regularly distributed over time, a halving of the estimation variance as validated in the European Society of Hypertension Working Group on Baroreflex and Cardiovascular Variability (EUROBAVAR) database, and the availability of the best delay as an extra BRS parameter.19 In an effort to limit the effect of antihypertensive agents on BRS, each measurement was performed 1 hour after the administration of routine antihypertensive agents. To address the possible influence of cervical plexus anesthesia on BRS as considered as a confounder, the first postoperative measurement was carried out 24 hours after surgery. If patients had received vasoactive drugs preoperatively, the type of medication was noted, as was any modification in medication made as a result of postoperative BP aberrations. Operative technique and postoperative management. Endarterectomy procedures were performed by an experienced board certified vascular surgeon under cervical plexus block by means of the eversion technique. All patients received 150 g of clonidine for its sedative, analgesic, and hemodynamic stabilizing effects.20 In brief, the E-CEA technique was performed by approaching the carotid bifurcation anterior to the internal jugular vein.21 After dividing the platysma muscle, the jugular vein was identified, and all tributaries were ligated up to the digastric muscle cranially. Next, the carotid artery was mobilized with isolation of the superior thyroid artery, external carotid artery, and the hypoglossal nerve. Complete circumferential mobilization of the carotid bifurcation with transection of the carotid sinus nerve was performed after systemic anticoagulation and clamping of the internal carotid artery. All postoperative antihypertensive medications decisions were coordinated by the two study physicians (S.D., N.A.). In the recovery room, hypertension was managed as necessary with intravenous (IV) clonidine at a dose of 75 g. Similarly, hypertension developing on the ward was treated with subcutaneous clonidine (75 g) or oral nifedipine (10 mg). With n ⫽ 35 patients, we had 80% power at the overall 0.05 significance level to detect a mean population difference between preoperative and 24 hours postoperative BRS values of 5.4 ms/mm Hg or greater with a two-tailed paired t test, assuming a standard deviation of 11 ms/mm Hg and adjusting for multiple testing (two time points and seven variables of interest). Statistics. The Shapiro–Wilk W test was used to quantify the normality of distribution for BRS and the hemodynamic parameters (systolic pressure [SP], diastolic pressure
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Table I. Demographics and indication for surgery of patients undergoing E-CEA Patients Male Female Age (years) (SD) Symptomatic stenosis Modified Rankin scale 0 1 Asymptomatic stenosis Hypertension Coronary artery disease Diabetes mellitus Hyperlipoproteinemia Symptomatic peripheral arterial disease Arrhythmia Nicotine use Body mass index (mean ⫾ SD) American Society of Anesthesiology scale 1 2 3 4 Stenosis ipsilateral (%) (SD) Severe contralateral stenosis (ⱖ70%) On antihypertensive medication
E-CEA (n ⫽ 35) 32 (91%) 3 (9%) 71 (8.86) 11 (31%) 33 (94%) 2 (6%) 24 (69%) 34 (97%) 12 (34%) 12 (34%) 32 (91%) 15 (43%) 11 (31%) 15 (43%) 26 ⫾ 2.8 0 10 (29%) 25 (71%) 0 84.4 (7%) 2 (5.7%) 33 (94%)
E-CEA, Eversion carotid endarterectomy; SD, standard deviation.
[DP], mean arterial pressure [MAP], CO, and TPR). BRS (P ⬍ .0001), HR (P ⫽ .02), and TPR (P ⬍ .0001) were unlikely to be from a normal distribution, as were the preto postoperative changes for all variables except HR. Therefore, for the purpose of uniformity of statistical testing and because the standard deviation is a poor measure of spread for skewed distributions, values were expressed as median and interquartile range (IQR). Nonparametric tests (Friedman test) for paired samples were performed. To maintain an overall significance level of 0.05 when conducting multiple tests (14 tests: baroreceptor sensitivity and six other hemodynamic parameters, each at 24 and 72 hours), the criterion for significance for each two-tailed test was P ⬍ .0036, applying the Bonferroni correction. The MannWhitney U test was performed to evaluate any association between the changes and baseline variables. Statsdirect software (Version 2.7.3, Statsdirect Ltd, Cheshire, UK) was used for all statistical analyses. RESULTS History of hypertension. Among the 35 patients in the final cohort, 34 (97%) had a history of hypertension, and 33 (97%) of these were receiving antihypertensive therapy at the time of enrollment (Table I). Among those patients receiving antihypertensive therapy, 22 (67%) had normal preoperative baseline BP (systolic BP ⬍140 mm Hg and diastolic BP ⬍90 mm Hg), and 11 (33%) had high BP (systolic BP ⬎140 mm Hg or diastolic BP ⬎90 mm Hg) despite antihypertensive medication. Neither of the remaining two patients (one with and one without a history
of hypertension) had elevated BP, and neither was on antihypertensive medication. Baroreceptor sensitivity. The median baseline BRS was 5.95 with an IQR of 4.68 to 10.86. Postoperatively, the median BRS fell to 4.71 (IQR 3.02-6.10) at 24 hours (P ⬍ .0001; Table II) and to 5.63 (IQR 3.23-7.69) at 72 hours (P ⫽ .0005; Table III). No baseline variable (age, gender, hyperlipidemia, hypertension, smoking, diabetes mellitus, coronary artery disease, arrhythmia, and peripheral artery disease) was associated with the pre- to postoperative change in BRS. The lowest preoperative BRS value was 2.06 ms/mm Hg, observed in a symptomatic patient with an acute stroke (mRS 1) and positive computed tomography findings in the insular region. BRS did not increase after E-CEA in this patient, with BRS values of 2.39 and 2.08 at 24 and 72 hours following operation, respectively. There was some restoration of BRS between the earlier (24-hour) and later (72-hour) time points (Fig 1). Overall, 29 (83%) patients had a reduction in BRS (Fig 2). There were four patients who were considered outliers on the basis of preoperative BRS, and their responses are illustrated in Fig 3. The postoperative increase of HR, reflecting the sympathetic activity, was significant at 72 hours (P ⫽ .001) after operation (Table III, Fig 4). Values of SP, DP, MAP, CO, and TPR were not significantly different from baseline at either the 24- or 72-hour time point (Tables II and III). The negative correlation between preoperative to postoperative BRS and HR did not achieve statistical significance (Spearman’s rank correlation coefficient ⫽ 0.25; 95% CI, 0.54-0.09; one-sided P ⫽ .07), nor were there any significant correlations between BRS and the other hemodynamic parameters (SP, DP, MAP, CO, and TPR). Requirements for antihypertensive therapy. Administration of at least one vasodilator for systolic BP of ⬎180 mm Hg or a ⬎40% rise above normal was required in 23 (66%) patients overall, including nine (26%) patients during the first 6 hours in the recovery room and 19 (54%) cases after transfer to the surgical ward. Among patients requiring acute administration of vasodilator, 14 belonged to the group with preoperatively normal BP (14/24 [58%]) and the remaining nine patients to the group with preoperatively high BP despite antihypertensive medication (9/11 [82%]). The dosage of existing antihypertensive medications during hospitalization was increased and/or additional antihypertensive medication was prescribed in seven (20%) patients. Among the 23 (66%) patients requiring supplemental antihypertensive medication, one (3%) experienced prolonged hypertension and required 2 additional hospital days. No patient experienced stroke, myocardial infarction, or death following operation. DISCUSSION Baroreceptor sensitivity falls following eversional carotid endarterectomy and denervation of the carotid sinus nerve. As well, HR and BP rise, indicative of increased sympathetic activity in the immediate and short-term pe-
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Table II. Baroreceptor sensitivity and other hemodynamic parameters n ⫽ 35 Baroreceptor sensitivityTD (ms/mm Hg) Systolic pressure Diastolic pressure Mean arterial pressure Heart rate (beats/min) Cardiac output (L/min) Total peripheral resistance (mm Hg.min/L)
Preoperative (median [IQR])
24 hours postoperative (median [IQR])
5.95 (4.68-10.86)
4.71 (3.02-6.10)
130 (115.9-145.1) 65 (56.6-72.7) 87 (79.7-97.2) 63 (57.9-73.2) 5.99 (4.8-7.4) 1150 (913-1664)
121 (108.8-138.6) 64 (55.8-73.5) 86 (76.3-96.3) 69 (61.3-77.7) 6.05 (5.0-7.6) 1144 (877-1487)
P valuea
Within-patient differences (median [99.64% CI])b
⬍.0001
⫺2.46 (–11.25 - ⫺1.06)
.63 .91 .81 .005 .91 .81
⫺4.3 (⫺24.6-5.4) ⫺2.1 (⫺9.1-5.0) ⫺1.7 (⫺13.3-4.7) 3.7 (0.4-10.8) ⫺0.2 (⫺0.7-1.2) ⫺27.6 (⫺2503.5-996.1)
CI, Confidence interval; IQR, interquartile range. Values represent the beat-to-beat averages over 10-minute recording periods; preoperative versus 24-hour postoperative values. Comparison of non-normally distributed values with Friedman test (nonparametric test). a Significance criterion for each test: P ⬍ .0036, adjusting for multiple testing. b Instead of the usual 95% CI, the 99.64% CI was calculated according to the P value .0036, which was obtained in the analysis.
Table III. Baroreceptor sensitivity and other hemodynamic parameters n ⫽ 35 Barorecepter sensitivityTD (ms/mm Hg) Systolic pressure Diastolic pressure Mean arterial pressure Heart rate (beats/min) Cardiac output (L/min) Total peripheral resistance (mm Hg.min/L)
Preoperative (median [IQR])
72 hour postoperative (median [IQR])
P valuea
Within-patient differences (median [96.64% CI])b
5.95 (4.68-10.86)
5.63 (3.23-7.69)
.0005
⫺1.58 (⫺11.47 - –0.63)
130 (115.9-145.1) 65 (56.6-72.7) 87 (79.7-97.2) 63 (57.9-73.2) 6.0 (4.8-7.4) 1150 (913-1664)
135 (111.6-154.5) 67 (56.2-75.0) 90 (77.8-101.0) 69 (65.4-77.5) 6.2 (4.6-7.9) 1132 (920-1636)
.81 .55 .91 .001 .91 .4
⫺1.4 (⫺17.7-12.7) 1.3 (⫺8.1-8.0) ⫺0.3 (⫺9.2-9.2) 5.5 (0.8-10.4) ⫺0.1 (⫺0.6-1.4) ⫺45.0 (⫺2505.4-1017.7)
CI, Confidence interval; IQR, interquartile range. Values represent the beat-to-beat averages over 10-minute recording periods; preoperative versus 72-hour postoperative values. Comparison of non-normally distributed values with Friedman test (nonparametric test). a Significance criterion for each test: P ⬍ .0036, adjusting for multiple testing. b Instead of the usual 95% CI, the 99.64% CI was calculated according to the P value .0036, which was obtained in the analysis.
riod after operation. While no significant differences in other hemodynamic parameters, including SP, DP, MAP, CO, and TPR were detected at the 24- and 72-hour time points, this observation was a likely result of recording of these parameters at just two discrete time points; hypertension was detected and treated rapidly such that a normotensive state was quickly achieved. Further, patients in the current study were routinely treated with clonidine, an agent known to decrease peripheral norepinephrine release. Through stimulation of prejunctional inhibitory ␣2 adrenoceptors and inhibition of neural transmission in different brainstem areas such as the nucleus-tractus solitarius and the lateral reticular nucleus in the ventrolateral medulla, clonidine may have attenuated the BRS effects on the hemodynamic parameters.20 Miyamoto et al examined the effects of clonidine on the HR response to dynamic cardiac sympathetic nerve stimulation in a rabbit model.22 Clonidine attenuated the dynamic HR response to sympathetic nerve stimulation. A decrease in mean HR was observed, but a residual increase in HR persisted. Other antihypertensives, includ-
ing -blockers, diuretics, calcium-channel blockers, angiotensin receptor-1 blockers, nitro-glycerin (in acute administration), and clonidine, increase BRS. Diuretics and other antihypertensives decrease BP and BP-variability, resulting in an increased BRS. Clonidine improves spontaneous BRS through parasympathetic activation.23-27 For ethical reasons, we were not able to withdraw antihypertensive drugs, agents that represent potential confounders of BRS and hemodynamic measurements. However, despite the fact that these drugs enhance BRS, the postoperative BRS values decreased significantly. The failure to detect significant changes in BP values such as SP, DP, and MAP, as well as TPR, suggests that medical interventions successfully controlled BP despite impaired BRS. Our results support the hypothesis that unilateral carotid sinus nerve denervation is sufficient to generate significant physiological changes, in parallel with the clinical findings of a previous study that demonstrated a rise in systolic BP through the 4th day following E-CEA.11 Speculatively, the explanation for the transience of this phenom-
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Fig 1. Notched box and whisker plots displaying postoperative change in baroreceptor sensitivity (BRS). A, The change in absolute values of the BRS. B, The preoperative-to-postoperative change in BRS. The length of each box represents the interquartile range, defined as the distance between the 25th and the 75th percentiles. The three horizontal lines running through the box represent the median (middle line) and the upper and lower bounds of the 95% confidence interval around the median (median ⫾ 1.58 ⫻ the quartile range.) The length of the whiskers above each box depicts 1.5 times the interquartile distance and the length of the whiskers below each box represents the interquartile distance times 1.5 as measured down from the top of the box. Outside values are defined as those data points that are 1.5 to 3.0 times the interquartile distance, while far outside values are defined as those that exceed three times the interquartile distance.
Fig 3. Baroreceptor sensitivity (BRS) of the four preoperative outliers at baseline, 24 hours, and 72 hours after surgery.
Fig 2. Baroreceptor sensitivity (BRS) change from baseline at 24 and 72 hours following operation.
enon may relate to recovery of BRS function through the baroreflex apparatus located on the contralateral side and the aortic arch; compensatory mechanisms that may require several days to adapt. Scher et al demonstrated a rise in mean BP lasting for 1 week in a large animal model of bilateral carotid sinus nerve denervation.28 However, to our knowledge, no experimental data exists on unilateral carotid sinus nerve denervation. Preoperative neurologic deficits have been reported to be an independent predictor of hypertension after CEA.29,30 This phenomenon could be contributed to impairment of the central component of the baroreflex.5 Patients with prior contralateral or ipsilateral carotid sur-
gery might have altered baroreflex function from damage to the carotid sinus nerve and the carotid sinus baroreceptors.13 Therefore, patients who had experienced a severe stroke causing major disability (mRS of 3-5) as well as patients with prior contralateral carotid surgery and ipsilateral restenosis were excluded from the current study. Seagard et al identified two types of carotid sinus baroreceptors with distinct contributions to the regulation of BP. Selective elimination of type one receptors, mainly large myelinated A-fibers, produced a decrease in BRS or attenuation of control of dynamic changes in BP, without an associated change in the tonic resting BP. Subsequent elimination of type-two receptors, mainly small A-fibers and nonmyelinated C-fibers, produced additional attenuation of BRS and significant increases in resting baseline BP.31 These observations are relevant to the observations of the present study. It appears that dissection of the carotid
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Fig 4. Notched box and whisker plots displaying postoperative change in heart rate (HR).
bulb and transection of the carotid sinus nerve during E-CEA at least impair the sensitivity of type two baroreceptors. Chronic impairment of the baroreflex results in sustained increases in sympathetic nerve activity with potentially serious pathologic and morbid consequences in cardiovascular disease states, such as hypertension, heart failure, myocardial infarction, and stroke.2-5 BRS lower than 3 ms/mm Hg is a powerful independent prognostic risk factor for sudden cardiac death.32,33 An enhanced BRS had beneficial effects on the outcome of patients with cardiovascular disease, possibly by preventing ventricular arrhythmias.34 Chao et al found that patients with carotid artery stenosis exhibited a significant reduction in BRS compared with controls.35 Sykora et al demonstrated that acute stroke with insular involvement was associated with significantly greater BRS impairment compared with BRS in stroke patients without insular involvement.36 Interestingly, the lowest initial BRS value in the current series (2.06) belonged to a patient with an acute insular stroke. In a sense, C-CEA might be protective against postoperative cardiovascular events, since the procedure may be associated with increased BRS. A longitudinal arteriotomy is generally employed during C-CEA, and unlike E-CEA, complete mobilization of the carotid bifurcation and division of the carotid sinus nerve is not necessary.13 As far back as 1974, Angell-James and colleagues demonstrated that removal of rigid atheroma at C-CEA improved carotid baroreflex sensitivity.9 The pathophysiological explanation of this phenomenon relates to a reduction pressure wave dampening after removal of the atherosclerotic plaque, increasing baroreceptor stimulation from increased vessel compliance.12 We previously reported an association between C-CEA and decreased BP in the immediate and short-term postoperative period.11 There exist clinical observations to support these hypotheses; Hirschl et al found BRS to be a predictor of cardiovascular morbidity and
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mortality in patients after C-CEA.15 Failure of BRS to increase postoperatively was associated with a significantly higher risk of major vascular events over 5-year follow-up. The main limitation of the current study is the fact that there is no control group. While the study size was sufficient to demonstrate significant impairment in BRS following E-CEA, it was not large enough to reliably detect a clinically prognostic association between impaired BRS and postoperative adverse events such as cardiovascular, neurologic, and other complications. As well, the potential masking of hemodynamic changes by the use of antihypertensive agents may have blunted the effect of baroreceptor disruption on hemodynamic parameters. In conjunction with the small sample size, such an effect may account for the failure to achieve statistically significant differences in the pre- to postoperative hemodynamic changes or in the correlations between BRS and hemodynamic variables. Further, the study protocol mandated recording of hemodynamic parameters at just two discrete time points, 24 and 72 hours, for purposes of data collection. This may explain the failure to detect a significant difference between the pre- and postoperative hemodynamic values; for instance, postoperative hypertension was relatively quickly identified and treated with normalization of hemodynamic variables by the time of the recordings. Lastly, the lack of a control group of patients treated without carotid sinus nerve denervation, for example, patients undergoing conventional carotid endarterectomy with preservation of the nerve, is a shortcoming of our study design. Inclusion of such a group might have allowed the detection of hemodynamic differences directly attributable to BRS and provided some evidence of causality. In conclusion, E-CEA might have a decreasing influence on BRS leading to higher sympathetic tone during the early postoperative period. Clearly, however, subsequent longer-term, larger-scale studies with inclusion of a group of patients undergoing C-CEA are warranted to discover whether the BRS impairment is chronic and if it is associated with long-term adverse outcomes. These findings should be interpreted with caution, noting the limitation of an absent control group. AUTHOR CONTRIBUTIONS Conception and design: SD Analysis and interpretation: SD, NA Data collection: LM Writing the article: SD, NA Critical revision of the article: DB, MH, TA Final approval of the article: SD Statistical analysis: HB Obtained funding: SD Overall responsibility: SD SD and NA contributed equally to this work. REFERENCES 1. Filippone JD, Bisognano JD. Baroreflex stimulation in the treatment of hypertension. Curr Opin Nephrol Hypertens 2007;16:403-8.
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Submitted Sep 6, 2011; accepted Nov 28, 2011.