Anesthetic aspects on implantation of the Baroreflex Activation Therapy Neo system
Daniel Heise1* , Manuel Wallbach2 , Dieter Zenker3 , Rolf Wachter4 , Luca-Yves Lehnig2 , Michael J. Koziolek2
1. Department of Anesthesiology, Georg-August-University, Göttingen, Germany
2. Department of Nephrology & Rheumatology, Georg-August-University, Göttingen, Germany
3. Department of Thoracic and Cardiovascular Surgery, Georg-August-University, Göttingen, Germany
4. Department of Cardiology & Pulmonology, Georg-August-University, Göttingen, Germany
Corresponding author: Dr. Daniel Heise, Department of Anesthesiology, Georg-August-University Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany; E-mail: email@example.com
Conflicts of interest: The authors declare that there are no conflicts of interest.
BAT: Baroreflex Activation Therapy
BMI: Body mass index
BP: Blood pressure
ICU: Intensive care unit
IBW: Ideal body weight
IPG: Implantable pulse generator
IQR: Interquartile range
SpO2: Peripheral saturation of oxygen
TBW: True body weight
Baroreflex Activation Therapy (BAT) represents a novel option in the treatment of resistant hypertension (HTN)[1,2] or congestive heart failure with reduced ejection fraction (HFrEF)[3,4] by modulating the autonomic nervous system.
In BAT, a programmable pulse generator (Rheos™ System, CVRx. Inc.) is placed underneath the fascia of the pectoralis major muscle and connected to an unipolar electrode (CVRx., Mod. 1030, 1032 and 1036) applied on carotid sinus to apply continuous baroreflex activation. This programmable pulse generator is capable of
delivering between 1 and 20 mA in a temporally variable pattern, via an electrode that is placed on the carotid bulb, requiring open surgical exposure and intraoperative mapping for the site of maximal hemodynamic effect. The device mimics the body’s blood pressure (BP) regulator by electrically activating the baroreceptors
that sense an aberrant increase in the BP level. Bypassing mechanotransduction by electrical activation of the carotid sinus provides sustained afferent baroreceptor input into the brain, and consequently chronically suppresses central sympathetic outflow but also augments parasympathetic activity. Due to the aforementioned effects, the BAT among others lowers BP[1,2] improves cardiac function[3,4] and glucose metabolism but also exerts vaso- and nephroprotective effects[9,10].
The surgical insertion of the device system poses many challenges for anesthesia providers
The goal of anesthetic management during implantation of this system is to preserve the carotid sinus baroreceptor sensitivity by avoiding administering anesthetic and non-anesthetic agents that inhibit the baroreceptor reflex during electrode placement and the testing period. E.g. several fluranes or distinct antihypertensives
but also the prevalence of diabetes mellitus blunt the excitability of baroreceptor neurons. For the first generation Rheos BATsystem, using bilateral leads positioned around both carotid sinus, one case report and a case series of ten patients have been published on anesthetic experiences limited to a very few variables.
Data on the second generation BAT Rheos-Neo™-device, acting with a unilateral stimulating lead placed unilaterally on or treated for therapy-resistant arterial HTN in our center. near the carotid bulb, but also of the before mentioned variables are so far lacking. Here we present our experiences on 55 patients.
Patients, BAT and study protocol
Patients with resistant HTN fulfilling indications for BAT as described in  were included into this retrospective analysis. All patients signed an informed consent, which included the implantation of BAT itself, but also the anonymized analysis of medical data for scientific purposes. The ethic committee of the University of Göttingen
gave permission for this retrospective trial (vote 19/9/11). Inclusion of patients was performed consecutively from 2012 to January 2015. For BAT, the Barostim Rheos-Neo™ (CVRx, Minneapolis, USA) was used as described previously[8-10]. The BAT device consists of a lead which is sutured directly to the carotid sinus on one side
(always the right side) and a pulse generator implanted in an infraclavicular position in a minimal invasive procedure including intraoperative testing for optimal placement of the lead for BP response. Thereafter, BAT was initiated 4 weeks after implantation and the stimulation was individually increased by adaption of programmed parameters during monthly follow-up. Follow-up data were acquired as described before[8-10]. Modification of antihypertensive medication by the treating physician was allowed during the observation period to adjust according to the individual office and/or BP self-measurements.
Carotid sinus mapping, electrode placement and testing period
This was similarly performed as described previously. After exposure of the right-sided carotid bifurcation, the electrode is centered on the carotid sinus, and the lead is temporarily attached to the implantable pulse generator (IPG). The IPG is controlled by a computer-based programming system that communicates with the IPG by using a radiofrequency link similar to that used for programming cardiac pacemakers. During the mapping procedure,
testing is initiated at a low voltage, and the BP-lowering effect is determined (this is generally seen within 60 seconds). The electrode position is adjusted, and testing is repeated to identify the area associated with the optimal hemodynamic response. When the optimal location is identified (defined as the greatest BP drop for a given current (6mA), pulse width (125µs) and frequency (80 Hz), the electrode is sutured in place at that location.
According to the current recommendations[11,14,16], all anesthetic agents with relevant influence on the baroreceptor reflex were avoided. For induction we used either etomidate or midazolam, whereas maintenance was carried out with continuous infusion of midazolam and remifentanil. For relaxation we used rocuronium or, in cases of severe liver insufficiency, cis-atracurium. Monitoring consisted of ECG, SpO2, temperature, CO2 and invasive BP.
Dosages of drugs showed a considerable variety and also the use of inotropes and/or vasopressors was inconsistent. For airway management we used endotracheal intubation in all patients, after surgery they were transferred into the anesthetic recovery room.
Patients with systolic BP reduction of ≥10mmHg in office or ≥5mmHg in ambulatory blood pressure monitoring or both were subsequently defined as responders to BAT.
All parameters subjected to statistical analysis were tested for normal distribution using the D`Agostino-Pearson test. To investigate the influence of vasopressors, we firstly divided the patients into two groups (with and without vasopressors) and compared how arterial BP changed i) from baseline to skin incisure, ii) from baseline to start of the mapping procedure and iii) during the mapping procedure in both groups. Additionally we tested the ratio of responders and nonresponders in the patient groups with and without vasopressors.
To investigate whether the extent of BP-decline during the mapping procedure can predict the therapeutic success, we secondly divided the patients in responders and nonresponders and compared the differences in systolic BP immediately before and after mapping.
Comparison of normal distributed parameters was done with t-tests for paired or independent samples, for not normal distributed parameters we use the Wilcoxon test for paired samples. Distributions of responders and nonresponders in patient groups with and without vasopressors were analyzed with a Chi2-test.
Patients and anesthetic management
We investigated the data from 55 patients, 31 male and 24 female, with ASA-status II (n=37) and III (n=18). Biometric data (age, height, weight, body mass index (BMI)) are summarized in table 1.
Anesthesia was inducted with etomidate in a dosage of 0.34 mg·kg ideal body weight (IBW)-1 (IQR: 0.27 – 0.4 mg·kg-1) and maintained with midazolam and remifentanil. Averaged infusion rate of midazolam was 0.33 mg·kg IBW-1·h-1 (IQR: 0.2 – 0.43 mg·kg IBW-1·h-1) resulting in a total dose of 0.23 mg·kg IBW-1 (IQR: 0.16 – 0.34 mg·kg IBW-1). During surgery, remifentanil was applied with 0.3 µg·kg IBW-1·min-1 (IQR: 0.2 – 0.3 µg·kg-1·min-1).
Neuromuscular relaxation was done with rocuronium (45 patients, 0.67 mg·kg IBW-1, IQR: 0.59 – 0.81 mg·kg IBW-1) or cis-atracurium (4 patients, 0.12 mg·kg IBW-1, IQR: 0.09 – 0.15 mg·kg IBW-1).
All patients were intubated orotracheally, monitoring consisted from ECG, pulse oximetry and invasive arterial BP. To maintain an adequate arterial BP, 28 patients received norepinephrine as vasopressor. The median dosage was 3 µg·min-1, IQR 2 – 5 µg·min-1.
The median of the duration of surgery was 46 minutes (IQR: 39 – 59 minutes), except for one patient who was transferred to the ICU due to anaphylactic reaction on gelatine infusion, all patients postoperatively were observed in the recovery room for 2.5 hours (IQR: 2.0 – 3.4 hours).
Hemodynamics and outcome (table 2)
Decrease of arterial systolic pressure between baseline (prior to induction of anesthesia) and skin incisure was -32.4 ± 35.0 mmHg in patients without vasopressors and -22.9 ± 34.5 mmHg in patients treated with vasopressors (p = 0.31). In contrast, patients without vasopressors showed a more pronounced decrease of arterial systolic pressure between baseline and values prior to mapping (-33.8 ± 38 mmHg) compared with patients with vasopressors (-7.3 ± 30.9 mmHg), this difference was statistically significant (p = 0.0068). During the mapping procedure, arterial systolic pressure decreased by -13 mmHg (IQR -24 to -8 mmHg) in patients without vasopressors, and by -20 mmHg (IQR -29 to -11 mmHg) in patients treated with vasopressors. This numerically difference between both groups did not reached statistically significance (p = 0.36).
To date, 46 patients passed the 6-months follow-up, so that only 46 of the 55 patients could be designated as responder or nonresponder at month 6.
The ratio between responders and nonresponders in patients without vasopressors was 18:6 and in patients treated with vasopressors 19:3, which also was not statistically significant different (p = 0.55) (table 3).
The drop of arterial systolic BP during mapping in patients who turned out as responders (-19 mmHg, IQR: -29 to -9.75) and patients who turned out as nonresponders (-19 mmHg, IQR: -25 to -13) was nearly identical (p = 0.91).
Prevalence of all relevant concomitant diseases listed in table 1 were compared between the responder and nonresponder groups. As summarized in table 4, the ratios between “present” and “absent” were similar for all concomitant diseases in the two outcome groups.
In patients with resistant HTN, implantation of baroreflex activating devices is a promising therapy[1,2]. In addition to the intended baroreflex activation via electric stimulation, there is some evidence that manipulation on carotid arteries itself can increase the sensitivity of baroreflex, which in turn can normalize the sympathovagal balance and reduce sympathetic activity. However, it is not clear in which extent this mechanism contributes to the beneficial effect on arterial blood pressure. BAT devices are easily implanted, and while the number of implanted devices increases constantly, implications for the anesthetic management become more and more important.
Optimal position of the electrodes is found with the mapping procedure, in which the extent of an efferent reaction after electrical stimulation is measured. Anesthesia therefore should attenuate baroreceptor reflex as little as possible. Propofol and volatile anesthetics cause a pronounced attenuation of baroreceptor reflex, and hence are not suitable for implantation of BAT devices. In contrast, midazolam affects baroreceptor reflex to much less extent, therefore it is recommended as hypnotic agent of choice. For remifentanil, there are no data available; it is frequently used in clinical practice for BAT device implantations.
Our results show that many patients receiving a BAT device are obese. To avoid overdosage of anesthetic agents, which in turn leads to an unnecessary depression of baroreceptor reflex, it is important to know whether dosage of anesthetic agents should be based on true body weight (TBW) or ideal body weight (IBW). Pharmacokinetics of remifentanil and rocuronium are not altered in obese patients, therefore they should be calculated by means of IBW[21,22]. Midazolam, in contrast, has an elevated volume of distribution in obese patients, but a normal plasma clearance. Hence, boluses for induction should be calculated by means of TBW, but IBW should be used for calculation of maintenance dosages.
For thrombendarterectomy of carotid arteries, regional anesthesia is an interesting option to general anesthesia[24,25]. Hofer et al. demonstrated that plasma norepinephrine levels are significant higher when thrombendarterectomy is done under regional anesthesia compared with general anesthesia, which often is undesirable during vascular surgery in cardiac risk patients. In contrast, the mapping procedure could benefit from high and unbiased baseline concentrations of norepinephrine and an unblunted baroreceptor reflex in the absence of any anesthetics. At the moment, no studies compared regional versus general anesthesia for BAT-device implantation with respect to efficacy, responder/nonresponder ratio and other outcome parameters.
After activating baroreceptors, the main efferent mechanism is a decrease of norepinephrine secretion into the blood. Exogenous norepinephrine therefore reduces the ability to respond, and therefore should be avoided. In case of acute hypotension prior to the mapping procedure, ß-agonists like dobutamine are recommended. However, in our patients the rate of nonresponders was similar in patients with and without vasopressors, patients receiving vasopressors showed a more pronounced drop of arterial BP during mapping procedure.
Implantation procedure of BAT appears to be safe without any severe side effects. However, the effective implantation and mapping of the BAT is crucial for the successful long-term BP reduction and critically dependent on anesthetic agents that minimally blunt the baroreceptor reflex. Therefore, anesthetic regime is critical for BAT therapy response. Anesthetists must be aware of special restrictions of some of the anesthetic agents and be vigilant to the patient’s cardiovascular changes, anesthesia depth, and responses to the surgical stimulations during the entire anesthetic procedure.
Agents of choice for general anesthesia for implantation of BAT-devices are etomidate, midazolam and remifentanil, severe hypotension should be treated with ß-mimetic drugs like dobutamine instead of norepinephrine or other vasopressors. Clinical trials to investigate the suitability of regional anesthesia (at least for placement of electrodes and the mapping procedure) would be of special interest to answer the question about the ideal anesthetic procedure for implantation of BAT-devices.
Research program, Faculty of Medicine, Georg-August-University Göttingen, to MW. MW, MK and RW have received speaking honoraria and research grant from CVRx. RW declares having received lecture fees and enumeration for including subjects into clinical trials from CVRx. RW has received consultant fees from CVRx. MK is member of the CVRx Barostim Hypertension Registry Steering Committee.
- Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol. 2011, 58(7): 765-773.
- Scheffers IJ, Kroon AA, Schmidli J, Jordan J, Tordoir JJ, Mohaupt MG et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol. 2010, 56(15): 1254-1258.
- Gronda E, Seravalle G, Brambilla G, Costantino G, Casini A, Alsheraei A et al. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study. Eur J Heart Fail. 2014,16(9): 977-983.
- Zile MR, Abraham WT, Weaver FA, Butter C, Ducharme A, Halbach M et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. Eur J Heart Fail. 2015,17(10): 1066-1074.
- Kougias P, Weakley SM, Yao Q, Lin PH, Chen C. Arterial baroreceptors in the management of systemic hypertension. Med Sci Monit. 2010,16(1): RA 1-8.
- Thai NN. Anesthetic management for implantation of a treatment device: the Rheos Baroreflex Hypertensive Therapy System. AANA J. 2012, 80(1): 18-24.
- Iliescu R, Tudorancea I, Lohmeier TE. Baroreflex activation: from mechanisms to therapy for cardiovascular disease. Curr Hypertens Rep. 2014, 16(8): 453.
- Wallbach M, Lehnig LY, Helms HJ, Schroer C, Muller GA, Wachter R et al. Long-term effects of baroreflex activation therapy on glucose metabolism. Acta Diabetol. 2015, 52(5): 829-835.
- Wallbach M, Lehnig LY, Schroer C, Hasenfuss G, Muller GA, Wachter R et al. Impact of baroreflex activation therapy on renal function–a pilot study. Am J Nephrol. 2014,40(4): 371-380.
- Wallbach M, Lehnig LY, Schroer C, Helms HJ, Luders S, Patschan D et al. Effects of baroreflex activation therapy on arterial stiffness and central hemodynamics in patients with resistant hypertension. J Hypertens. 2015, 33(1): 181-186.
- Nagasaki G, Tanaka M, Nishikawa T. The recovery profile of baroreflex control of heart rate after isoflurane or sevoflurane anesthesia in humans. Anesth Analg. 2001, 93(5): 1127-1131.
- Wray DW, Raven PB, Sander M. Diminished baroreflex-induced vasoconstriction following alpha-2 adrenergic receptor blockade in humans. Auton Neurosci. 2008, 138(1-2):114-117.
- Rowaiye OO, Jankowska EA, Ponikowska B. Baroreceptor sensitivity and diabetes mellitus. Cardiol J. 2013, 20(5): 453-463.
- Illig KA, Levy M, Sanchez L, Trachiotis GD, Shanley C, Irwin E et al. An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J Vasc Surg. 2006, 44(6):1213-1218.
- Koziolek M, Beige J, Wallbach M, Zenker D, Henning G, Halbach M et al. [Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. Internist (Berl). 2017, 58(10): 1114-1123.
- Tordoir JH, Scheffers I, Schmidli J, Savolainen H, Liebeskind U, Hansky B et al. An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension. Eur J Vasc Endovasc Surg. 2007, 33(4): 414-421.
- Wallbach M, Lehnig LY, Schroer C, Luders S, Bohning E, Muller GA et al. Effects of Baroreflex Activation Therapy on Ambulatory Blood Pressure in Patients With Resistant Hypertension. Hypertension. 2016, 67(4): 701-709.
- Dalla Vecchia L, Barbic F, Galli A, Pisacreta M, Gornati R, Porretta T et al. Favorable effects of carotid endarterectomy on baroreflex sensitivity and cardiovascular neural modulation: a 4-month follow-up. Am J Physiol Regul Integr Comp Physiol. 2013, 304(12): R1114- R1120.
- Sato M, Tanaka M, Umehara S, Nishikawa T. Baroreflex control of heart rate during and after propofol infusion in humans. Br J Anaesth. 2005, 94(5): 577-581.
- Marty J, Gauzit R, Lefevre P, Couderc E, Farinotti R, Henzel C et al. Effects of diazepam and midazolam on baroreflex control of heart rate and on sympathetic activity in humans. Anesth Analg. 1986, 65(2): 113-119.
- Ingrande J, Lemmens HJ. Dose adjustment of anaesthetics in the morbidly obese. Br J Anaesth. 2010,105 Suppl 1:i16-23.
- Meyhoff CS, Lund J, Jenstrup MT, Claudius C, Sorensen AM, Viby-Mogensen J et al. Should dosing of rocuronium in obese patients be based on ideal or corrected body weight? Anesth Analg. 2009, 109(3):787-792.
- van Rongen A, Vaughns JD, Moorthy GS, Barrett JS, Knibbe CA, van den Anker JN. Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents. Br J Clin Pharmacol. 2015, 80(5):1185-1196.
- Schechter MA, Shortell CK, Scarborough JE. Regional versus general anesthesia for carotid endarterectomy: the American College of Surgeons National Surgical Quality Improvement Program perspective. Surgery. 2012,152(3): 309-314.
- Stoneham MD, Stamou D, Mason J. Regional anaesthesia for carotid endarterectomy. Br J Anaesth. 2015, 114(3): 372-383.
- Hoefer J, Pierer E, Rantner B, Stadlbauer KH, Fraedrich G, Fritz J et al. Ultrasound-guided regional anesthesia for carotid endarterectomy induces early hemodynamic and stress hormone changes. J Vasc Surg. 2015, 62(1): 57-67.
Table 1: Baseline characteristics at screening.
|Number of patients (n)||55|
|Male n (%)
Female n (%)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Number of antihypertensives (n)
|Relevant concomitant diseases
Diabetes mellitus n (%)
Coronary heart disease
Congestive heart failure
Peripheral artery occlusive disease
History of cerebrovascular ischemia
Hyperlipoproteinemia n (%)
History of smoking n (%)
Chronic kidney disease ≥ CKD stage 1 n (%)
Chronic kidney disease ≥ CKD stage 3 n (%)
Values are mean±SD or n(%)
Table 2: Hemodynamic changes during anesthesia
|Timepoints||No vasopressors (n=27)||Vasopressors (n=28)||p-value|
|Baseline – skin incision||-32.4 ± 35.0 mmHg||-22.9 ± 34,5 mmHg||0.31|
|Baseline – start mapping||-33.8 ± 38 mmHg||-7.3 ± 30.9 mmHg||<0.01|
|Before mapping – after mapping||-13 [-24 – (-8)] mmHg||-20 [-29 – (-11)] mmHg||0.36|
Baseline indicates prior to induction of anesthesia; Values are mean±SD, or median [IQR]
Table 3: Responder/nonresponder-ratio in patients treated with and without vasopressors
|No vasopressors (n=24)||Vasopressors (n=22)|
Table 4: Prevalence of relevant concomitant diseases in responder- and nonresponder-groups
|Concomitant diesease (present/absent)||Responder||Nonresponder||p-value|
|Coronary heart disease||13/24||2/7||0.64|
|Congestive heart failure||5/32||1/8||0.86|
|Peripheral artery occlusive disease||3/34||0/9||0.59|
|History of cerebrovascular ischemia||4/33||1/8||0.75|
|History of smoking||23/14||7/2||0.62|
|Chronic kidney disease ≥ CKD stage 1||17/20||6/3||0.45|
|Chronic kidney disease ≥ CKD stage 3||14/23||4/5||0.99|