Peripheral Chemoreflex/Arterial Baroreflex Interaction in Patients With Electrical Carotid Sinus Stimulation

Hannover Medical School11 enrolled

Overview

Peripheral chemoreceptors and baroreceptors are located in close proximity in the carotid artery wall at the level of the carotid bifurcation. Baroreceptor stimulation lowers sympathetic activity and blood pressure. In contrast, chemoreceptor stimulation raises sympathetic activity and blood pressure. Thus, beneficial effects of electrical carotid sinus stimulation on blood pressure could be diminished by chemoreceptor overactivity and/or concomitant chemoreceptor activation through the device. Therefore, our study will assess baroreflex/chemoreflex interactions in patients with resistant hypertension equipped with carotid sinus stimulators. The study will inform us of potential additional anti-hypertensive benefits of simultaneous chemoreceptor denervation during electrode placement. Furthermore, the results may provide information about suitable electrode design to spare co-activation of peripheral chemoreceptors. Taken together, the study will help develop strategies for improving responder rate and efficacy of carotid sinus stimulators in patients with resistant hypertension.

Patients with implanted devices for electrical baroreflex stimulation are recruited according to inclusion and exclusion criteria until good quality recordings have been obtained in 10 out of maximally 15 patients. After obtaining written informed consent patients will be investigated in the laboratory on one day. In up to 20% of the patients we may fail to find an appropriate nerve recording position. In these cases we will ask the patient to repeat the experiment. Patients will be investigated in the post-absorptive state after emptying their bladder. During instrumentation and measurements they will rest in supine position. We will fix chest electrodes for ECG and impedance cardiography. A peripheral venous catheter will be introduced for later dopamine infusion. Cuffs will be used at the upper arm and the finger in order to monitor blood pressure and to allow for pulse-contour analysis. Finally, we will search for a suitable nerve recording position in the peroneal nerve for recordings of muscle sympathetic nerve activity (MSNA, postganglionic vasoconstrictor sympathetic drive). All bioelectric signals will be recorded continuously for the duration of the experiments. After the preparations baseline recordings will be performed. Subsequently, the electrical baroreflex stimulator is switched OFF and ON repeatedly (toggling) under normoxic conditions. Every OFF and ON state will last for 4 minutes. Oscillometric blood-pressure readings are taken every two minutes so as to acquire two readings per stimulation period. Toggling under normoxia is meant to ensure that the patient is a responder at the experimental day and to rule out that the blood pressure rises are too high off stimulation (safety concern). Afterwards, the breathing gas will be changed in order to have the patient inhale a hypoxic or hyperoxic mixture in a blinded manner. After reaching a stable ventilatory and autonomic state, stimulator toggling and blood-pressure measurements will be repeated. The same procedures will take place after establishing the opposite oxygenation state. Stimulation will be ON in between the oxygen states implying that the first switches will be OFF switches with all oxygenation conditions. Afterwards, the last oxygenation state will be maintained and additional low-dose dopamine infusion will be applied. Again, the electrical baroreflex stimulator will be switched off and on repeatedly and blood-pressure readings are taken. During the last two stimulator toggling states of each oxygenation level, venous blood samples are drawn for hormone measurements and inert gas rebreathing will take place for cardiac output determination. Finally, the correct positioning of the microneurography electrode is checked again. The duration of such an experiment depends on the time needed to find the sympathetic nerve bundles before the measurements and during the experiment, in case the recording position gets lost. However, experiments will rarely exceed 5 hours in total.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Implanted device for electrical baroreflex stimulation. * The patient is a 'responder', i. e. carotid-sinus stimulation causes a drop in systolic arterial pressure by at least 15 mmHg. * The patient gave informed consent. Exclusion Criteria: * The patient is an investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol. * The mental condition renders the patient unable to understand the nature, scope, and possible consequences of the study. * The patient is unlikely to comply with the protocol. * The patient is pregnant or breast-feeding. * Hypoxic conditions for half an hour are considered harmful, e. g. in patients with shunts. * History of drug or alcohol abuse. * Discontinuation of diuretic medication for one day is considered harmful. (Reason: Bladder distension is a sympathoexcitatory stimulus and shortens experimental time. In order to prevent these shortcomings three measures are taken: Dispensation with beverages and diuretics as well as complete bladder voiding immediately before the experiment.)

Outcomes

Primary Outcomes

Muscle sympathetic nerve activity (MSNA)

Muscle sympathetic nerve activity (MSNA) will be determined as burst frequency, i. e. as the number of bursts per minute \[bursts/min\]. In responders, electrical carotid sinus stimulation will lead to a decline in MSNA: \[-\]MSNA. According to our primary hypothesis, \[-\]MSNA during hyperoxic conditions (\[-\]MSNA\_hyperoxia) is larger than during hypoxia (\[-\]MSNA\_hypoxia). Therefore, the primary endpoint of the study is the difference \[-\]MSNA\_hyperoxia - \[-\]MSNA\_hypoxia. The study is successful as soon as the difference between the reduction in the hyperoxic and the hypoxic condition is significantly different from zero. A positive value would confirm our primary hypothesis. In case of a negative difference, we would conclude that the potency of electrical baroreflex stimulation to lower sympathetic activity is larger under conditions of an activated chemoreflex.

Time frame: Over 24 minutes of stable de/oxygenation +/- dopamine infusion.

Secondary Outcomes

Systolic blood pressure (SBP)

In responders, electrical carotid sinus stimulation will lead to a decline in systolic blood pressure: \[-\]SBP. According to our primary hypothesis, \[-\]SBP during hyperoxic conditions (\[-\]SBP\_hyperoxia) is larger than during hypoxia (\[-\]SBP\_hypoxia). Therefore, the secondary endpoint of the study is the difference \[-\]SBP\_hyperoxia - \[-\]SBP\_hypoxia. A positive value would confirm our secondary hypothesis. If the difference turns out to be negative, we would conclude that the potency of electrical baroreflex stimulation to lower blood pressure is larger under conditions of an activated chemoreflex. However, such a finding would not necessarily imply that chemoreceptor activation is a prerequisite for optimal baroreflex activation therapy because SBP \*level\* could be lower with \*inactive\* chemoreceptors.