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

NCT02587533 | Completed DMC

• 1 other identifier: CRC-KliPha-004
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hypertension, Resistant to Conventional Therapy

Keywords

Baroreflex; Chemoreflex; Autonomic nervous system; Sympathetic activity; Muscle sympathetic nerve activity (MSNA); Microneurography; Electrical baroreflex stimulation; Resistant hypertension; Device-based therapy

Outcome Measures

Primary Outcomes (1)

• 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.

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

Secondary Outcomes (1)

• Systolic blood pressure (SBP)

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

Other Outcomes (7)

• End-tidal partial carbon dioxide pressure (etCO2)

  Over 24 minutes of normoxia.

• Individual responses (MSNA, BP) without dopamine

  Over 24 minutes of stable de/oxygenation.

• Individual responses (MSNA, BP) with dopamine

  Over 24 minutes of dopamine infusion.

Study Arms (4)

Hypoxia without dopamine

ACTIVE COMPARATOR

Target hemoglobin oxygen saturation (SpO2) 80%. No pharmacologic suppression of chemoreflex afferents. Readout: Responses to electrical baroreflex stimulation.

Other: Hypoxia without dopamine

Hypoxia with dopamine

ACTIVE COMPARATOR

Target hemoglobin oxygen saturation (SpO2) 80%. Counteracting pharmacologic suppression of chemoreflex afferents. Readout: Responses to electrical baroreflex stimulation.

Other: Hypoxia with dopamine

Hyperoxia without dopamine

ACTIVE COMPARATOR

Nearly complete hemoglobin oxygen saturation. No additional pharmacologic suppression of chemoreflex afferents. Readout: Responses to electrical baroreflex stimulation.

Other: Hyperoxia without dopamine

Hyperoxia with dopamine

ACTIVE COMPARATOR

Nearly complete hemoglobin oxygen saturation. Additional pharmacologic suppression of chemoreflex afferents. Readout: Responses to electrical baroreflex stimulation.

Other: Hyperoxia with dopamine

Interventions

Hypoxia without dopamine OTHER

Target hemoglobin oxygen saturation (SpO2) 80%.

Hypoxia without dopamine

Hypoxia with dopamine OTHER

Target hemoglobin oxygen saturation (SpO2) 80%. Dopamine dose 3 µg/kg/min.

Hypoxia with dopamine

Hyperoxia without dopamine OTHER

Nearly complete hemoglobin oxygen saturation.

Hyperoxia without dopamine

Hyperoxia with dopamine OTHER

Nearly complete hemoglobin oxygen saturation. Dopamine dose 3 µg/kg/min.

Hyperoxia with dopamine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.)

Sponsors & Collaborators

• Hannover Medical School: lead
• Charite University, Berlin, Germany: collaborator
• Vanderbilt University School of Medicine: collaborator
• Mayo Clinic: collaborator
• University of Bristol: collaborator

Study Sites (1)

Hannover Medical School

Hanover, LSX, 30625, Germany

Location

Related Publications (20)

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• Trzebski A, Tafil M, Zoltowski M, Przybylski J. Increased sensitivity of the arterial chemoreceptor drive in young men with mild hypertension. Cardiovasc Res. 1982 Mar;16(3):163-72. doi: 10.1093/cvr/16.3.163.

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• McBryde FD, Abdala AP, Hendy EB, Pijacka W, Marvar P, Moraes DJ, Sobotka PA, Paton JF. The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension. Nat Commun. 2013;4:2395. doi: 10.1038/ncomms3395.

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  PMID: 1251739 BACKGROUND

• Heusser K, Tank J, Engeli S, Diedrich A, Menne J, Eckert S, Peters T, Sweep FC, Haller H, Pichlmaier AM, Luft FC, Jordan J. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. 2010 Mar;55(3):619-26. doi: 10.1161/HYPERTENSIONAHA.109.140665. Epub 2010 Jan 25.

  PMID: 20101001 BACKGROUND

• Schroeder C, Heusser K, Brinkmann J, Menne J, Oswald H, Haller H, Jordan J, Tank J, Luft FC. Truly refractory hypertension. Hypertension. 2013 Aug;62(2):231-5. doi: 10.1161/HYPERTENSIONAHA.113.01240. Epub 2013 May 20. No abstract available.

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• Jordan J, Heusser K, Brinkmann J, Tank J. Electrical carotid sinus stimulation in treatment resistant arterial hypertension. Auton Neurosci. 2012 Dec 24;172(1-2):31-6. doi: 10.1016/j.autneu.2012.10.009. Epub 2012 Nov 9.

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• Janssen C, Beloka S, Kayembe P, Deboeck G, Adamopoulos D, Naeije R, van de Borne P. Decreased ventilatory response to exercise by dopamine-induced inhibition of peripheral chemosensitivity. Respir Physiol Neurobiol. 2009 Sep 30;168(3):250-3. doi: 10.1016/j.resp.2009.07.010. Epub 2009 Jul 18.

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• Niewinski P, Tubek S, Banasiak W, Paton JF, Ponikowski P. Consequences of peripheral chemoreflex inhibition with low-dose dopamine in humans. J Physiol. 2014 Mar 15;592(6):1295-308. doi: 10.1113/jphysiol.2013.266858. Epub 2014 Jan 6.

  PMID: 24396060 BACKGROUND

• Niewinski P, Janczak D, Rucinski A, Jazwiec P, Sobotka PA, Engelman ZJ, Fudim M, Tubek S, Jankowska EA, Banasiak W, Hart EC, Paton JF, Ponikowski P. Carotid body removal for treatment of chronic systolic heart failure. Int J Cardiol. 2013 Oct 3;168(3):2506-9. doi: 10.1016/j.ijcard.2013.03.011. Epub 2013 Mar 29.

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• Lipp A, Schmelzer JD, Low PA, Johnson BD, Benarroch EE. Ventilatory and cardiovascular responses to hypercapnia and hypoxia in multiple-system atrophy. Arch Neurol. 2010 Feb;67(2):211-6. doi: 10.1001/archneurol.2009.321.

  PMID: 20142529 BACKGROUND

• Breskovic T, Valic Z, Lipp A, Heusser K, Ivancev V, Tank J, Dzamonja G, Jordan J, Shoemaker JK, Eterovic D, Dujic Z. Peripheral chemoreflex regulation of sympathetic vasomotor tone in apnea divers. Clin Auton Res. 2010 Apr;20(2):57-63. doi: 10.1007/s10286-009-0034-1. Epub 2009 Oct 10.

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MeSH Terms

Conditions

Hypertension Resistant to Conventional Therapy

Interventions

Dopamine

Intervention Hierarchy (Ancestors)

Biogenic Monoamines; Biogenic Amines; Amines; Organic Chemicals; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Jens Tank, MD

  Hannover Medical School

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2015
• First Posted: October 27, 2015
• Study Start: November 1, 2015
• Primary Completion: December 1, 2017
• Study Completion: December 1, 2017
• Last Updated: January 9, 2018

Record last verified: 2018-01

Locations

DE (1)