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WO1999009971A1 - Combinaison de substances pharmacologiques dans les asystoles induites par le nerf vague - Google Patents

Combinaison de substances pharmacologiques dans les asystoles induites par le nerf vague Download PDF

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Publication number
WO1999009971A1
WO1999009971A1 PCT/US1998/016411 US9816411W WO9909971A1 WO 1999009971 A1 WO1999009971 A1 WO 1999009971A1 US 9816411 W US9816411 W US 9816411W WO 9909971 A1 WO9909971 A1 WO 9909971A1
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WO
WIPO (PCT)
Prior art keywords
composition
asystole
vagal
bromide
stimulation
Prior art date
Application number
PCT/US1998/016411
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English (en)
Inventor
John D. Puskas
Original Assignee
Emory University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Emory University filed Critical Emory University
Priority to AU86956/98A priority Critical patent/AU8695698A/en
Publication of WO1999009971A1 publication Critical patent/WO1999009971A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/452—Piperidinium derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • MIDCAB Minimally invasive direct coronary artery bypass
  • MIDCAB shows an undesirably higher rate of early graft failure than conventional coronary artery bypass procedures using cardiopulmonary bypass and cardioplegia.
  • the technical difficulty of sewing the coronary artery anastomosis on a beating heart is likely an important factor in this difference in outcome between the two techniques.
  • Controlled intermittent asystole (CIA) during brief intervals required for placing anastomotic sutures is suitable for improving the precision of MIDCAB anastomoses and reduce graft-failure while increasing ease of operation.
  • CIA intermittent asystole
  • Cardiopulmonary bypass (CPB) and chemical arrest using cardioplegia solutions have provided surgeons with optimal operative conditions: hemodynamic control and cardiac quiescence. This optimal field has contributed to technical success in increasingly complex cardiac surgical operations.
  • CPB cardiovascular disease
  • Coronary artery bypass graft failure rates reported with "minimally invasive direct coronary artery bypass" (MIDCAB) range from 3.8 to 8.9%, while CABG on CPB has a reported anastomotic failure rate of 0.12%).
  • the key difference in the anastomotic results between conventional CABG and MIDCAB is related to achieving elective asystole during construction of the distal anastomosis. Cardiac motion can be minimized during MIDCAB procedures via pharmacologic bradycardia (adenosine, ⁇ blockade) and mechanical stabilization using various devices. Although these techniques do improve operative conditions, they only approximate the advantages of elective asystole achieved with CPB and cardioplegia.
  • CIA intermittent asystole
  • Applicants demonstrate that elective, controlled intermittent asystole is produced by vagus nerve stimulation before and after treatment with an acetylcholinesterase inhibitor, a ⁇ -adrenergic receptor blocker, or a calcium channel blocker, or combination thereof.
  • Figure 1 Duration of asystole achieved during 60 second vagal stimulation. Lines connect the periods of asystole observed in the non-drug treated and drug treated states. Drug administration lengthened significantly the period of asystole.
  • FIG. 1 Representative left ventricular and aortic pressure tracings during 60 second vagal stimulation in the non-drug treated (A) and drug treated states (B). Dark and open arrows mark the initiation and termination of the vagal impulse, respectively Before drug treatment, a short pause followed by escape and bradycardia was observed during the 60 second impulse. After drug treatment, prolonged asystole occurred during the 60 second impulse with return of mechanical function after termination, lvp - left ventricular pressure; aop - aortic pressure.
  • FIG. 3 Representative left ventricular and aortic pressure tracings during sequential 15 second vagal stimulations in the non-drug treated (A) and drug treated states (B). Dark and open arrows mark the initiation and termination of the vagal impulses, respectively.
  • each 15 second stimulation produced a short pause followed by bradycardia, while after drug treatment, asystole lasted the duration of each 15 second stimulation, lvp - left ventricular pressure; aop - aortic pressure.
  • MIDCAB Minimally invasive direct coronary artery bypass
  • acetylcholine activity by acetylcholinesterase inhibition and prevention of electromechanical escape activity by ⁇ -adrenergic receptor and calcium channel blockade during vagal stimulation produces a marked potentiation of vagal- induced asystole and a means of achieving CIA.
  • CIA achieved by pharmacologic potentiation of vagal-induced asystole is a suitable technique to facilitate MIDCAB operations.
  • anastomoses and other complex suturing is facilitated during such controlled asystolic events, a readily appreciated advantage in surgery involving minimally invasive direct coronary artery bypass operations on a beating heart.
  • the present invention relates to a pharmaceutical composition, comprising an acetylcholinesterase inhibitor, or a ⁇ -adrenergic receptor blocker, or a calcium channel blocker, or combination thereof, said composition useful for minimally invasive direct coronary artery bypass heart surgery.
  • the composition is useful for controlled intermittent asystole in minimally invasive direct coronary artery bypass surgery.
  • the composition is administered in combination with vagus nerve stimulation.
  • the pharmaceutical composition comprises an acetylcholinesterase inhibitor, a ⁇ -adrenergic receptor blocker, and a calcium channel blocker.
  • the acetylcholinesterase inhibitor is pyridostygmine bromide.
  • the ⁇ -adrenergic receptor blocker is propranolol hydrochloride.
  • the calcium channel blocker is verapamil bromide.
  • composition comprises the acetylcholinesterase inhibitor pyridostigmine bromide, or the ⁇ - adrenergic receptor blocker propranolol hydrochloride, or the calcium channel blocker verapamil bromide, or combination thereof, said composition useful for controlled intermittent asystole in minimally invasive direct coronary artery bypass heart surgery.
  • the pharmaceutical composition comprises the acelylcholinesterase inhibitor pyridostigmine bromide, the ⁇ -adrenergic receptor blocker propranolol hydrochloride, and the calcium channel blocker verapamil bromide, said composition useful for controlled intermittent asystole in minimally invasive direct coronary artery bypass heart surgery.
  • MIDCAB The principal challenge of MIDCAB has been to recreate the advantageous operative conditions of a quiescent, bloodless operative field provided during conventional CABG with CPB and cardioplegic arrest.
  • a variety of pharmacologic manipulations and mechanical stabilizing techniques assist in performing CABG off pump. These interventions to date minimize, but do not eliminate, cardiac motion.
  • CIA is defined as operator-initiated and controlled intervals of mechanical cardiac standstill that coincide with placement of sutures in the anastomosis, after which normal cardiac rhythm and hemodynamics are restored while preparations are made for the next successive stitch.
  • bradycardia known to be produced by vagus nerve stimulation is suitable for the functional electromechanical "on-off switch" by inhibition of acetylcholinesterase and blockade of ⁇ -adrenergic receptors and calcium channels.
  • the chronotropic effects of vagal nerve stimulation have been well described and typically produce an initial pause followed by a "vagal escape” beat and sustained bradycardia during continuous optimal stimulation of the vagus nerve.
  • Cardiac responses to a 60 second vagal stimulation without adjunctive therapy achieved an average pause of 1.6 seconds terminated by vagal escape beats with a 19% reduction in heart rate.
  • Vagus nerve stimulation alone did not produce a controlled period of asystole desired for CIA.
  • a triple pharmacologic regimen of e.g., pyridostigmine, propranolol and verapamil inhibited vagal escape, and allowed sustained periods of asystole lasting up to 60 seconds and sequential asystoles of 15 seconds each. Segmental asystoles had no significant homodynamic consequences. It is apparent that suppression of the electromechanical escape during vagal stimulation is necessary to produce a sufficient interval of asystole to allow during which a single stitch may be reliably placed during construction of a distal CABG anastomosis. The negative chronotropic effects of vagal stimulation are produced by acetylcholine release.
  • Acetylcholine activity may be enhanced by inhibition of acetylcholinesterase activity by agents such as pyridostigmine. Additionally, it is known that calcium channel blockade by e.g. verapamil potentiates the negative chronotropic effect of vagus nerve stimulation.
  • Another component in electromechanical escape may be related to increased catecholamine activity in the sympathetic nervous system, triggered by hypotension. Catecholamines increase the rate of diastolic depolarization and decrease the threshold potential, ⁇ -adrenergic receptor blockade via e.g. propranolol reduces the effects of catecholamine activity and facilitates suppression of electromechanical escape.
  • Asystolic intervals would produce cerebral hypoperfusion similar in duration to that which occurs during placement and testing of automatic implantable cardioverter-defribrilator (AICD) devices.
  • Careful electroencephalographic (EEG) studies have documented reversible EEG changes of ischemia at 7.5 seconds after fibrilatory arrest, however neurologic and neuropsychometric evaluation has demonstrated no new deficits after AICD implantation in patients undergoing asystolic intervals.
  • the pharmacologic regimen used in this investigation sustained the period of vagal-induced asystole for about sixty minutes. This interval would allow more than sufficient time for construction of a distal CABG anastomosis.
  • vagal-induced secretions An untoward effect of the pharmacologic regimen which requires consideration before clinical application is vagal-induced secretions. All animals displayed significant salivation after initiation of vagal stimulation. However, there were no problems with oxygenation and ventilation due to tracheobronchial secretions in these experiments. Vagal-induced oripharyngeal and tracheobronchial secretions are pertinent in the clinical setting. Additionally, the effects on recurrent laryngeal nerve function require consideration.
  • vagal-mediated chronotropic control at two hours after completion of the experimental protocol was similar to the non-drug treated state.
  • controlled intermittent asystole can be achieved by potentiation of vagal-induced asystole via a pharmacologic combination of e.g., propranolol and verapamil for suppression of electromechanical escape and e.g., pyridostigmine for acetylcholinesterase inhibition.
  • Asystole can be reproducibly achieved for prolonged intervals and for shorter multiple sequential intervals using this technique.
  • Nerve Stimulation To achieve consistent asystole, applicants have found that nerve stimulation of the right vagus nerve before or after treatment with the pharmacological combinations of the present invention is preferred.
  • vagus nerve stimulation is carried out on the right vagus nerve, preferably at a site on the neck.
  • Other suitable locations for vagus nerve stimulation include, but are not limited to, stimulation in the chest after sternotomy, stimulation with an esophageal probe or in the internal jugular vein.
  • the nerve stimulator is typically a Grass wire with a single point of contact, but other suitable stimulators include a pair of pacing wires placed about 1 cm apart to allow prodromic stimulation.
  • a single continuous impulse is applied of between about 5 seconds to about 90 seconds, preferably between about 5 seconds and about 15 seconds to allow single stitch during surgery.
  • Impulse parameters can readily be varied, e.g., a frequency range of between about 1Hz and about 500Hz, preferably between about 20 Hz to about 80Hz, more preferably about 40 Hz, with an amplitude between about 1 to about 40 volts.
  • the acetylcholinesterase inhibitor is also known as a cholinesterase inhibitor.
  • Suitable acetylcholinesterase inhibitors include, but are not limited to tacrine hydrochloride, pyridostigmine bromide, neostigmine methylsulfate, and edrophonium chloride.
  • One preferred acetylcholinesterase inhibitor is pyridostigmine bromide.
  • Acetylcholinesterase inhibitors are administered in a dosage range between about 0.01 mg/kg and about 100 mg/kg, preferably between about 0.1 mg/kg and about 2.0 mg/kg, more preferably about 0.5 mg/kg.
  • the beta-adrenergic receptor blocker is also known as a beta-adrenergic blocking agent.
  • Suitable beta-adrenergic receptor blockers include, but are not limited to, sotalol HC1, timolol maleate, esmolol hydrochloride, carteolol hydrochloride, propranolol hydrochloride, betaxolol hydrochloride, penbutolol sulfate, metoprolol tartrate, acetbutolol hydrochloride, the combination of atenolol and chlorthalidone, metoprolol succinate, pindolol, and bisoprolol fumarate.
  • Beta-adrenergic receptor blockers are administered in a dosage range between about 0.01 ⁇ g/kg and about 100 mg/kg, preferably between about 0.2 ⁇ g/kg and about 2.0 mg/kg, more preferably about 80 ⁇ g/kg.
  • Suitable calcium channel blockers include, but are not limited to, nifedipine, nicardipine hydrochloride, diltiazem HC1, isradipine, verapamil hydrochloride, nimodinpine, amlodipine besylate, felodipine, bepridil hydrochloride, and nisoldipine.
  • One prefererred calcium channel blocker is verapamil hydrochloride.
  • Calcium channel blockers are administered in a dosage range of between about 1 ⁇ g/kg to about 1000 ⁇ g/kg, preferably between about lO ⁇ g/kg and about 200 ⁇ g/kg, more preferably about 50 ⁇ g/kg.
  • dosage combinations may be effective.
  • the appropriate dosage is determined by the age, weight, sex, health status of the patient, and may vary with a variety of other factors according to conventional clinical practice.
  • the sheep in the examples of the present invention received humane care in compliance with "Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the "Guide for Care and Use of Laboratory Animals” prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1985).
  • the experimental protocol was approved by the Institutional Animal Care and Use Committee of Emory University.
  • a right cervical incision was performed, the vagus nerve was carefully isolated and a nerve stimulation probe (Harvard Apparatus, South Natick, MA) was placed on the nerve.
  • a median sternotomy was made to expose the heart.
  • a high-fidelity solid- state micromanometer (Millar Inc., Houston, TX) was secured in the ascending aorta for aortic blood pressure monitoring.
  • An additional micromanometer was introduced into the left ventricle through the apex for left ventricular pressure monitoring.
  • the pharmacologic regimen consisted of pyridostigmine (0.5 mg/kg) for acetylcholinesterase inhibition, propranolol (80 ⁇ g/kg) for ⁇ -adrenergic receptor blockade, and verapamil (50 ⁇ g/kg) for calcium channel blockade.
  • Vagal stimulation was performed with a nerve stimulator (Grass Instrument Co., Quincy, MA) in the monopolar mode at a frequency of 40 Hz, an impulse duration of 0.4 msec, and an amplitude of 2-6 volts. Vagal stimulations were delivered in two regiments: 1) continuous 60 second impulse and 2) sequential 15 second impulses.
  • the continuous 60 second stimulation was designed to determine the longevity of vagal-induced asystole and the physiologic effects of prolonged vagal-induced hypotension. Sequential 15 second vagal stimulations were performed to simulate the suturing intervals required for graft anastomoses and to determine whether cardiac fatigue, electromechanical escape, and physiologic effects occurred under these practical conditions.
  • Electrocardiographic and hemodynamic data were gathered via an analog-to-digital conversion board (Data Translation, Inc , Marlboro, MA) and processed, stored, and analyzed via a microprocessor personal 486 computer (Compaq Computer Corp , Houston, TX) using interactive proprietary software (SpectrumTM, Triton Technology, San Diego, CA)
  • the system was configured to collect 4 channels of physiologic data at a frequency of 50 Hz (sufficient for slow- wave waveforms and mean pressure data) over a 200 second period that encompassed the 60 second stimulation or the sequential 15 second train of stimulations
  • the software allowed subsequent videographic display and analysis of the hemodynamic data
  • vagal stimulation for 60 seconds produced a brief pause in electromechanical activity (1 6 ⁇ 0 9 seconds) followed by vagal escape and resumption of sinus rhythm with a reduction m heart rate by 19 4 ⁇ 11 9% compared to pre-stimulation heart rate
  • sequential 15 second vagal stimulation performed to stimulate the suturing intervals required for CABG anastomoses produced a short pause (1 1 ⁇ 0 4 seconds) followed by vagal escape and sinus rhythm with a reduction in heart rate of 37 ⁇ 6%
  • 60 second vagal stimulation produced asystole averagmg 52 ⁇ 5 6 seconds
  • the individual responses of the animals before and after drug administration are shown in Figure 1
  • One individual displayed no asystolic responses either before or after drug treatment, incremental doses of drugs did not improve responsiveness in this animal This animal was termed a non-responder and was excluded from further analysis
  • the effects of 60 second vagal stimulation before and after drug treatment in responsive animals are contrasted by representative left ventricular and aortic pressure tracings are shown for a representative experiment m
  • Figure 2 Before drug regimen treated, vagal stimulation produced no appreciable change in cardiac rhythm or hemodynamics In contrast, the triple drug regimen facilitated a consistent asystole and circulatory arrest until the stimulus was withdrawn, after which hemodynamics were rapidly restored to pre-stimulation values The prolonged asystole and circulatory arrest produced no significant differences m the hemodynamic parameters measured before and after drug-aided 60 second vagal stimulation (Table
  • bpm beats per minute
  • dP/dt max maximum developed left ventricular pressure
  • LVEDP left ventricular end diastolic pressure
  • MAP mean aortic pressure
  • NS not significant
  • SEM standard error of the mean

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Abstract

L'interruption commandée des battements du coeur lors d'opérations de pontage coronaire, qui constitue une amélioration des techniques chirurgicales, s'obtient normalement par une stimulation électrique du nerf vague combinée à l'administration de médicaments.
PCT/US1998/016411 1997-08-26 1998-08-06 Combinaison de substances pharmacologiques dans les asystoles induites par le nerf vague WO1999009971A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU86956/98A AU8695698A (en) 1997-08-26 1998-08-06 Pharmacologic drug combination in vagal-induced asystole

Applications Claiming Priority (4)

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US5699497P 1997-08-26 1997-08-26
US60/056,994 1997-08-26
US7228498P 1998-01-23 1998-01-23
US60/072,284 1998-01-23

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026320A1 (fr) 2000-09-26 2002-04-04 Medtronic, Inc. Procede et systeme de stimulation endotracheale/oesophagienne avant et pendant une procedure medicale
WO2002026140A1 (fr) 2000-09-26 2002-04-04 Medtronic, Inc. Procede et systeme medicaux destines a diriger un ecoulement sanguin
WO2002026318A1 (fr) 2000-09-26 2002-04-04 Medtronic, Inc. Methode et systeme destines a la stimulation nerveuse et a la detection des battements cardiaques pre- et peroperatoires
US6487446B1 (en) 2000-09-26 2002-11-26 Medtronic, Inc. Method and system for spinal cord stimulation prior to and during a medical procedure
WO2003026741A1 (fr) 2001-09-26 2003-04-03 Medtronic,Inc. Procede et systeme permettant de realiser une stimulation endotracheale/oesophagienne avant et pendant un acte medical
US6628987B1 (en) 2000-09-26 2003-09-30 Medtronic, Inc. Method and system for sensing cardiac contractions during vagal stimulation-induced cardiopalegia
US7072720B2 (en) 1999-06-25 2006-07-04 Emory University Devices and methods for vagus nerve stimulation
US7142910B2 (en) 1997-08-26 2006-11-28 Emory University Methods of indirectly stimulating the vagus nerve with an electrical field
US7187970B2 (en) 1996-01-11 2007-03-06 Impulse Dynamics (Israel) Ltd Excitable tissue control signal delivery to the right ventricular septum
US7225019B2 (en) 1996-04-30 2007-05-29 Medtronic, Inc. Method and system for nerve stimulation and cardiac sensing prior to and during a medical procedure
US7269457B2 (en) 1996-04-30 2007-09-11 Medtronic, Inc. Method and system for vagal nerve stimulation with multi-site cardiac pacing
US8036741B2 (en) 1996-04-30 2011-10-11 Medtronic, Inc. Method and system for nerve stimulation and cardiac sensing prior to and during a medical procedure
US8406868B2 (en) 2010-04-29 2013-03-26 Medtronic, Inc. Therapy using perturbation and effect of physiological systems
US8620425B2 (en) 2010-04-29 2013-12-31 Medtronic, Inc. Nerve signal differentiation in cardiac therapy
US8639327B2 (en) 2010-04-29 2014-01-28 Medtronic, Inc. Nerve signal differentiation in cardiac therapy
US8706223B2 (en) 2011-01-19 2014-04-22 Medtronic, Inc. Preventative vagal stimulation
US8718763B2 (en) 2011-01-19 2014-05-06 Medtronic, Inc. Vagal stimulation
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US8934975B2 (en) 2010-02-01 2015-01-13 Metacure Limited Gastrointestinal electrical therapy
US8958872B2 (en) 1996-01-08 2015-02-17 Impulse Dynamics, N.V. Electrical muscle controller
US8977353B2 (en) 2004-03-10 2015-03-10 Impulse Dynamics Nv Protein activity modification
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US9713723B2 (en) 1996-01-11 2017-07-25 Impulse Dynamics Nv Signal delivery through the right ventricular septum
US9931503B2 (en) 2003-03-10 2018-04-03 Impulse Dynamics Nv Protein activity modification
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification

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Cited By (46)

* Cited by examiner, † Cited by third party
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US9289618B1 (en) 1996-01-08 2016-03-22 Impulse Dynamics Nv Electrical muscle controller
US9186514B2 (en) 1996-01-08 2015-11-17 Impulse Dynamics Nv Electrical muscle controller
US8958872B2 (en) 1996-01-08 2015-02-17 Impulse Dynamics, N.V. Electrical muscle controller
US7187970B2 (en) 1996-01-11 2007-03-06 Impulse Dynamics (Israel) Ltd Excitable tissue control signal delivery to the right ventricular septum
US9713723B2 (en) 1996-01-11 2017-07-25 Impulse Dynamics Nv Signal delivery through the right ventricular septum
US7184829B2 (en) 1996-04-30 2007-02-27 Medtronic, Inc. Method and system for nerve stimulation prior to and during a medical procedure
US8036741B2 (en) 1996-04-30 2011-10-11 Medtronic, Inc. Method and system for nerve stimulation and cardiac sensing prior to and during a medical procedure
US6449507B1 (en) 1996-04-30 2002-09-10 Medtronic, Inc. Method and system for nerve stimulation prior to and during a medical procedure
US6735471B2 (en) 1996-04-30 2004-05-11 Medtronic, Inc. Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure
US7269457B2 (en) 1996-04-30 2007-09-11 Medtronic, Inc. Method and system for vagal nerve stimulation with multi-site cardiac pacing
US7225019B2 (en) 1996-04-30 2007-05-29 Medtronic, Inc. Method and system for nerve stimulation and cardiac sensing prior to and during a medical procedure
US6532388B1 (en) 1996-04-30 2003-03-11 Medtronic, Inc. Method and system for endotracheal/esophageal stimulation prior to and during a medical procedure
US7310552B2 (en) 1997-08-26 2007-12-18 Puskas John D Apparatus for indirectly stimulating the vagus nerve with an electrical field
US7340299B2 (en) 1997-08-26 2008-03-04 Puskas John D Methods of indirectly stimulating the vagus nerve to achieve controlled asystole
US7142910B2 (en) 1997-08-26 2006-11-28 Emory University Methods of indirectly stimulating the vagus nerve with an electrical field
US7072720B2 (en) 1999-06-25 2006-07-04 Emory University Devices and methods for vagus nerve stimulation
US6487446B1 (en) 2000-09-26 2002-11-26 Medtronic, Inc. Method and system for spinal cord stimulation prior to and during a medical procedure
WO2002026320A1 (fr) 2000-09-26 2002-04-04 Medtronic, Inc. Procede et systeme de stimulation endotracheale/oesophagienne avant et pendant une procedure medicale
US7184828B2 (en) 2000-09-26 2007-02-27 Medtronic, Inc. Method and system for spinal cord stimulation prior to and during a medical procedure
WO2002026140A1 (fr) 2000-09-26 2002-04-04 Medtronic, Inc. Procede et systeme medicaux destines a diriger un ecoulement sanguin
WO2002026318A1 (fr) 2000-09-26 2002-04-04 Medtronic, Inc. Methode et systeme destines a la stimulation nerveuse et a la detection des battements cardiaques pre- et peroperatoires
US6628987B1 (en) 2000-09-26 2003-09-30 Medtronic, Inc. Method and system for sensing cardiac contractions during vagal stimulation-induced cardiopalegia
WO2003026741A1 (fr) 2001-09-26 2003-04-03 Medtronic,Inc. Procede et systeme permettant de realiser une stimulation endotracheale/oesophagienne avant et pendant un acte medical
US11439815B2 (en) 2003-03-10 2022-09-13 Impulse Dynamics Nv Protein activity modification
US9931503B2 (en) 2003-03-10 2018-04-03 Impulse Dynamics Nv Protein activity modification
US9440080B2 (en) 2004-03-10 2016-09-13 Impulse Dynamics Nv Protein activity modification
US10352948B2 (en) 2004-03-10 2019-07-16 Impulse Dynamics Nv Protein activity modification
US11779768B2 (en) 2004-03-10 2023-10-10 Impulse Dynamics Nv Protein activity modification
US8977353B2 (en) 2004-03-10 2015-03-10 Impulse Dynamics Nv Protein activity modification
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