Reversal & prevention of perioperative coronary graft vasospams

AstellasPharmabv.Foreducationaluseonly.
Nicardipine characteristics of
reversal & prevention of
perioperative arterial graft vasospasms
(clinical & pharmacological data integration)
January 2014
*Rydene I.V. is not registered for reversal or prevention of perioperative arterial graft vasospasms.
Consult SPC before using Rydene I.V..

Introduction
• Vasospasm is an important concern in coronary artery bypass grafting
• Leads to premature constriction of graft conduits
– perioperatively
– postoperatively
• Multiple mechanisms of vasospasms have been elucidated
– surgical manipulation
– biochemical factors
• Some arterial conduits are more susceptible to intense vasospasm
• Recent antispasm protocol have been developed to improve outcomes
Chanda et al. Ann Thorac Surg 2001;72:476-80. He GW. Ann Cardiothorac Surg 2013;2(4):507-518.

Versatility of arterial graft’s biological characteristics
Internal mammary artery:
• somatic
• higher levels of elastic laminae
• α1-adrenoceptor-dominant
• more endothelium-dependent relaxation
– release more NO
– greater EDHF-mediated hyperpolarisation1
• less atherosclerosis
Radial artery: Gastroepiploic artery:
• limb splanchnic
• more smooth muscle / less elastic more smooth muscle / less elastic
• α1- and α2-function higher pharmacological reactivity
• higher pharmacological reactivity prone to spasm
to vasoconstrictors
He GW. Arterial grafts: clinical classification and pharmacological management. Ann Cardiothorac Surg 2013;2(4):507-518.
1. EDHF: endothelium-derived hyperpolarizing factor

Versatility of spasmogenic stimuli
True cause of vasospasm remains unclear
• Presumed to be the extreme form of vasoconstriction responses to
spasmogenic stimuli (spasmogens)
Possible stimuli:
• Physical:
– mechanical stimulation
– temperature changes
• Pharmacological:
– nerve stimulation
– vasoconstrictors
• Type I
• Type II

Pharmacological spasmogenic stimuli
Spasmogens:
• Type I: (most potent; endothelium-independent)
– endothelin
– prostanoids: TxA2 and PGF2α
– α1-adrenoreceptor agonists
• Type II: (weak when the endothelium is intact)
– 5-HT

Versatility of vasospasm mechanisms
Possible mechanisms:
• Voltage-dependent:
– voltage-operated channels
• Receptor-dependent:
– receptor-operated channels
No single vasodilator is expected to be effective
to reverse or prevent all mechanisms.

GW HE Protocol for arterial grafting (modified UHK protocol)
Antispasm solution for storage of graft after dissection:
• Nicardipine: 5 mg [30 µMol/L; -4.5 logM]
• Nitroglycerine: 5 mg [60 µMol/L; -4.3 logM]
• Multiple Electrolytes Injection: 300 ml [PLASMA-LYTE Baxter ]
Antispasm protocol once the harvesting has initiated:
• Intraoperative and postoperative low dose of Rydene I.V.*:
– nicardipine 0.5 mg/h I.V. systematically
• Ambulatory: 6-12 months of Rydene PO:
– Rydene Retard 35 mg bid
He GW. Arterial grafts: clinical classification and pharmacological management. Ann Cardiothorac Surg 2013;2(4):507-
518. *Rydene I.V. is not registered for reversal or prevention of perioperative arterial graft vasospasms.

Antispastic nicardipine and nitroglycerin cocktail solution
Free blood flow (cc/min):
• distal end of left thoracic artery (LITA) immediately after dissection
• wrapping plus injection of NG1 cocktail versus normal saline
Zheng et al. J Cardiovascular Surg 2012;53:783-8. 1. Nicardipine-Nitroglycerin cocktail solution
p=0,025 compared with Saline

Antispastic nicardipine and nitroglycerin cocktail solution
Ultrasound probe (cc/min):
• left thoracic artery after the grafting procedure
• NG1 cocktail versus normal saline
Zheng et al. J Cardiovascular Surg 2012;53:783-8. 1. Nicardipine-Nitroglycerin cocktail solution
p=0,028 compared with Saline

Potassium (K+)
Vasoconstrictor
Induces:
• depolarization of smooth muscle membrane
• opening of voltage-dependent calcium channel
• vascular contraction (ITA and saphenous vein)
Inhibited by:
• Ca2+ channel antagonists
Guo-Wei He et al. J Thorac Cardiovasc Surg 2000;119:94-100. ITA: Internal Thoracic Artery.

Antispastic effects of Ca2+ channel antagonists in radial artery
Potency (EC50 -logM) in relaxation of K+-precontracted RA:
• nicardipine potency is 2.2- and 3.6-fold higher than that of verapamil and
diltiazem1
Guo-Wei He et al. J Thorac Cardiovasc Surg 2000;119:94-100. 1. p=NS.

Preventive antispastic effects of nicardipine in radial artery
Mean concentration (-logM) -contraction (%) curves for nicardipine-
pretreated RA:
• nicardipine prevent K+-induced contraction of RA1
Guo-Wei He et al. J Thorac Cardiovasc Surg 2000;119:94-100. 1. p=0.003.
Control: maximum K+-induced
contraction
Pretreatment with systemic
concentration of nicardipine
• 20 ηM (-7.7 logM)
Pretreatment with topical
concentration of nicardipine
• 30 µM (-4.5 logM)

Antispastic effects of verapamil and diltiazem in radial artery
Mean concentration (-logM) -contraction (%) curves for nicardipine-pretreated RA:
• neither verapamil nor diltiazem showed any depressive effect on K+-induced
contraction of RA at systemic therapeutic range
Guo-Wei He et al. J Thorac Cardiovasc Surg 2000;119:94-100.
Control: maximum K+-induced
contraction
concentration of diltiazem
• 60 ηM (-7.2 logM)
Pretreatment with topical
concentration of diltiazem
• 30 µM (-4.5 logM)
concentration of verapamil
• 20 ηM (-7.7 logM)

Endothelin: cardiovascular function
Endothelium-derived vasoconstrictors
Important role in the aetiology of:
• hypertension
• cerebral vasospasm
• coronary vasospasm
• myocardial ischaemia
• renal artery stenosis
• atherosclerosis
Stimulation of endothelin receptors:
• increases the inward Ca2+ current
• raises cytosolic Ca2+
Amenta et al. J. Auton. Pharmacol. 1994;14:129-136

Interactions between endothelin and nicardipine in artery1
Influence of increasing concentration of endothelin on nicardipine binding:
• 10 ηM endothelin-1 reduced nicardipine binding by about 85%
Amenta et al. J. Auton. Pharmacol. 1994;14:129-136. 1. Human renal artery.
endothelin-1
endothelin-3

Thromboxane A2: cardiovascular function
Vasoconstrictor
Important role in the perioperative stress:
• vascular injury
• platelet activation
• vasoconstriction
• systemic hypertension = “presenting symptom”
Potentially related to:
• vasospasm-related myocardial ischemia after surgery
Tanaka et al. British Journal of Anaesthesia 2004;93(2):257–62.

TxA2 agonist-induced vasoconstriction in human IMA1
Concentration-response curves in human IMA contracted with TxA2:
• Maximum relaxation with nicardipine: 74%
Tanaka et al. British Journal of Anaesthesia 2004;93(2):257–62. 1. IMA: internal mammary artery
Concentration of nicardipine in topical use: -4.5 logM.

TxA2 agonist-induced vasoconstriction in human IMA1
Concentration-response curves in human IMA precontracted with TxA2:
• Labetalol: lack of response at the therapeutic concentration
Tanaka et al. British Journal of Anaesthesia 2004;93(2):257–62. 1. IMA: internal mammary artery
Precontraction with TxA2:
• maximum relaxation with
labetalol at the highest C°: 27%
Precontraction with
Norepinephrine:
• maximum relaxation with
labetalol: 88%

Effect of Nic + NTG on a mixture of vasoconstrictors
Human arterial and venous conduits1 precontracted
with a mixture of 10 times the maximum plasma concentrations of:
• endothelin-1: endothelium-derived
• + norepinephrine: sympathomimetic
• + angiotensine II: renin-angiotensin system-related
• + 5-HT: platelet derived
Average therapeutic plasma concentration of vasodilators:
• Nicardipine (56 ηMol/L; -7.3 logM) + Nitroglycerine (10 ηMol/L; -7.7 logM)
• Nitroglycerine (20 ηMol/L; -8 logM)
Chanda et al. Ann Thorac Surg 2001;72:476-80. 1. RA: radial artery, ITA: internal thoracic artery, SV: saphenous vein.

Precontraction effect of a mixture of vasoconstrictors1
precontraction (g) of human arteries and veins2:
• radial artery is vulnerable to the most intense vasospasm
Chanda et al. Ann Thorac Surg 2001;72:476-80. 2. RA: radial artery; ITA: internal thoracic artery; SV: saphenous vein.
1. Mixture of 10x the
maximum human plasma
concentration of:
• endothelin-1
• norepinephrine
• angiotensine II
• 5-HT

Vasodilative effects of NTG alone or with Nicardipine
% vasodilation in precontracted human artery and veins:
• nicardipine + nitroglycerin achieved >90% vasodilation in RA
Chanda et al. Ann Thorac Surg 2001;72:476-80. RA: radial artery, ITA: internal thoracic artery, SV: saphenous vein.
Comparison between segments: RA>ITA>SV; p<0.0001.
Precontraction with a
mixture of 10x the
maximum human plasma
concentration of:
• endothelin-1
• norepinephrine
• angiotensine II
• 5-HT

Nicardipine-NTG cocktail1: a new antispastic solution (NG)
new antispastic protocol:
• rapid onset, almost full relaxation
• prophylactic effects
• against different vasospasms mechanisms2
• in various arteries3
• respect of endothelial function
Guo-Wei He et al. J Thorac Cardiovasc Surg 2008;136:673-80. 1. Nicardipine (30 µmol/L) + Nitroglycerin (30 µmol/L).
2. NE: norepinephrine; K+: potassium chloride; U46619: TxA2 agonist. 3. Radial artery, Internal thoracic artery.

Relaxation effects of Nicardipine-NTG cocktail1 (NG)
% relaxation induced by NG cocktail in precontracted human artery:
• almost full relaxation against 3 vasoconstrictors (>90%)
IMA (ITA): internal thoracic artery; RA: radial artery; NE: norepinephrine; K+: potassium chloride; U46619: TxA2 agonist.

Onset and time course of relaxation by NG cocktail1 (NG)
Relaxation induced by NG cocktail in precontracted human artery:
• relaxation reached almost the maximal in the first 20 minutes
A: Internal thoracic artery; B: Radial artery; NE: norepinephrine; K+: potassium chloride; U46619: TxA2 agonist.

Prophylactic action of NG cocktail1 on induced contraction (1)
Mean concentration-contraction curves for TxA2 agonist:
• contraction was depressed to 76.4% and 69.2% of the maximal contraction
force in ITA and RA
A: Internal thoracic artery; B: Radial artery; U46619: TxA2 agonist. Comparison vs control: ** p<.01 *** p<.001

Mean concentration-contraction curves for K+:
force in ITA and RA
A: Internal thoracic artery; B: Radial artery; K+: potassium chloride. Comparison vs control: ** p<.01 *** p<.001

Mean concentration-contraction curves for NE:
force in ITA and RA
A: Internal thoracic artery; B: Radial artery; NE: norepinephrine. Comparison vs control: ** p<.01 *** p<.001

Preservation of endothelial function by NG cocktail1
Mean concentration-relaxation curves for Ach in precontracted arteries:
• unchanged Ach-induced relaxation
• preserved endothelial function
A: Internal thoracic artery; B: Radial artery; ACh: acetylcholine.

General conclusion
• Vasospasm remains an important concern in coronary artery bypass
grafting
• Perioperative and postoperative premature constriction of graft conduits
may be reversed or prevented by antispasm protocols.
• No single vasodilator is expected to be effective to reverse or prevent all
mechanisms.
• Arterial conduits that are more vulnerable to the most intense vasospasm
are also the most efficaciously treated.
• Nicardipine + nitroglycerin cocktail achieved rapid onset effective
relaxation and prophylactic antispastic effect at therapeutic concentration
Chanda et al. Ann Thorac Surg 2001;72:476-80. He GW. Ann Cardiothorac Surg 2013;2(4):507-518.

Reversal & prevention of perioperative coronary graft vasospams

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Reversal & prevention of perioperative coronary graft vasospams

Similar to Reversal & prevention of perioperative coronary graft vasospams (20)

Reversal & prevention of perioperative coronary graft vasospams