Reversal & prevention of perioperative coronary graft vasospams

Astellas Pharma bv. For educational use only.

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:

• limbsplanchnic

• more smooth muscle / less elastic more smooth muscle / less elastic

• α1- and α2-function higher pharmacological reactivity

• higher pharmacological reactivity prone to spasm to vasoconstrictorsHe 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

He GW. Arterial grafts: clinical classification and pharmacological management. Ann Cardiothorac Surg 2013;2(4):507-518.


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

Pretreatment with systemic concentration of diltiazem• 60 ηM (-7.2 logM)

Pretreatment with topical concentration of diltiazem• 30 µM (-4.5 logM)

Pretreatment with systemic concentration of verapamil• 20 ηM (-7.7 logM)


Endothelin: cardiovascular function

Endothelium-derived vasoconstrictorsImportant 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

VasoconstrictorImportant 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%)

Guo-Wei He et al. J Thorac Cardiovasc Surg 2008;136:673-80. 1. Nicardipine (30 µmol/L) + Nitroglycerin (30 µmol/L). 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

Guo-Wei He et al. J Thorac Cardiovasc Surg 2008;136:673-80. 1. Nicardipine (30 µmol/L) + Nitroglycerin (30 µmol/L). 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

Guo-Wei He et al. J Thorac Cardiovasc Surg 2008;136:673-80. 1. Nicardipine (30 µmol/L) + Nitroglycerin (30 µmol/L). A: Internal thoracic artery; B: Radial artery; U46619: TxA2 agonist. Comparison vs control: ** p<.01 *** p<.001



Mean concentration-contraction curves for K+:• contraction was depressed to 52.5% and 40.3% of the maximal contraction

force in ITA and RA

Guo-Wei He et al. J Thorac Cardiovasc Surg 2008;136:673-80. 1. Nicardipine (30 µmol/L) + Nitroglycerin (30 µmol/L). A: Internal thoracic artery; B: Radial artery; K+: potassium chloride. Comparison vs control: ** p<.01 *** p<.001



Mean concentration-contraction curves for NE:• contraction was depressed to 32.5% and 15.6% of the maximal contraction

force in ITA and RA

Guo-Wei He et al. J Thorac Cardiovasc Surg 2008;136:673-80. 1. Nicardipine (30 µmol/L) + Nitroglycerin (30 µmol/L). 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

Guo-Wei He et al. J Thorac Cardiovasc Surg 2008;136:673-80. 1. Nicardipine (30 µmol/L) + Nitroglycerin (30 µmol/L). 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.





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Reversal & prevention of perioperative coronary graft vasospams