Brewing the right cocktail for radial intervention
Tycho Vuurmans, David Hilton,
Victoria Heart Institute, Victoria, British Columbia, Canada.

Introduction

Radial artery structure and function
The radial artery is a muscular, so called type III (limb) artery17. The inner layer of the artery consists of the tunica intima, a single layer of endothelial cells and is supported by an internal elastic lamina. The tunica media consists of connective tissue, elastic fibers and smooth muscle cells arranged in concentric layers18. The outer layer or tunica adventitia consists of all the connective tissue beyond the external elastic lamina. It mainly consists of collagen and elastic fibers, fibroblasts, and clusters of smooth muscle cells. In the radial artery there are also adventitial sympathetic and parasympathetic nerves that may be involved in arterial spasm19. The endothelium is important in preventing platelet aggregation and thrombus formation as well as regulating smooth muscle contraction and vasodilation.  Vasodilation may be caused in response to a variety of agonists by the release of endothelium-derived factors that include nitric oxide, prostacyclin and endothelium derived hyperpolarizing factor20. These vasodilators act through inhibition of calcium release from intracellular stores and reduced calcium influx by hyperpolarizing the cell membrane. Vasospasm can be the response of a vessel to many stimulants. The stimulants may be physical (mechanical stimulation by the sheath or needle) or pharmacological (through nerve stimulation or vasoconstrictor substances). The smooth muscle cells of the tunica media contract in response to activation of α-1-receptors, and to a lesser extent α-2-adrenoreceptors and β-adrenoreceptors21. Other specific receptors that modulate contraction exist for, endothelin-1, angiotensin II, vasopressin, thromboxane and prostaglandin22.

Pharmacological prevention of radial artery occlusion
To date, as pharmacological agents, only heparin intravenous 23 or intra-arterial10 has been studied prospectively to prevent RAO in the setting of transradial angiography or angioplasty. In a study by Spaulding, et al23   asymptomatic radial artery occlusion at two months after transradial coronary angiography was found to be 71% when no heparin was given, 24% when 2.000 or 3.000 units of heparin were given and 4.3% when 5.000 units of heparin was given. Stella et al10 found persistent occlusion of 2.8% at 2 months of follow-up after 5.000-10.000 units of heparin. None of these patients with temporary or persistent RAO had any major clinical symptoms. Saito et al24 found no radial artery occlusion after administration of 10.000 units of heparin. A recent, though small, study25 found no RAO at one month and no bleeding complications when the combination of heparin 5.000 units and bivalirudin was given in the setting of ad hoc transradial angioplasty. In a study by Sanmartin et al clopidogrel use was a predictor for RAO13. There are, however no studies that have prospectively investigated clopidogrel for prevention of RAO.
Non-pharmacological prevention of RAO

Pharmacological prevention of RAS
Because of the many mechanisms that can modulate vasoconstriction and vasodilation it is unlikely that a single technical aspect of the procedure or pharmacological agent can completely prevent radial artery spasm 29. It is most likely that substances that are effective against all earlier described mechanisms would be the most reliable method.  First of all, spasm can be provoked by pain and anxiety via stimulating catecholamine release. Adequate analgesia and sedation are helpful in reducing RAS. Most often midazolam and fentanyl are used30. Pain reduction prior to puncture has been suggested with the application of a topical lidocaine-prilocaine cream two hours before the procedure on the puncture site31. Under these preparations the rate of arterial spasm remains high. A number of intra-arterial vasodilators have been studied alone and as ‘cocktails’ for the prevention of RAS during transradial angiography and angioplasty and are summarized in Table 1. Of note, the definition of RAS as an endpoint varies significantly between the studies and is specified under the table. Most studies have scored RAS by subjective criteria except in one study that used an automatic pullback device for sheath removal32. The description of the various agents used is discussed below in detail.
Nitrates and nitrate derivatives
These agents act by indirectly releasing nitric oxide as well as by antagonizing the rise in smooth muscle cell calcium22. Nitroglycerin is an exogenous nitric oxide donor that releases nitric oxide when diffused into the vascular smooth muscle. Nitroglycerin and nitroprusside are particularly effective in reversing contraction mediated by a number of receptor-mediated vasoconstrictors such as alpha-adrenoreceptor, thromboxane A2, angiotensin-II and the K+-mediated contraction29. In one study the intra-arterial infusion of nitroglycerin (100 mg) reduced RAS in comparison to placebo from 20.4 to 4.4 %33. Subcutaneous nitroglycerin facilitates radial artery cannulation after an initial failed attempt12. Isosorbide dinitrate is a highly potent agent for radial artery vasodilation prior to transradial angiography34 but has not been studied for the prevention of RAS in this setting. It has been shown to prevent spasm in patients undergoing coronary artery bypass surgery35. Isosorbide mononitrate is an active metabolite of isosorbide dinitrate and was not shown to dilate the radial artery after transradial coronary angiography36. Sodium nitroprusside is a potent vasodilator at low doses but can cause significant hypotension at higher doses22. Nitroprusside was not studied as a sole agent, but was shown to decrease RAS at a dose of 100 μg in combination with nitroglycerin (100 μg), lidocaine (20 mg) and diltiazem (5 mg)37. Nicorandil exerts a dual vasodilator effect, first as a nitrovasodilator and second as a K-ATP channel opener. Nicorandil (4 mg) was shown to induce radial artery vasodilation after transradial administration and have similar effects on RAS as low dose verapamil (100 μg) in combination with nitroglycerin (200 μg) 38. Molsidomine is a nitric oxide releasing pro-drug. It was shown to reduce RAS at a dosage of 1 mg from 22.2 to 13.3% and was most effective when given in combination with verapamil (2.5 mg)39.

Table. Agents used for RA dilation and prevention of RAS in patients undergoing transradial coronary angiography or angioplasty. Definitions of RAS are specified under the table.

RT= Randomized trial, D=change, RA= radial artery, ISDN= Isosorbide dinitrate, V=verapamil, L=Lidocaine, ISMN= Isosorbide mononitrate, D=diltiazem, NTG= nitroglycerin, NTP= nitroprusside, Ph=Phentolamine (non-selective alpha-blocker), M= molsidomine (a nitric oxide releasing pro-drug), MSu=magnesium sulphate
*spasm not defined, # spasm defined as: maximum pullback force with automated pullback device> 1 kg, † spasm defined as: ‘inability to freely manipulate the catheter, difficulty in removing the catheter at the end of the procedure, or presence of arm pain’, ‡spasm defined as: >2 of: presence of continuous forearm pain, forearm pain only due to catheter manipulation, forearm pain while sheath retrieval, firm grip of the catheter during manipulation, augmented resistance to sheath removal, £ spasm defined as: 'severe limitation of the catheter movement with or without angiographic confirmation', § spasm defined as: by patients’ feeling of pain and in advancing or withdrawing the catheters or guidewires detected by the operators, ¶ spasm defined as: <30% stenosis of the RA diameter, ¥ spasm defined as: severe limitation of catheter movement, with or without angiographic confirmation

Calcium channel blockers
These agents act by selectively blocking L-type voltage-operated calcium channels on the smooth muscle cell membrane, thereby inhibiting calcium influx and attenuating the contractile response. These agents are particularly effective in reversing or preventing membrane potential depolarizing agent potassium ion-mediated contraction29. Verapamil has been studied the most extensively at dosages from 100 μg to 5 mg and has been shown to effectively dilate the radial artery 34, 40, 41 and reduce RAS as compared to placebo39. Diltiazem was shown to be less potent then other calcium antagonists for the abrogation of radial artery vasoconstriction42. It has been studied in combination with lidocaine and nitrates for the prevention of RAS37 and was shown to increase radial artery diameter after transradial angiography when added to isosorbide mononitrate36. Both verapamil and diltiazem have limited use in patients with poor left ventricular function, hypotension or bradycardia because of their negative chronotropic and inotropic effects.
Alpha blockers
The only alpha-blocker that has been tested for RAS is the non-selective alpha-blocker phentolamine. It was shown at a dosage of 2.5 mg to be less effective then verapamil (2.5 mg) in preventing RAS40.

Lidocaine
Lidocaine has been used in combination with diltiazem and nitrates for the prevention of RAS37 but was shown to decrease the RA diameter when injected directly into the radial artery34, possibly due to the acidity of the formulation16 and has been largely abandoned.
Magnesium sulphate
Magnesium sulphate when given intra-arterially acts as a natural calcium antagonist, although the precise mechanism of action has not been fully elucidated. Byrne et al41 showed an increase in RA diameter at a dosage of 150 mg after intra-arterial injection and a similar incidence of RAS as compared to verapamil (1 mg). The advantage of magnesium sulphate is that it does not cause a fall in the mean arterial pressure as compared to verapamil.

Most effective combination of agents
The most effective combination of agents that has been tested for the prevention of RAS during transradial angiography and angioplasty is nitroglycerin (100-200 mg) together with verapamil (1.25-5 mg).  This ‘cocktail’ reduced RAS from 20-22% to 4-8%16,33. Another effective combination is verapamil (2.5 mg) with molsidomine (1 mg) that decreased RAS from 22 to 5%39. The combination of verapamil and nitroglycerin was earlier developed for the prevention of RAS in the surgical setting43 and found to be most effective. Recently the same authors showed that a combination of nicardipine and nitroglycerin successfully fully relaxed and protected against all known mechanisms of vasospasm in combination with nitroglycerin in isolated radial artery segments from patients undergoing bypass surgery29. Nicardipine is a second-generation dihydropyridine calcium antagonist that does not intrinsically decrease myocardial contractility or influence AV conduction and is useful in patients with depressed left ventricular function and bradycardia. This agent alone or in combination with nitroglycerin has not been tested in the prevention of RAS during transradial angiography or angioplasty.
Non-pharmacological prevention of RAS
Long and difficult procedures with multiple catheter exchanges and operator inexperience are predictors of RAS39 that can be prevented by proper selection of equipment and by increasing use of the radial approach. Sheath-induced spasm is minimized by the use of sheaths with hydrophilic coating. Kiemeneij et al 32 have shown that both patient discomfort and the force required to remove a sheath as measured by an automatic pullback device was significantly less with hydrophilic-coated sheaths as opposed to non-coated sheaths. In the inability to advance the catheter in the radial artery anatomic factors also play a role such as fixed atherosclerotic lesions, vessel tortuousity, small radial artery or erroneous entrance into small side branches30. These causes can be distinguished from RAS by proper patient examination and by performing a radial artery angiogram once resistance is encountered.

Brewing the right cocktail.
Radial access site angioplasty and angiography has proven its merits over the femoral access site because of the virtual elimination of access site complications and patient comfort. Because of the smaller size of the radial artery in a minority of cases radial artery spasm and radial artery occlusion occurs. At present there is a very effective approach to prevent radial artery spasm and occlusion. The ‘cocktail’ we propose is based on the current literature. It consists of a comforting approach to the patient thereby reducing anxiety, the use of a hydrophilic sheath, heparin (>5.000) intra-venous or intra-arterial, and a combination of verapamil (1.25-5 mg) and nitroglycerin (100-200 mg) or molsidomine (1 mg) intra-arterial. In patients with hypotension, bradycardia or left ventricular dysfunction magnesium sulphate intra-arterial (150 mg) can be given. In anxious patients we give low doses fentanyl (25-50 g) and/or midazolam (1-2 mg) intravenous but this can depend on local protocol. The radial artery sheath should be removed immediately after the procedure and if possible pneumatic compression of the radial artery guided by plethysmography or the mean artery pressure (MAP) should be used

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