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Ann Thorac Surg 2008;85:1483-1489. doi:10.1016/j.athoracsur.2007.10.042
© 2008 The Society of Thoracic Surgeons
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Right arrow Cardiac - pharmacology

Reviews

Clinical and Potential Use of Pharmacological Agents to Reduce Radial Artery Spasm in Coronary Artery Surgery

Saina Attaran, MD, Lindsay John, MD*, Ahmed El-Gamel, MD

Department of Cardiothoracic Surgery, Kings College Hospital, London, United Kingdom

* Address correspondence to Dr John, Department of Cardiothoracic Surgery, Kings College Hospital, Denmark Hill, London, SE5 9RS, United Kingdom (Email: lindsay.john{at}kch.nhs.uk).


   Abstract
Top
 Abstract
Introduction
 Methods
 A Classification of...
 Comment
 References
 
The radial artery has increased in popularity as a conduit for use in coronary artery bypass surgery. However, concerns remain regarding the risk of radial artery spasm. Although the use of different pharmacological agents to prevent and treat this has been described, there is currently no clear agreement as to the optimal agent. To clarify which agents are most suitable for clinical use, all pertinent studies to date (January 2007) that have reported the efficacy of pharmacological agents in the prevention and treatment of radial artery spasm have been reviewed. It can be argued that verapamil–glycerine tri-nitrate solution represents the optimum agent when used in the perioperative period.


   Introduction
Top
 Abstract
 Introduction
Methods
 A Classification of...
 Comment
 References
 
The use of the radial artery as a potential conduit for coronary bypass surgery was first described in 1973 [1]. Its use was soon discontinued after reports of early graft occlusion and spasm. However, later descriptions of long-term patency of up to 18 years for some of the original grafts encouraged its reappraisal [2]. Technically it is an attractive conduit to use. It is both easy to dissect and to handle as well as having sufficient length to be able to reach any coronary artery. Its harvest is associated with minimal complications and the avoidance of leg wounds is a significant advantage. Its 5-year patency compares favorably with that of the long saphenous vein [3]. However, an inhibition to its use is the continued concern regarding its tendency to spasm, which has been reported to be as high as 5% to 10% [4, 5]. To combat this, a wide variety of different pharmacological agents have been used. To determine the optimum pharmacological strategy, it is necessary to understand the complex regulatory mechanisms underlying radial artery spasm [6, 7].

Arteries have been classified into three types: (1) type I (somatic), (2) type II (splanchnic), and (3) type III (limb arteries.) The radial artery is an example of a type III artery, which is reported to be more prone to spasm than somatic arteries, such as the internal mammary artery [8, 9]. The structure of the radial artery is shown in Figure 1. The tunica intima is a thin layer that is limited by a prominent internal elastic membrane. The tunica media contains myocytes, connective tissue, and elastic fibers. Its thickness (500 µm) is greater than that of the internal mammary artery (300 µm) [10]. 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, unlike the internal mammary, there are also adventitial sympathetic and parasympathetic nerves that may be involved in arterial spasm [11, 12].


Figure 1
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  		Fig 1. Structure of the radial artery.

 
The endothelium is particularly important in regulating smooth muscle activity together with preventing platelet aggregation and thrombus formation [13]. Endothelium dependent relaxation and vasoconstriction can be mediated by different mechanisms [14]. Vasodilation may be caused by the release of endothelium-derived hyperpolarizing factors and endothelium-derived relaxing factors that include nitric oxide, prostaglandin, and prostacyclin I2 [15]. These vasodilators act through inhibition of calcium release from intracellular stores and reduced calcium influx by hyerpolarizing the cell membrane. Vasoconstrictors act via specific receptors. Endothelin-1 is one of the most potent vasoconstrictors and the highest concentration of its receptors is found in the distal radial artery. Other vasoconstrictors, such as thromboxane A2 and prostaglandin 2a, cause a more slowly developing concentration-dependent contraction [16]. The resting membrane potential is mainly determined by transmembrane potassium efflux [17]. Any change in this potential can induce rapid and strong smooth muscle cell contraction. This may occur with stretching during harvesting, which emphasizes the importance of tissue handling as one approach for reducing radial artery spasm.

Apart from local factors, systemic hormones may also modulate vasoconstriction via their specific receptors on the vascular smooth muscle. Angiotensin II and arginine vasopressin are both potent vasoconstrictors. Noradrenaline is a strong vasoconstrictor, even at a low concentration acting by opening calcium channels and via the {alpha}1-adrenergic receptor. This last receptor is most dominant in muscular arteries such as the radial [18–20]. Some of the factors responsible for vasoconstriction or vasodilation of the radial artery are summarized in Figure 2.


Figure 2
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  		Fig 2. Different vasoconstricting and vasodilating agents. (AT = angiotensin; Ca = calcium; ET = endothelin; H = histamine; Pg2a = Prostaglandin 2a; PGI2 = prostaglandin I2; TXA = thromboxane; V = vasopressin.)

 
The radial artery is an attractive conduit for coronary artery surgery, but its Achilles heal is its propensity for spasm. As has been discussed, there are a number of mechanisms that can modulate vasoconstriction and vasodilation. Therefore, it is unlikely that a single pharmacological agent can completely eliminate radial artery spasm. Nevertheless, a number of agents have been used in clinical practice with the aim of reducing this problem. Unfortunately there is no clear agreement as to what are the optimum agent(s). The aim of this article is to review the relevant literature in an attempt to clarify this issue.


   Methods
Top
 Abstract
 Introduction
 Methods
A Classification of...
 Comment
 References
 
A computerized literature search for abstracts was performed using MEDLINE, EMBASE, CINAHL, BIOSIS, EICompendix, SIGLE, and the Cochrane Library from the earliest available date to January 2007. The initial key words and MESH terms were: perioperative care, radial artery spasm, spasmogenic agents, vasculorelaxants, arterial conduit, coronary artery bypass grafts, total arterial grafts, radial artery as a conduit, and radial artery versus internal mammary artery vasospasm. More than 100 citations were found. Those that discussed the prevention of radial artery spasm during cardiology investigations and those that were not in English were excluded. There were 34 studies that compared the effects in vitro of different antispasmodic agents used on radial artery conduits for coronary revascularization. Relatively few clinical trials have been reported. The reference lists of pertinent articles were assessed, and the Science Citation Index was examined for cited references. Original manuscripts and review articles focusing on intraoperative, early, and late postoperative use of antispasmodic agents were included for evaluation. After this review, all the agents that have been used or introduced to date were classified according to their structure and function, and their stated advantages and disadvantages were assessed.


   A Classification of Vasorelaxants Used on the Radial Artery
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 Abstract
 Introduction
 Methods
 A Classification of...
Comment
 References
 
A summary of those vasorelaxants whose effects on the radial artery have been investigated together with their advantages and disadvantages are shown in Table 1. This includes both those agents used in clinical practice, as well as those that have only been assessed in vitro. In more detail the classification is as follows:


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  		Table 1 Comparison of the Agents
 
Nitrates and Nitrate Derivatives
These act by indirectly releasing nitric oxide, as well as by antagonizing the rise in smooth muscle cell calcium. They seem to be more effective when used as a prophylactic to prevent contraction rather than reversing it once it has occurred. Major drawbacks include tolerance phenomenon or tachyphylaxis and withdrawal symptoms. Endothelial dysfunction and reflex vasospasm can occur on stopping treatment [21, 22]. They include the following:

Glycerine tri-nitrate
Glycerine tri-nitrate (GTN) is an exogenous nitric oxide donor that releases nitric oxide when diffused into the vascular smooth muscle [23]. Its vasodilatory effect seems to be superior to that of sodium nitroprusside [24]. It has been demonstrated to be an effective vasodilator when used systemically [25]. When given intravenously intraoperatively and for 24 hours postoperatively, it is better tolerated and more effective in preventing perioperative infarction than diltiazem [22, 26]. However, it has a relatively short half-life and is less effective alone than in combination with a calcium antagonist [27].

Isosorbide dinitrate
When isosorbide dinitrate (ISDN) is used intravenously in patients undergoing coronary bypass surgery, it seems effective in preventing spasm and ensuring early patency [28].

Sodium nitroprusside
Sodium nitroprusside (SNP) is a potent vasodilator at a very low dose, but it can cause significant hypotension at higher doses. It has been reported to be inferior to GTN, both when used in vitro on pre-contracted segments of the radial artery as well as with systemic administration postoperatively [24, 25].

Nicorandil
Nicorandil is an N-2-hydroxyethylnicotinamide nitrate. It acts as a vasodilator by both being a nitric oxide donor as well as an adenosine triphosphate-sensitive potassium channel opener. One advantage is that it has a significantly lower negative inotropic effect than calcium channel antagonists [29].

Calcium Channel Blockers
These are probably the most commonly used antispastic agents with the radial artery. They act by the selective blocking of L-type voltage-operated calcium channels on the smooth muscle cell membrane, thereby inhibiting calcium influx and attenuating the contractile response [30]. They are widely available and have a high potency and long duration of action. However, their use is limited by their contraindication with poor left ventricular function. They can induce bradycardia, hypotension, arrhythmia, and heart block. In comparison with the nitrates they have a slower onset of action. They include the following:

Diltiazem
Diltiazem [19, 22, 26, 31] has significant negative chronotropic and inotropic effects that can increase the requirement for temporary cardiac pacing in the perioperative period. Although it has been used both intravenously and orally by many surgeons, it has been demonstrated to be one of the least effective of the calcium channel blockers. Neither in vitro nor in vivo does it completely eliminate radial artery contraction, and in addition it is more expensive than nitrates and the other calcium channel blockers. When used orally for 1 year postoperatively, no effect was demonstrated on graft patency [32].

Verapamil
Verapamil seems to be more potent than diltiazem and has a half-life of up to 4.8 hrs [27], although when used alone it is not sufficiently effective on the radial artery [22]. However, when it is combined with GTN it has proved useful.

Verapamil-GTN solution
The combination of verapamil and GTN solution seems to have advantages compared with the use of GTN or other calcium channel blockers alone [27, 33]. The verapamil-GTN solution has a neutral pH, an isotonic nature, and it is effective against a broad range of vasoconstrictors. When compared with papaverine, it causes more rapid vasodilation and better preserves endothelial function.

Amlodipine
Amlodipine has the advantage of being more vascular selective than most other calcium channel blockers; therefore, it has less effect on the myocardium. It has a long half-life and also some antioxidant effects. When compared with diltiazem it seems more effective when acting on pre-contracted segments of the radial artery in vitro [19]. Although oral administration of amlodipine for 6 months after surgery has been recommended [34], comparative studies are still being awaited.

Nifedipine and nicardipine
Nifedipine and nicardipine are both dihydropyridine derivatives that are available orally and intravenously, respectively. Both are vascular selective and highly potent when acting on radial artery segments [35].

Alpha Blockers
Phenoxybenzamine, butadione monoxime (BDM), phentolamine, tolazoline, prazocin, and yohimbine have all been tested on radial artery segments. However, phenoxybenzamine is the only alpha-blocker that has been clinically used.

Phenoxybenzamine
Phenoxybenzamine [11, 36, 37–40] is a nonselective irreversible {alpha}-adrenoreceptor antagonist that causes a long lasting noncompetitive block. The {alpha}-adrenergic receptors must be re-synthesized de novo before the response to noradrenaline can be re-established. In addition, it reacts irreversibly with calmodulin (ie, the protein that integrates the rise in cellular calcium to activate myosin light chain kinase). It has a long half-life due to its irreversible receptor binding, so that only a single topical application is required to be effective on the conduit. However, it is a highly acidic solution and should be adequately buffered with blood or crystalloid base solution. It has been reported that its use reduces the incidence of perioperative myocardial events [41].

Phosphodiesterase Inhibitors
Phosphodiesterase inhibitors act by inhibiting phosphodiesterase isoenzyme 3, which is present in the cytosolic fraction of the artery. This induces smooth muscle relaxation by accumulation of secondary messengers including cyclic adenosine monophosphate and cyclic guanine monophosphate, which result in decreased intracellular calcium [42–44].

Papaverine
Papaverine [11, 13, 27, 29, 45] is the most commonly used phosphodiesterase inhibitor. Its mechanism of action is not fully understood, but it is known to act directly on calcium channels and raises intracellular cyclic adenosine monophosphate. It leads to activation of protein kinase and inhibits many of the processes antagonized by nitric oxide, thereby eliciting smooth muscle relaxation nonselectively. Papaverine is unlikely to bind to the receptors; therefore, it can be washed off and rapidly metabolized. Intraluminal administration seems more effective than simple topical application. Although it is regarded by many as the "gold standard" prophylactic treatment against intraoperative vasospasm, it does have a number of drawbacks. These include its short action (ie, 1 to 2 hours), its association with a dose-dependent direct endothelial cytotoxicity, and also its relative instability in nonacidic solution.

Milrinone
Milrinone [42, 46, 47] is a phosphodiesterase inhibitor that has a direct vessel selective effect. It seems to be greater in the internal mammary artery than in the radial artery. Its associated hemodynamic effects as a positive inotrope and in reducing pulmonary and systemic resistance may confer additional benefits in the postoperative period. Although it can inhibit vasoconstriction by pre-treatment, it seems more effective in reversing spasm that has already occurred in the radial artery. Its intraluminal use in skeletonized radial arteries has been advocated [47].

Other Agents
These have mainly been tested in vitro on pre-contracted radial artery segments. Although some have shown promising results, they are yet to be clinically assessed. These include the following:

Direct nitric oxide donors
Direct nitric oxide donors [48] release nitric oxide by cyclic guanine monophosphate production. They also inhibit platelet aggregation and have an antithrombotic action.

C-natriuretic peptide
C-natriuretic peptide [49] is produced by human vascular endothelium cells. Experimentally it has been shown to have concentration-dependent relaxation of pre-contracted radial artery segments. Relaxation is caused by increasing cyclic guanine monophosphate through the natriuretic receptors, which counteracts the chronic vasoconstrictor effects of the rennin-angiotensin system.

Cerivastatin
Cerivastatin [50, 51] is a lipid-lowering drug that can produce endothelium-dependent vasodilation, which is effective for up to 24 hours in vitro.

Glibenclamide
High levels of glibenclamide [52] reverses prostanoid-induced contraction by a thromboxane A2 analogue in vitro and causes endothelium-independent relaxation of segments of the radial artery. This possibly acts by competititive antagonism with thromboxane A2 receptors.

Thromboxane A2 antagonist GR32191B
Thromboxane A2 antagonist GR32191B is a highly potent and specific receptor antagonist that has demonstrated an inhibitory effect against prostanoids in vitro [53].


   Comment
Top
 Abstract
 Introduction
 Methods
 A Classification of...
 Comment
References
 
As has been discussed in the Introduction, the radial artery is an attractive conduit for coronary artery bypass grafting. However, its Achilles’ heal is its tendency to spasm, which initially resulted in its discontinuation after its first introduction and still causes concern in the current era after the resurgence in its use.

Pharmacological agents to prevent radial artery spasm may be used in the perioperative period, which are often applied topically to the conduit, or continued chronically with the aim of preventing late spasm and hopefully thereby improving long-term patency. Although optimizing long-term patency is an attractive aim, unfortunately there is little published data that chronic use of pharmacological agents to prevent radial artery spasm achieves this effect. The most commonly used agents for this approach are calcium channel blockers. However, it has been reported that calcium channel blocker therapy commenced immediately after surgery and continued for the first postoperative year does not affect radial artery graft patency or clinical outcomes [32, 35]. The assumption that prevention of spasm directly leads to improved long-term patency may also not be valid. Permanent graft occlusion implies the presence of intrinsic graft disease rather than an exaggerated vasomotor sensitivity resulting in temporary radial artery spasm. The tendency to spasm and the tendency to chronic occlusion may be two different pathological processes. If this is the case, then does the use of pharmacological agents to prevent radial artery spasm have any benefit, and has this review comparing such agents any relevance? The answer can not be certain, but it is very likely that the prevention of spasm in the perioperative period is clinically beneficial. This is a time when spasm is more likely secondary to harvest trauma and to increased levels of circulating catecholamines (either intrinsic or extrinsic). It is also a time when the hemodynamic consequences of acute occlusion secondary to such a spasm are likely to be more serious.

An unanswered question is which pharmacological agent is most effective in the perioperative period? This is the question that this review aims to clarify. The basis by which a comparison can be made is to determine effectiveness for each of the alternative agents. Are there any potential adverse hemodynamic effects? Has its use in clinical practice been sufficiently common that potential disadvantages have become apparent? How effective is it in preventing spasm? Is there any risk of damage to the radial artery that might predispose to long-term disease?

Obviously all of the pharmacological agents when used systemically can cause a hemodynamic effect, which depending on the circumstances may be adverse. Therefore, in regard to the purposes of this particular comparison, only those agents that are topically used or injected within the lumen of the radial artery will be considered. As is apparent from the review, there is a wide range of potential agents, but those that have been commonly used include the following: GTN solution, verapamil-GTN solution, phenoxybenzamine, and papaverine. Although these all seem to be effective in preventing radial artery spasm, both GTN and papaverine have relatively short durations of action, which is a disadvantage. Verapamil-GTN solution seems to be more effective than GTN or verapamil alone [27, 33]. It also causes more rapid vasodilation and preserves endothelial function better than papaverine. Intraluminal papaverine seems to cause arterial endothelial denudation [13]. Such an effect may have an adverse long-term effect on graft patency. Although phenoxybenzamine seems to cause less damage than papaverine [45], it is a highly acidic solution, and although it can be buffered with blood or crystalloid-base solution, there is certainly the potential for endothelial damage. Based on the criteria chosen to compare these agents, it can be argued that the use of verapamil-GTN solution is the optimum choice to prevent radial artery spasm in the perioperative period.


   References
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 Introduction
 Methods
 A Classification of...
 Comment
 References
 

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Saina Attaran
Lindsay John
Ahmed El-Gamel
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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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