FIGURE 9-1 Different layers of the radial artery.
A similar study by Vanson et al.7 has also shown that the radial artery is a muscular artery and the intima-media thickness is around 529 ± 52 µm, which may predispose the artery to spasm, causing occlusion and ischemia in patients undergoing bypass surgery. The radial artery is prone to accelerated intimal hyperplasia following endothelial injury or focal damage to the intima.
Physiologic Basis of Radial Artery Spasm and Vascular Function
According to the functional classification of the arterial grafts,7 the radial artery belongs to type 3, a type of graft that is more spastic than type 1 arteries. To further investigate the spasmogenic nature of the radial arteries, He and Yang10 investigated the subtype of adrenoreceptors found in the human radial artery in an ex vivo study. They, for the first time, were able to demonstrate that the radial artery is an α-1-adrenoceptor-dominant artery with little β-adrenoceptor function and that the post-α-1-adrenoceptor is dominant, although α-2 functions also exist. Therefore, circulating catecholamines will primarily contract the radial arteries through the α-1 mechanism, and the use of β-blockers will be unlikely to evoke radial artery contraction or spasm during or after coronary artery bypass surgery. RAS can result in the occlusion of radial artery in some cases. This understanding of radial artery physiology is important in the pathophysiology of RAS and occlusion and their avoidance and treatment.
Definition of Radial Artery Spasm
Radial artery vasospasm is induced by the introduction of a sheath or catheter into the radial artery and is usually manifest as difficulty in manipulating the catheter and/or the experience of discomfort in the forearm or upper arm by the patient. This is usually caused by the friction between the outer lining of the arterial sheath and the radial artery wall or pressure due to the overstretching of the arterial wall. Several operator- and patient-specific questionnaires have been developed and used to qualitatively assess RAS. These questionnaires rate the difficulty perceived by the operator and the discomfort experienced by the patient during the procedure. Some investigators have tried to quantify RAS using an automated pull-back device.11 They have shown that all patients who experienced clinical RAS, as assessed subjectively by the difficulty perceived by the operator or pain perceived by the patient during the procedure, had a mean pull-back force of greater than 1 kg, while all other patients without a clinical spasm had a mean pull-back force of less than 1 kg. Similarly, Saito et al.12 tested in vitro friction resistance as a surrogate for RAS. They concluded that a hydrophilic coating on the introducer sheath results in significantly less friction resistance. Objective methods of assessing RAS are cumbersome and impractical in a clinical setting.
Several studies have used a combination of definitions using operator- and patient-completed questionnaires used in previous studies2–4,11 to quantify RAS both objectively and subjectively. Kiemeneij et al.,11 using 6F 23-cm-long radial sheaths, have shown a direct correlation between the patient’s assessment of pain during withdrawal of the radial artery sheath and the maximum pull-back force using an automated pull-back device. In a previous study,11 these scores correlate with significant RAS measured objectively.
Measurement of Radial Artery Spasm
In clinical practice, RAS is mainly described as increased resistance during manipulation of the intra-arterial equipment and may or may not be associated with the patient complaining of pain in the forearm. Researchers have used a combination of operators and patients questionnaires to measure the extent of RAS. There have also been attempts to quantify the RAS objectively by the use of an automatic pull-back device (APD) for removal of the arterial sheath.11 This device consists of a motorized trolley that railroad over a fixed platform. The trolley houses a digital force gauge (DFG) and a controller unit, which are connected to a personal computer for system control and data collection. The controller unit guides the movement of the trolley as per the commands set by the operator, and the DFG makes multiple instantaneous recordings during the pullback. With the use of this device, the researchers have shown, in 50 consecutive patients, the mean maximal pull-back force was 0.53 ± 0.52 kg (range, 0.1–3.0 kg). In 48 patients, the maximal pull-back force was reached within the first 5 seconds of the pullback. All patients with clinical RAS, as assessed by the combination of operators and patients questionnaires, had a maximum pull-back force greater than 1.0 kg, while the remaining patients had a maximum pull-back force of less than 1.0 kg. In this study, clinical RAS was defined as the pain perceived by the patient and/or difficulty perceived by the operator during sheath insertion, removal, or catheter manipulation.
As mentioned above, there are quantitative and qualitative methods of assessing RAS during transradial procedures. However, the quantitative methods can only measure the spasm during sheath withdrawal, but this is not the clinical spasm that may prevent completion of the procedure. The clinical spasm during the procedure and the pull-back force needed to remove the sheath may be related. There is no way of quantifying the spasm that grips the catheter and makes torsion difficult during the procedure. Therefore, there is the need to use qualitative definition of spasm for our study. The qualitative definition of RAS has been used widely by several researchers to assess the efficacy of different drugs and equipment used during transradial procedures, and their impact on RAS.
Mechanism of and Factors Predisposing to Radial Artery Spasm
The radial artery has a prominent medial layer, composed of smooth muscle, which is largely dominated by α-1-adrenoreceptor function.13 Thus, increased levels of circulating catecholamines predispose the artery to RAS.
It has also been well established that the vascular endothelium synthesizes and releases potent vasoactive factors that play active roles in vascular biology and pathophysiology. Among the various compounds formed in the endothelium are nitric oxide (NO) and endothelin-1 (ET-1), vasoactive factors that strongly influence the modulation of vascular tone.14 In the intact blood vessel wall, there is a continuous basal release of both NO and ET-1. Mechanical forces such as shear stress and the activation of various receptors regulate the release of these vasoactive substances.15 However, the balance between the two antagonistic substances, together with other released factors and the reactivity of smooth muscle cells, play an important role in the determination of vascular tone and various other physiologic processes. In the vascular wall, endothelial cells and smooth muscle cells also generate superoxide, which is involved in the pathogenesis of RAS through its effects on NO scavenging, on peroxynitrite generation, and on redox-sensitive cell-signaling pathways.16 An in vitro study by Aksungar et al.17 has shown that basal and thrombin-stimulated release of NO from the internal mammary artery is higher than from the radial artery, while the release of ET-1 from the internal mammary artery is less than from the radial artery. This observation shows the functional difference between the two arterial beds and the higher tendency to spasm in the radial artery in reaction to various stimuli. Similarly, a better understanding of the contractile properties of radial artery smooth muscle will help address the critical question of RAS and its pathogenesis. Vascular smooth muscle tone is directly dependent on intracellular calcium concentration, which in turn is largely determined by the regulation of calcium influx through voltage-gated calcium channels. Potassium and calcium currents also play important roles in regulating the vascular tone. Several factors, including stretching and injury to the radial artery following radial artery manipulation, could affect ion channel function and subsequently interfere with the vasomotor response. It is known that potassium channel function is intricately regulated by endothelium-released autocoids, including prostaglandin I2, NO, and endothelium-derived hyperpolarizing factors.18
Local anesthesia and adequate sedation to control anxiety during sheath insertion and catheter manipulation are potentially important preventative measures. Moreover, the friction or pressure caused by the mismatch between the outer diameter of the introducer sheath and the inner diameter of the radial artery could result in RAS by the various mechanisms discussed above. Therefore, increasing the mismatch between the size of the radial artery and the radial sheath could potentially cause more irritation, damage, and stimulation of the endothelium and smooth muscle cells. This would result in increased secretion of procoagulant and other vasoactive agents (ET-1 and superoxide radicals) causing RAS and injury. The length and coating of the introducer sheath could also have an impact on the occurrence of RAS. A long sheath, extending into the larger-diameter brachial artery, allows insertion, manipulation, and withdrawal of multiple catheters, without friction between the moving catheter and the surface of the radial artery. This results in less mechanical stimulation of the wall and also less irritation and damage to the endothelium and smooth muscle cells, and therefore could be associated with less spasm. However, if spasm develops, it could be more difficult to retrieve a longer sheath. Sheaths with hydrophilic or lubricious coating may be easier to retrieve in the event of spasm.
Patient-related factors might play a role in the genesis of RAS (e.g., fixed atherosclerotic lesions,19–21 vessel tortuousity, reduced radial artery diameter, or erroneous entrance into small side branches).
Impact of Vasodilator Agents on Radial Artery Spasm
It has been demonstrated in isolated radial artery ring segments that nitroglycerine and verapamil are effective agents in preventing arterial spasm.22 A study using the APD has shown that an intra-arterial cocktail of verapamil and nitroglycerine reduces the incidence of pain from 14% to 34%. The mean pull-back force was also significantly lower (0.53 ± 0.52 kg vs 0.76 ± 0.45 kg) as compared to that in the patients not receiving any vasodilating drug.12 In this study, clinically important RAS was seen in 8% of patients receiving a spasmolytic cocktail as compared to 22% in the control group (P = 0.029).
Salmeron et al. have shown, in a randomized controlled trial, that verapamil is more effective in preventing RAS than is phentolamine.3 Both vasodilator agents induced a significant increase in radial artery diameter (2.22 ± 0.53 to 2.48 ± 0.57 mm for verapamil and 2.20 ± 0.53 to 2.45 ± 0.53 mm for phentolamine). However, verapamil was more effective in preventing RAS (13.2% vs 23.2% in phentolamine-treated patients) measured qualitatively.
SPASM study23 group randomized patients to placebo, molsidomine, verapamil, or a combination of both verapamil and molsidomine, administered via the radial sheath. They concluded that the incidence of RAS was lowest in patients receiving verapamil and molsidomine (4.9%) than in patients receiving verapamil 2.5 or 5 mg (8.3% and 7.9%), molsidomine 1 mg (13.3%), or placebo (22.2%) (P < 0.0001). Filho et al.24 have also shown in a randomized double-blind trial of 50 patients that the use of diltiazem, as an adjunctive drug to isosorbide mononitrate, administered through the transradial sheath, decreases the rate of vascular complications. Coppola et al.25 have shown that the addition of nitroprusside to nitroglycerine did not further reduce the incidence of spasm. However, after multivariate analysis, the following variables were found to be independent predictors of RAS: radial artery diameter (RD)/height index (P = 0.005), RD/body surface area (BSA) index (P = 0.012), and sheath outer diameter (OD)/RD index (P = 0.024). The sex of the patient, presence of diabetes, BSA, and smoking history did not play any role in predicting the occurrence of RAS.
Similarly, Chen et al.26 have shown the effectiveness of heparin and nitroglycerine combination in preventing RAS. In this study, there was no difference seen in the incidence of RAS between heparin + nitroglycerine+ verapamil and heparin + nitroglycerine groups. Recently, Kim et al.27 have shown the effectiveness of nicorandil in preventing RAS. In a randomized study comparing 4 mg of nicorandil and 200 µg of nitroglycerine, the authors concluded that both agents induced a significant radial artery vasodilatation. Nicorandil caused a significant increase in the mean radial artery diameter compared to the cocktail at the midsegment of the radial artery (0.32 ± 0.23 mm for nicorandil and 0.24 ± 0.15 mm for nitroglycerine, P < 0.05). There was no significant difference between the rates of RAS, defined as discomfort during pullback of the sheath (50.7% vs 50.2%).
Fukuda et al.28 have examined the incidence of RAS by radial arteriography immediately after and 5 months after the procedure in 48 patients. They quantified RAS by the degree of stenosis in the radial artery as compared to between the first (performed just after the transradial procedure) and the second arteriography (performed 5 months after the procedure using transbrachial approach). The radial artery diameter soon after the transradial procedure may be small because of RAS, and the investigators compared the radial artery diameter with baseline radial artery diameter on arteriography few months after the procedure. In this study, the authors defined more than 75% stenosis in the radial artery, 25% to 75% stenosis, and less than 25% stenosis as severe spasm, moderate spasm, and mild spasm, respectively. They concluded that some degree of radial spasm was seen in all patients, with severe spasm seen in 50% patients, moderate spasm in 23%, and mild spasm in 27%. They also found that the diameters of both the proximal and distal radial arteries in the severe spasm group were significantly smaller than those in the mild and moderate spasm groups (proximal site: severe group 2.39 ± 0.70 mm vs mild group 2.98 ± 0.46 mm, P < 0.05, and moderate group 2.96 ± 0.77 mm, P < 0.05; distal site: severe group 2.26 ± 0.60 mm vs mild group 2.73 ± 0.47 mm, P < 0.05, and moderate group 2.86 ± 0.71 mm, P < 0.05). This study showed a correlation between severe spasm and the diameter of the artery.
Impact of the Introducer Sheath on Radial Artery Spasm
There are several different types of transradial introducer sheaths available from different manufacturers. The introducer sheaths from different manufacturers differ in sheath design and physical properties of the sheath. Broadly they can be divided into two groups: sheaths with different length and sheaths with or without hydrophilic coating.
The force required to remove an introducer sheath from the radial artery is the summative effect of various different forces: friction between the outer wall of the sheath and the inner radial artery wall, and friction between the outer wall of the sheath and the skin and the subcutaneous connective tissue. The former depends on the ratio of the inner luminal diameter of the vessel to the outer diameter of the sheath and the tone of the arterial wall musculature (anxiety and repeated punctures increase the tone and spasm) at the time of the procedure. The force required to insert or remove the sheath also depends on the surface properties of the two surfaces (hydrophilic coating might reduce friction) and also the surface area of contact between two surfaces (impact of length of sheath in contact with radial artery wall).
Therefore, the potential advantage of a long sheath may be the free movement of the guide and the guide wire in relation to the radial artery wall. This less mechanical stimulation of radial wall might be associated with less RAS and endothelial injury. However, if the spasm develops, it might be difficult to retrieve the long sheath. The opposite may be true for the short-length introducer sheath; they may be easier to retrieve in the event of spasm but could provide more substrate for the spasm because of the mechanical stimulation between the guide catheters and the guide wires. Similarly, the introducer sheaths coated with lubricious material could be easier to retrieve in the event of spasm because of less frictional force.
Saito et al.12 have tested in vitro the static friction resistance between the introducer sheath with the hydrophilic coating and without the hydrophilic coating and also tested the durability of the lubricant. For the experiment, the sheath introducers were fixed to a strain gauge, and the glass tube filled with water and plugged by silicon rubber was slowly removed. The static friction resistance between the sheath introducer and the silicon rubber plug was defined as the maximum force between the glass tube moved away from the sheath introducer. They have also assessed the incidence of clinical RAS in both the groups. The researchers used a 6F (outer diameter 2.6 mm), 16-cm-long sheath from Terumo, Japan. Hydrophilic coating caused a 70% decrease in the friction force in the in vitro model (1,060 ± 105 to 312 ± 40 g force, P <0.0001). Dynamic friction resistance, measured during 200 repeated forward and backward movements of the sheath introducers at a constant rate of 1,000 per minute, was highest in both groups at the beginning of the tests and was preserved during the tests. At all time points during the tests, dynamic friction resistance was significantly lower in sheaths with hydrophilic coating. The easiness of sheath insertion into the radial artery was not different in either group. The position stability of the sheath introducer was worse in hydrophilic group (P = 0.0242). The easiness of sheath removal was better in hydrophilic group (P = 0.00003). RAS occurred in one patient in the hydrophilic group (2.7%) and in four patients in the uncoated group (11%), P = 0.15. They concluded that the hydrophilic coating of the introducer sheath is useful during the transradial procedures.
Dery et al.29 have assessed the impact of hydrophilic coating in a small randomized study of 90 patients. They used 6F, 19-cm-long hydrophilic-coated sheath or a 6F, 21-cm-long uncoated sheath, both from Cook, Inc, Bloomington, IN, USA. The researchers assessed the peak traction force by electronic traction gauge and quantification of pain at the time of removal of the introducer sheath. The mean ± SD peak traction force at sheath removal was 265 ± 167 g and 865 ± 318 g in the coated and uncoated groups, respectively (69% reduction; P < 0.001). Mean maximal pain score was 0.6 ± 1.2 and 4.8 ± 2.9 in the coated and uncoated groups, respectively (88% reduction; P < 0.0001). They concluded that the use of the hydrophilic-coated introducer sheath considerably reduces the traction force and the pain experienced by the patient during sheath removal.
Keimeneij et al.30
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