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J Thorac Cardiovasc Surg 1999;117:906-911
© 1999 Mosby, Inc.
SURGERY FOR ADULT CARDIOVASCULAR DISEASE |
From the Department of Cardiothoracic Surgerya and Evans Department of Medicine,b Boston University School of Medicine, Boston, Mass.
This work was supported by grants from the American Heart Association, National Center (J.F.K), and the National Institute of Health (HL53398 and HL55993 to J.A.V. and HL59346 to J.F.K). J.A.V. is an Established Investigator of the American Heart Association, and J.F.K. is the recipient of a Clinical Investigator Development Award (HL03195) from the National Institutes of Health.
Received for publication July 28, 1998. Revisions requested Nov 5, 1998. Revisions received Jan 11, 1999. Accepted for publication Jan 12, 1999. Address for reprints: Oz M. Shapira, MD, Department of Cardiothoracic Surgery, Boston Medical Center, 88 E Newton St, Boston, MA 02118.
| Abstract |
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| Introduction |
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The radial artery was first introduced as an alternative arterial conduit in the early 1970s,
4 only to be abandoned shortly thereafter because of early graft failure related to accelerated intimal hyperplasia and vasospasm.
5 The use of the radial artery was recently rejuvenated with encouraging early results attributed to modifications in harvesting techniques and routine prolonged administration of antispasmodic agents, of which diltiazem is the most frequently used.
6-8 However, diltiazem is costly, and its use may be associated with negative inotropic and chronotropic side effects.
9 For example, we have shown that up to 40% of patients receiving diltiazem therapy require temporary cardiac pacing in the perioperative period, resulting in a longer intensive care unit stay.
10 In contrast, Gurevitch and colleagues
11 have used long-acting nitrates as an alternative to diltiazem for prevention of composite arterial conduit spasm and reported satisfactory clinical results.
This study was designed to compare the vasodilatory and antispasmodic properties of diltiazem to those of nitroglycerin. In vitro response was assessed with the use of organ-chamber methods, and in vivo response was assessed by the use of ultrasonographic measurement of radial artery vasodilation in patients with known coronary artery disease.
| Patients and methods |
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Materials
The PSS contained the following elements: NaCl, 118.3 mmol/L; KCl, 4.7 mmol/L; CaCl2, 2.5 mmol/L; MgSO4, 1.2 mmol/L; KH2PO4, 1.2 mmol/L; NaHCO3, 25 mmol/L; glucose, 11.1 mmol/L; Na2EDTA, 0.026 mmol/L; and indomethacin, 0.01 mmol/L. Nitroglycerin was obtained from Baxter Healthcare Corp (Deerfield, Ill). Diltiazem and U46619 were purchased from Sigma Chemical Co (St Louis, Mo).
Organ chamber methodology
The vessels were carefully dissected from their surrounding fat tissue and cut into 2 to 3 rings measuring 4 mm. The rings were placed in organ chambers (37°C) containing 10 mL PSS, suspended between 2 tungsten stirrups for the measurement of isometric tension as described,
12 and constantly aerated with 95% oxygen/5% carbon dioxide. Each vessel was then progressively stretched in 1-g increments to its optimal resting tension that produced a maximal response to 80 mEq of KCl. Vessels were then allowed to equilibrate for 1 hour before the introduction of vasoactive drugs as described.
13 Relaxation studies were performed after vessels were contracted with 0.1 to 1 µmol/L of U46619, such that contraction was 50% to 60% of the maximal KCl-induced contraction. Vessel segments were then exposed to increasing doses of nitroglycerin or diltiazem (109105 mol/L), and dose-response curves were recorded. The ability to prevent radial artery spasm was assessed by dose-response curves to U46619 in baths containing PSS alone (control) or physiologic concentrations of nitroglycerin (0.1 µmol/L)
14 or diltiazem (1 µmol/L).
9
In vivo radial artery vasodilatory studies
The study was approved by the Boston Medical Center Institutional Review Board. Subjects were fasted overnight, calcium channel blockers were withheld for 48 hours before the study, and all other vasoactive medications were withheld for 24 hours. If applicable, patients were asked not to smoke overnight before the study. On the day of the study, images of the radial artery diameter 5 to 10 cm distal to the antecubital crease were recorded with an ultrasound system (Toshiba 140a; Toshiba, American Medical Systems, Tustin, Calif ) equipped with a 7.5 MHz linear array transducer. The transducer position was marked and used for subsequent scans. Serial 10-minute infusions of intravenous nitroglycerin (0.060.36 µmol/min) were then given into the contralateral arm vein with an infusion pump (Baxter Healthcare Corp, Irvine, Calif). At the end of each infusion, repeat ultrasound images of the radial artery were recorded. After a 2-hour period, the radial artery diameter was recorded, and patients were given a 0.25-mg/kg bolus of diltiazem over 2 minutes, followed by serial 20-minute diltiazem infusions (0.12-0.36 µmol/min). Radial artery diameter was determined with the use of customized image analysis software
15by personnel blinded to infused medication and image sequence.
Data analysis
Unless otherwise specified, all data are expressed as mean ± SEM. Vessel relaxation is expressed as percent reduction in tension induced by U46619. The median effective dose (EC50) represents the drug concentration producing 50% of maximum relaxation/contraction determined graphically by commercially available software (Origin; Microcal Inc, Northhampton, Mass). In vitro and in vivo dose-response curves for nitroglycerin, diltiazem, and U46619 were compared among the groups using 2-way analysis of variance (ANOVA) for repeated measures.
| Results |
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| Discussion |
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The calcium channel blocker diltiazem has been empirically selected by most surgeons.
6-8,10,16-19 However, diltiazem is costly and its use may be associated with negative inotropic and chronotropic side-effects.
9 Up to 30% to 40% of patients undergoing CABG and treated with diltiazem may experience hypotension, bradycardia, or heart block requiring lowering the dose, discontinuing the drug, or temporary pacing.
7,10 Moreover, use of diltiazem does not completely eliminate spasm. In early and midterm angiographic studies radial artery spasm was identified in 1% to 9.7% of cases.
6,16-20 Recently, Cable and colleagues
23 demonstrated that diltiazem and verapamil had little effect on radial artery receptor-dependent and receptor-independent contraction, whereas nifedipine and nitroglycerin were much more effective. In another study,
24 the authors demonstrated that the use of verapamil and nitroglycerin solution to prepare radial artery grafts maximally preserves endothelial function. A systematic comparison of diltiazem to nitroglycerin has not been previously performed. With this information in mind, we sought to compare the vasodilatory response of the most commonly used coronary bypass conduits to nitroglycerin to that of diltiazem.
The data presented in this study demonstrate that the in vitro maximum relaxation of all 3 coronary bypass conduits to nitroglycerin is significantly greater than the response of these conduits to the calcium channel blocker diltiazem. We found diltiazem to be ineffective in vessels precontracted with U46619. Similar results were reported in radial arteries precontracted with potassium chloride or norepinephrine.
23 In our study, these in vitro observations were also found to be valid in vivo. Intravenous administration of nitroglycerin in patients with documented coronary artery disease induced significantly greater increase in radial artery diameter compared with diltiazem. Finally, within the therapeutic dose range, nitroglycerin was found to be much more effective in preventing U46619-induced radial artery spasm than was diltiazem. In accordance with our findings, Canver and colleagues
25 have recently used ultrasonography and Doppler studies to document strong vasodilatory responses to oral nitroglycerin of both in situ and grafted internal thoracic arteries.
The clinical experience with the use of nitrates for the specific indication of prevention of arterial conduit spasm is limited, with only one published report.
11 Gurevitch and colleagues
11 have used high-dose isosorbide dinitrate in patients undergoing myocardial revascularization with composite arterial grafts. They reported hospital mortality rates of 2.6%, postoperative hypoperfusion syndrome in 2.6% of patients, and a postoperative myocardial infarction rate of 1.3%. At a mean follow-up of 24 months, all hospital survivors were alive, with 97% being angina-free; 97% of the angiographically studied anastomoses were patent.
11
A major potential limitation of the use of nitrates is the development of tolerance.
26 The cause of tolerance is unclear and is a subject of intense investigation.
27 It is not related to altered pharmacokinetics, because drug plasma levels remain the same or even higher after prolonged use compared with the initial therapy.
28 Although there can be no doubt that loss of hemodynamic effects is a true phenomenon, it is also clear that some vascular effects of nitrate therapy persist during continued therapy and that cessation of treatment may be associated with withdrawal symptoms.
26 Similar to the variability of different vessel responses to nitroglycerin,
29,30 there are differences in the susceptibility of veins, arteries, and arterioles to develop nitrate tolerance and that arterial or arteriolar response may persist although venous tolerance exists.
30 To eliminate the tolerance effect as a confounding factor in the present study, none of the patients from whom vascular tissues were obtained for organ-chamber studies received intravenous nitroglycerin treatment, and oral nitroglycerin medications were withheld for 48 hours in subjects recruited for the in vivo studies. Undoubtedly, the mechanism and the clinical implications of tolerance in this treatment setting need to be further explored.
In conclusion, in this study nitroglycerin was found to be a superior arterial vasodilator and more effective in preventing radial artery spasm than diltiazem. Although a prospective randomized study comparing these agents clinically is clearly indicated, the data presented here strongly suggest that nitroglycerin should be considered as the drug of choice to prevent arterial conduit spasm after CABG.
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