Eur J Cardiothorac Surg 1999;16:560-563
© 1999 Elsevier Science NL
Preparation of the internal thoracic artery by vasodilator drugs: is it really necessary?
A randomized double-blind placebo-controlled clinical study
Moshe Nilia,
Alon Stamlera,
Jaqueline Sulkesa,b,
Bernardo A. Vidnea
a Department of Cardiothoracic Surgery, Rabin Medical Center (Beilinson Campus), Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
b Epdemiology Unit, Rabin Medical Center (Beilinson Campus), Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Corresponding author. Department of Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel. Tel.: +972-3-937-6701; fax: +972-3-924-0762
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Abstract
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Objective: The internal thoracic artery has become the conduit of choice for coronary artery bypass grafting. To avoid spasm of the artery, and increases in its diameter and flow, various vasodilators have been used either intraluminally or by topical application by different surgeons. In order to define the best vasodilating agent for preparation of the internal thoracic artery, a randomized double-blind placebo-controlled clinical study was performed in a group of patients submitted for elective coronary artery bypass grafting. Methods and results: Eighty (80) consecutive patients submitted for elective first time coronary artery bypass grafting were randomly subdivided into five treatment groups. Free flow of the left internal thoracic artery was measured using an electromagnetic flow meter. The first measurement was performed shortly after the internal thoracic artery was dissected from the chest wall and the second just prior to performing distal anastomosis to the left anterior descending coronary artery. During the time interval between the two measurements the internal thoracic artery was immersed in a special applicator tube containing 20 ml solution of one of the following drugs: papaverin 2 mg/ml, nitroglycerin 1 mg/ml, verapamil 0.5 mg/ml, nitroprusside 0.5 mg/ml, normal saline 0.9%. Results: No statistically significant differences were found between the groups in respect to age, body surface area, bypass time, cross clamping time, and time interval between the two flow measurements. Mean arterial pressure at the time of the first and second internal thoracic artery flow measurements did not show statistically significant differences either within or between the groups. In all five groups, the free flow of the internal thoracic artery increased significantly with time. However, no statistically significant differences were shown between the five groups with respect to second flow (P=0.2). Conclusions: Within the limits of our study design, we suggest that preparation of the LITA by topical vasodilator drugs using a special applicator tube does not result in a significantly superior free flow than placebo.
Key Words: Coronary disease • Vasospasm • Vasodilators • Cardiopulmonary bypass
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1. Introduction
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The internal thoracic artery (ITA) is the conduit of choice for myocardial revascularization because of its proven long-term patency rate [1,2]. However, vasospasm during isolation of the vessel with insufficient early graft flow has been reported and can cause perioperative morbidity and mortality [3,4]. In order to overcome this relatively common problem, various topical or intraluminal vasodilators, as well as mechanical dilatation of the artery, have been used to prevent or reverse vasospasm [5,6]. Most of the studies examining the effect of topical vasodilators were done in vitro or following different mechanical manipulations [7,8]. This study was designed to determine the effectiveness of commonly used vasodilator drugs in inhibiting vasospasm and increasing flow of the ITA prior to ITA-left descending artery (LAD) anastomosis.
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2. Patients and materials
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Eighty consecutive patients submitted for elective first time coronary artery bypass grafting (CABG) were randomly subdivided into five treatment groups. The same surgeon (M.N.) performed all operations. Drugs were prepared in sealed bottles and coded in the institute's pharmacy. Both surgeon and staff were blinded to the drug type.
2.1. Surgical procedure
The left ITA was harvested as a pedicle from the subclavian vein to just beyond the bifurcation into the superior epigastric artery and musculophrenic arteries, with the aid of diathermy and metal clips. Five minutes after systemic heparinization (300 units/kg) had been administered intravenously, the artery was divided before its bifurcation, free flow was measured, and the artery was clipped at its distal end. The pedicle was immersed in a special applicator tube containing 20 ml solution of the study drug. The tube was then left beneath the left sternal edge until the time of anastomosis of the LITA to the LAD. CPB was established and core temperature was reduced to 28°C. Antegrade cold crystalloid cardioplegia and topical cold saline were used for myocardial preservation. In all patients, the left ITA was grafted to the LAD and was the last distal anastomosis. Re-warming of the patient was commenced shortly after the ITA-LAD anastomosis was begun. Systemic vasopressors or vasodilators were not used during CPB.
2.2. ITA flow measurements
Free flow of the left ITA was measured using an electromagnetic flow meter (MFV-3200 Nihon Kohden, Tokyo, Japan). In order to ensure good contact between the probe and the ITA, a 1.5–2-cm long segment was skeletonized. The average flow of three consecutive readings of the electromagnetic flow meter was recorded. The first measurement was done immediately after division of the artery, before treatment and before CPB. The second measurement was performed after trimming the distal end of the artery and just prior to the last anastomosis to the LAD. The artery was usually trimmed a few millimeters before its previously clipped end. The time interval between the two measurements, MAP and CPB flow were all recorded.
2.3. Topical solutions
Drug dosage was arbitrarily chosen on the basis of daily clinical practice. All solutions were at room temperature (18–20°C) when applied: papaverin 2 mg/ml, nitroglycerin 1 mg/ml, verapamil 0.5 mg/ml, nitroprusside 0.5 mg/ml, normal saline 0.9%.
2.4. Statistical analysis
Results are expressed as mean±standard error. In order to analyze statistically significant differences in mean continuous parameters (age, BSA, number of grafts, time, CPQ, etc.) between the five groups (normal saline, papaverine, verapamil, nitroglycerine and sodium nitroprusside) analysis of variance was done using the Duncan multiple comparison option. A non-parametric analysis of Kruskal–Wallis was also done due to sample size restrictions in the subgroups.
Paired t-test was done in order to analyze statistically significant differences between first and second flow measurements specific for each groups.
P-values less or equal to 0.05 were considered statistically significant.
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3. Results
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Demographic, hemodynamic and CPB data between the five groups are shown in Table 1. No statistically significant differences were found between the groups with respect to age, body surface area (BSA), number of grafts, time intervals between the two flow measurements, bypass time, cross clamp time and CPB flow. Mean arterial pressure (MAP) at the time of the first and second ITA flow measurements was not significantly different either within or between the groups.
In all groups the free flow of the ITA immediately prior to ITA-LAD anastomosis was significantly higher compared to the post division free flow (P<0.002, 0.0004, 0.0001, 0.03, 0.0001, respectively) (Table 2). However, no statistically significant differences were shown between the five groups. No patient demonstrated clinical evidence of ITA spasm during the study. There were no systemic vasodilatory effects of the different drugs.
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4. Discussion
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This study confirms previous observations [3,9,10] that ITA flow is low immediately after its mobilization from the chest wall. This is most probably due to vasospasm triggered by mechanical manipulation of the artery and physical factors such as diathermy [11,12]. However, our study shows that with time the spasm subsides, the artery dilates, and its flow increases by two-fold with no significant advantage of topical application of vasodilator drugs over placebo alone.
These findings differ from those reported in other studies where topical usage of similar vasodilator drugs showed a clear advantage over saline in increasing the ITA flow [10]. On the other hand, Sasson et al., have shown that topical vasodilators had no effect on ITA flow and the only factor influencing the flow was time [8]. However, there are a few major differences in the methods used by our group compared to previously reported works. Firstly unlike other cited reports our study was randomized, double-blind and placebo-controlled. Secondly, whereas in most studies the ITA was wrapped in a drug-soaked swab, we kept the ITA pedicle in a special applicator tube containing the drug solution in which the ITA was completely immersed. We believe that this approach creates a more homogeneous, precise and consistent distribution of the drug under study.
In previous studies, the effect of topical or intraluminal use of vasodilators was examined by measuring the ITA free flow before initiation of CPB, thus the time interval between the pre and post-treatment was usually shorter than 20 min [4]. Instead, we performed the second ITA flow measurement just prior to constructing the ITA-LAD anastomosis on CPB. This allowed an average time interval of 70 min between the two flow measurements. This would appear to more realistically reflect the sequence of steps in a routine elective first time CABG operation, when three to four grafts are performed and ITA to LAD anastomosis is done as the last distal anastomosis. Although post-anastomotic ITA flow may not correlate with pre-anastomotic flow, previously described evidence suggests that if free flow is at least 100 ml/min, post-anastomotic flow is equivalent to that through a vein graft, regardless of the recipient coronary artery diameter. Accepting a free flow of at least 50 ml/min does not protect against hypoperfusion [13,14]. Hence it is important to optimize ITA flow just prior to anastomosis of the LAD. In this study, all groups including the control saline group, achieved satisfactory flows in the range of 78±9–98±12 ml/min, and there was no clinical evidence of hypoperfusion during the immediate perioperative period. These results coincide with the findings of other studies [8] but are different from those reported by Cooper et al., when satisfactory flows were achieved only in the sodium nitroprusside treated ITA [10]. However, in their study the time interval between flow measurements was significantly shorter (±18 min) compared to our study.
Clinical comparisons of the effect of the various vasodilators used in our study on ITA free flow are scarce [8,10], hence most of our knowledge is taken from in vitro studies [5,7,15,16]. In Jett et al., experimental inhibition of the contraction of precontracted ITA rings was best achieved with nifedipine, sodium nitroprusside and papaverine, with the least or no effect achieved with nitroglycerin [7]. He and his coworkers found that glyceril trinitrate was more potent than papaverine in relaxing precontracted ITA rings, while nifedipine took a longer time to achieve this relaxation [12]. From our data, it appears that verapamil and sodium nitroprusside, both of which are known to have direct and indirect effect on smooth muscle relaxation [7], were not superior to treatment with saline. This may be explained by the fact that this time the artery underwent spontaneous dilatation.
Vasoconstriction may be evoked by mechanical stimulation, as well as by various vasoconstrictor substances [17]. It is widely accepted that the endothelium of the ITA spontaneously releases significant amounts of nitric oxide (NO) which plays an important role in arterial vasodilatation. In addition, production of NO can be stimulated by a variety of vasoactive substances. It has been suggested that blood vessels with intact endothelium reacts poorly to vasoconstrictors whereas they contract strongly when endothelium is lost or damaged [17,18]. One possible explanation for the salutary effect of time on ITA flow is that after the first mechanical or thermal insult to the ITA occurs, if the endothelium is intact a time related recovery takes place. This is probably due to the release of endothelial relaxing factors.
In this study, drug dosage was arbitrarily chosen according to routine clinical practice. Therefore it may be argued that a high drug dosage would have had a different effect on ITA flow. This issue was left unsolved.
In conclusion, this study has shown that careful harvesting and handling of the ITA pedicle is sufficient to achieve adequate flow prior to its anastomosis to the LAD, and that there is no need for further pharmacological treatment of the ITA. However, if the ITA-LAD anastomosis is performed much earlier after harvesting of the ITA, i.e. before the artery has made a fully spontaneous recovery from the spasm, vasodilator treatment may be beneficial.
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Acknowledgments
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We would like to thank Miriam Hadad MGR from Rabin Medical Center's pharmaceutical service for assisting in the drug preparation.
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References
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Received May 10, 1999;
received in revised form August 25, 1999;
accepted September 1, 1999.
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Abstract
1. Introduction
