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Ann Thorac Surg 1997;64:1742-1746
© 1997 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Effect of Low-Dose Positive Inotropic Drugs on Human Internal Mammary Artery Flow

Pharmacology Laboratory and Departments of Cardiac Surgery, Internal Medicine, and Cardiology, Grenoble University Hospital, Grenoble, France

Accepted for publication June 29, 1997.

	Abstract

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background. Dobutamine (a ß-receptor agonist), enoximone (a type III selective phosphodiesterase inhibitor), and epinephrine (an - and ß-mimetic) frequently are used in the perioperative management of patients undergoing coronary artery bypass grafting.

Methods. We performed a double-blind clinical study to compare the effects on internal mammary artery free flow of low doses of these three positive inotropic drugs. Thirty patients in whom the left internal mammary artery was used for coronary artery bypass grafting were randomized into three groups. Internal mammary artery free flow and hemodynamic measurements were evaluated before and 10 minutes after the intravenous infusion of dobutamine (3 µg • kg^-1 • min^-1), enoximone (200 µg/kg), or epinephrine (0.05 µg • kg^-1 • min^-1).

Results. A significant increase in free flow occurred only in the dobutamine group (33 ± 7.5 and 42.2 ± 7.9 mL/min before and after drug infusion, respectively; p = 0.013). Comparison of the increase in flow between the groups, however, showed no difference. These drugs, at doses designed to produce a positive inotropic effect, caused little increase in the free flow of the internal mammary artery.

Conclusions. The use of dobutamine, enoximone, and epinephrine as low-dose positive inotropic treatments in the perioperative and postoperative periods of coronary artery bypass grafting should depend on their positive inotropic effects rather than their vasodilative effects on the arterial grafts.

	Introduction

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
See also page 1746.

The internal mammary artery (IMA) is the arterial graft most commonly used for coronary artery bypass grafting because of its superior long-term patency compared with the saphenous vein and its improved long-term patient survival [1–3]. However, the IMA has a smaller distal diameter than vein grafts and a greater tendency to spasm, which is a recognized clinical problem. Perioperative IMA spasm could cause morbidity and even mortality [4, 5], making its prevention with vasodilative drugs important in the postoperative period.

Pharmacologic agents used in the perioperative and postoperative periods may alter graft flow. Inotropic drugs have been studied in a few clinical trials to measure their ability to increase IMA blood flow [6, 7]. These studies suggested the superiority of phosphodiesterase inhibitors over ß-agonists, and the former drugs subsequently have been recommended for clinical use [7]. Because these drugs frequently are required in the postoperative management of patients undergoing coronary artery bypass grafting, we compared the effects on human IMA free flow of low-dose dobutamine, enoximone, and epinephrine in a double-blind, randomized study. The purpose of the study was to test whether the vasomotor effects of these drugs on the IMA should be taken into consideration when selecting a low-dose positive inotropic treatment in the perioperative and postoperative periods.

	Patients and Methods

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Study Population
Thirty consecutive patients (29 men and 1 woman; median age: 60 years, range: 43 to 79 years) undergoing elective coronary artery bypass grafting involving at least the left IMA were included in the study. The protocol was approved in January 1996 by the investigational committee for human studies at Michallon Hospital in Grenoble, France. The study was performed in accordance with the international guidelines for good clinical practice, including the fully informed, written consent of every patient. Criteria for admission into the study group were elective coronary artery bypass grafting using the left IMA, hemodynamic stability, and no history of ventricular arrhythmia. All patients underwent coronary angiography. Contrast ventriculography was performed to estimate the left ventricular ejection fraction.

Study Protocol
The reproducibility of IMA free flow measurements was tested in a pilot study. The left IMA free flow was measured, using the same conditions as in the final study, at 10-minute intervals in 15 patients undergoing coronary artery bypass grafting. The mean free flow was 51.2 ± 8.7 mL/min on the first measurement and 50.4 ± 8.3 mL/min on the second measurement. The intraindividual coefficient of variation was 10%, or 4.5 mL/min, demonstrating the good reproducibility of the method.

After admission into the study, the 30 patients were allocated randomly to one of three equal-sized treatment groups. All patients were anesthetized with 50% oxygen, alfentanil, midazolam, and atracurium. They all had a Swan-Ganz catheter (Baxter, Maurepas, France) inserted into the right internal jugular vein and a catheter inserted into a radial artery, connected to a Siemens Sirecust recorder (Siemens, Caluire, France).

After sternotomy, the left IMA was dissected from the chest wall as a pedicle, from the subclavian vein to its bifurcation. Its side branches were clamped with metal clips. No pharmacologic agents were applied to the tissue. Systemic heparinization was performed, aortic and right atrial cannulation was accomplished in preparation for cardiopulmonary bypass, and macromolecules or blood was transfused when necessary.

After a 5-minute stabilization period, the left IMA was cut distally as necessary for the coronary artery bypass graft and distal free flow was measured. The IMA flow was determined by measuring the volume of blood expelled from the end of the freely bleeding artery in a 30-second period. Heart rate; systolic, mean, and diastolic systemic and pulmonary arterial pressures; and central venous and pulmonary capillary wedge pressures were measured. Cardiac output and cardiac index, recorded by thermodilution, were measured as the average of three consecutive determinations, and systemic resistances were calculated. Then, the tip of the IMA was occluded with a plastic bulldog clamp and the artery was laid on a moist swab in its anatomic position.

Infusion of the positive inotropic drug was begun after the injection of a bolus corresponding to the catheter volume. This ensured that the effective drug infusion was not delayed. Predetermined doses of dobutamine and epinephrine were infused for 10 minutes, whereas enoximone was administered as a bolus. The drugs were given intravenously through a central venous catheter used for no other purpose. The doses of the general anesthetics were not changed and no other treatments were administered between the two measurements. The blood pressure was left to change under the influence of the inotropic agent.

Ten minutes after the first measurement, the IMA was unwrapped and the plastic bulldog clamp was taken off. The second IMA free flow measurement was obtained and hemodynamic data again were recorded. To ensure that the experiment was double-blinded, at no time was the surgeon measuring the blood flow aware of the drug administered. After the second measurement, the blind was removed for all the patients. For 4 patients in the enoximone group, a third measurement was made after an additional 10-minute period. Extraluminal papaverine solution was applied only after the end of the protocol for all patients. The coronary artery bypass graft then was performed.

Systemic Infusions
The drugs and doses used were dobutamine (3 µg • kg^-1 • min^-1, total infused dose 30 µg/kg; Lilly France S.A., St. Cloud, France), enoximone (200 µg/kg; Marion Merrel Dow, Levallois-Perret, France), and epinephrine (0.05 µg • kg^-1 • min^-1, total infused dose 0.5 µg/kg; Aguettant, Lyon, France).

Statistical Analysis
Each patient served as his or her own control. The significance of the changes in IMA flow and hemodynamic data was tested by Student's t-test for paired differences. Differences between groups were tested by analysis of variance. Regression analysis was performed using the least-squares method. Probability values of less than 0.05 were considered statistically significant. Data are expressed as mean plus or minus standard error.

	Results

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
There were no statistically significant differences in the sex ratio, age, body surface area, or left ventricular ejection fraction among the three groups (Table 1). The number of patients who received ß-blockers, nitrates, and calcium channel blockers in each group was not different.

View larger version (24K): [in this window] [in a new window]   Fig 1. . Internal mammary artery (IMA) free flow during control and drug infusion periods, expressed as mean plus or minus standard error. The asterisk indicates p < 0.05 versus control flow; there were 10 patients in each group.

	Comment

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

The use of positive inotropic agents is common in the perioperative management of patients undergoing coronary artery bypass grafting. These drugs also have vasomotor properties and may have direct and indirect effects on the flow of the engrafted left IMA. Therefore, we studied the effects of three positive inotropic drugs on IMA free flow. We tested dobutamine (a ß-receptor agonist), enoximone (a type III selective phosphodiesterase inhibitor), and epinephrine (an - and ß-mimetic) because these drugs are among the most frequently used in cardiac operations. We tested the lower drug doses necessary to produce a positive inotropic effect because low doses of these drugs frequently are required in the postoperative management of patients undergoing coronary artery bypass grafting.

Internal mammary artery free flow depends on the perfusion pressures and on the vasomotor properties of the graft. Once the artery has been engrafted, its flow depends in part on variations in coronary vascular resistance, which may be an important factor in the variations in graft flow [8]. Free flow measurement of the IMA is easy to perform, but attention should be paid to the study protocol for good reproducibility. We performed aortic and right atrial cannulation before the first measurement of IMA flow instead of between the two measurements (as done by other investigators [7, 9]) because these maneuvers may be associated with important variations in blood volume leading to variations in IMA flow [8]. Further, the blood pressure was left to change under the influence of the inotropic agent, with the effect of the inotropic agent being the result of both the vasoactive effect and changes in blood pressure. However, for ethical reasons, this protocol does not allow for more than 10-minutes between the two measurements. We also decided to occlude the tip of the artery with a smooth plastic bulldog clamp. The second measurement was made after this clamp was removed, whereas other investigators have trimmed the end of the IMA to remove the part that had been occluded by the bulldog clamp [7]. Trimming the end of the IMA may cause variations in flow according to Poiseuille's law (the flow is correlated inversely with the vessel length and is correlated with the fourth power of the vessel radius). Conversely, our method could have underestimated the second flow measurement because of potential IMA spasm or crushing caused by the clamp. However, our pilot experiment, performed using the same experimental protocol, showed good reproducibility of IMA flow measurements before and after clamping, reducing this possibility.

Our study shows that systemic low-dose inotropic drugs induce a weak increase in IMA free flow. Although the increase in the dobutamine group appeared to be significant, no significant difference was shown among the groups. These increases in all cases were less than 30% of the control values and they do not compare with the 65% to 180% flow increase observed after extraluminal papaverine application [10, 11].

Low-dose dobutamine infusion induced a significant but weak increase in IMA free flow, similar to that shown by Izzat and colleagues [7], although they did not find it to be significant. Conversely, the infusion of 5 µg • kg^-1 • min^-1 of dobutamine did not increase significantly flow through saphenous vein grafts as measured by implantable pulsed Doppler microprobes [12]. In IMA flow studies, this increase is independent of arterial blood pressure variations and therefore may be related directly to vasodilation of the graft. The increases in cardiac output and cardiac index were not found to be significant in our study, whereas the increase in heart rate was. This might result from the relatively low number of patients producing weak statistical power. This hypothesis is supported by other studies that have demonstrated that dobutamine at a dose of 4 µg • kg^-1 • min^-1 increases the cardiac index in patients recovering from cardiac operations [13, 14]. This increase also has been found for even lower doses (2 µg • kg^-1 • min^-1) [15].

Enoximone (200 µg/kg) induced no significant variations in IMA free flow, but it showed a tendency to increase cardiac output without changing the arterial blood pressures. The delay between the two measurements to achieve a maximum drug effect was used because the time required to reach the maximum plasma concentration is 5 minutes in both normal volunteers [16] and patients recovering from coronary artery bypass grafting [17]. Further, repeated IMA measurements made with implantable pulsed Doppler microprobes [18] show that the maximum IMA flow increase after bolus administration of enoximone (500 µg/kg) is observed after 10 minutes. Finally, we found no significant increase in IMA flow after 20 minutes, and there was no further increase between the 10th and 20th minutes (21% versus 16% increase, respectively). However, these last data should be interpreted with caution because they were obtained on only 4 patients and after removal of the blind study at the 10th minute.

Izzat and colleagues [7] found a 90% increase in IMA free flow after a bolus infusion of enoximone (500 µg/kg), whereas Payen and associates [18] found a 38% increase in IMA free flow measured by implantable Doppler microprobes. Care should be taken in comparing these studies because the latter was performed after IMA engrafting, and IMA flow also depends on variations in the coronary vascular resistance. Nevertheless, our results are not fully consistent with those reported by Izzat and colleagues [7]: for a 2.5-fold increase in the enoximone dose injected, there was a 4.6 fold-increase in the IMA flow, which was much more than we can expect on the basis of our results. This apparent disproportion may be explained by the different methodology used, as described earlier. We believe that aortic cannulation should not be performed between the two measurements because it is a potentially important cause of variations in blood volume and hemodynamic parameters. These variations cannot be reversed entirely by macromolecules or blood transfusion based on the hemodynamic data because the drug infusion itself may be responsible for part of the variation in hemodynamic data. Therefore, we recommend that aortic cannulation be done before the first measurement is made to avoid confounding factors.

Comparison of the IMA flow increase between the enoximone and dobutamine groups did not show any differences, whereas it did in the study by Izzat and colleagues [7]. The main reason might be that the drug concentrations used in their study were not comparable to those used in our study. The dobutamine concentration was 3 µg • kg^-1 • min^-1 in the former versus 1 to 3 µg • kg^-1 • min^-1 in the latter. The respective enoximone concentrations were 200 µg/kg and 500 µg/kg. It is important to compare drug effects at the same level of positive inotropic effect (ie, without differences in the increase in cardiac index), as we did in our study.

Epinephrine caused no variations in IMA free flow, but it did increase systolic blood pressure, heart rate, cardiac index, and cardiac output. Epinephrine produced the least effect on IMA blood flow, probably because of the lack of a vasodilative effect. Von Segesser and colleagues [8] have shown that high doses (5 µg/kg) of intravenous epinephrine given to dogs increase the IMA blood flow proportionate to the increase in mean aortic pressure under stable hemodynamic conditions. However, IMA flow decreases in response to intravenous epinephrine under severe hypovolemic conditions. All the studies performed in patients have been done after IMA engrafting [6], preventing comparison with our results.

In conclusion, the choice between dobutamine, enoximone, and epinephrine as low-dose positive inotropic agents for use in the perioperative and postoperative periods after myocardial revascularization should not take into consideration their vasodilative effects on the IMA graft. Further studies are required to determine whether higher doses of these drugs, inducing an equivalent positive inotropic effect, may have different and clinically significant effects on the flow of the IMA.

	Acknowledgments

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
We thank Dr Rachid Hacini and Dr Marianne Noirclerc for their help in the realization of this study.

	Footnotes

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Cracowski, Laboratoire de pharmacologie, PCEBM, Faculté de Médecine de Grenoble, 38706 La Tronche Cedex, France.

	References

Top Footnotes Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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3. Okies JE, Page S, Bigelow JC, Krause AH, Salomon NW. The left internal mammary artery: the graft of choice. Circulation 1984;70(Suppl 1):213–21.
4. Jones EL, Lattouf OM, Weintraub WS. Catastrophic consequences of internal mammary artery hypoperfusion. J Thorac Cardiovasc Surg 1989;98:902–7.[Abstract]
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12. Beloucif S, Laborde F, Beloucif L, Piwnica A, Payen D. Determinants of systolic and diastolic flow in coronary bypass grafts with inotropic stimulation. Anesthesiology 1990;73:1127–35.[Medline]
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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Dominique Blin Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cracowski, J.-L. Articles by Blin, D. Search for Related Content PubMed PubMed Citation Articles by Cracowski, J.-L. Articles by Blin, D. Related Collections Related Article