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The effects of fenoldopam on coronary conduit blood flow after coronary artery bypass graft surgery
The Effects of Fenoldopam on Coronary Conduit Blood Flow After Coronary Artery Bypass Graft Surgery Michele Halpenny, MRCPI, FFARCSI, Stinivasan Lakshmi, MB, Aonghus O’Donnell, FFARCSI, Sheila O’Callaghan-Enright, FFARCSI, Damian O’Connell, PhD, and George Shorten, MD Objective: To quantify the effects of fenoldopam, 0.1 g/ kg/min, on left internal mammary artery (LIMA) and saphenous vein blood flow after coronary anastomosis. Design: Prospective, randomized, double-blind, placebocontrolled trial. Setting: University teaching hospital, single institution. Participants: Thirty-one American Society of Anesthesiologists III patients undergoing elective coronary revascularization. Interventions: A perivascular ultrasonic flow probe (Linton Instrumentation, Norfolk, UK) was placed around the LIMA and saphenous vein graft after coronary anastomosis. Measurements and Main Results: Immediately before and at 5-minute intervals for 15 minutes after starting the infusion, blood flow was measured in the LIMA and one saphenous vein graft using a transit time ultrasonic flow probe.
Heart rate, blood pressure, and central venous pressure were documented at these time points. Administration of fenoldopam, 0.1 g/kg/min, did not alter heart rate or blood pressure. A small, nonsignificant increase in LIMA blood flow occurred during the 15-minute study period (30 ⴞ 12 to 35 ⴞ 10 mL/min) in patients who received fenoldopam. No significant changes occurred in the placebo group. Conclusions: The findings indicate that fenoldopam, 0.1 g/kg/min, did not influence coronary conduit blood flow to a clinically significant extent. The small increase in LIMA blood flow may be of greater importance in high-risk patients or in the prevention of coronary arterial spasm. Copyright © 2001 by W.B. Saunders Company
S
hypothesis, a prospective, randomized, double-blind, placebocontrolled trial was performed to assess the effect of fenoldopam on coronary conduit blood flow after anastomosis to the distal coronary circulation.
APHENOUS VEINS and internal mammary arteries are used as conduits in patients undergoing coronary revascularization.1 In terms of long-term patency, the internal mammary artery is superior to the saphenous vein graft.2-4 The internal mammary artery is a dynamic coronary graft, whereas the saphenous vein graft is passive. Potential exists for pharmacologically induced vasodilation or vasoconstriction of the artery.5 It is likely that a selective coronary artery vasodilator would increase total myocardial oxygen delivery after coronary artery bypass graft (CABG) surgery, a time of risk for ischemia-related adverse events. Perioperative internal mammary artery spasm is associated with morbidity and mortality, and its prevention is a reasonable clinical objective in the postoperative period.6 Fenoldopam is a highly selective agonist at peripheral dopamine (DA1) receptors.7 The presence of DA1 receptors in human coronary and mammary arteries, and in saphenous vein smooth muscle, has been shown using immunocytochemical techniques.8,9 Agonist activity at DA1 receptors results in smooth muscle relaxation and vasodilation.10 The precise role and functional significance of these receptors in the coronary circulation have not been defined, however. In vitro studies have shown that fenoldopam relaxes precontracted human coronary arteries.11 In a dog model, fenoldopam increased myocardial blood flow in normal and ischemic border myocardium.12 It was hypothesised that fenoldopam, 0.1 g/kg/min, may increase the coronary conduit blood flow after CABG surgery through its agonist activity at DA1 receptors. To test this
From the Departments of Anesthesia, Intensive Care Medicine, and Surgery, Cork University Hospital, Wilton, Cork, Ireland. Supported in part by Neurex/Elan Pharmaceutical. Address reprint requests to Michele Halpenny, MRCPI, FFARCSI, 3 Waltham, Clonfadda Wood, Mount Merrion Avenue, Blackrock, Co. Dublin, Ireland. Copyright © 2001 by W.B. Saunders Company 1053-0770/01/1501-0015$35.00/0 doi:10.1053/jcan.2001.20374 72
KEY WORDS: coronary artery bypass, dopamine receptors, fenoldopam, internal mammary artery, saphenous vein
METHODS The protocol was approved by the ethics committee of the Cork Teaching Hospitals and by the Irish Medicines Board. Written informed consent was obtained from study patients. Criteria for inclusion in the study were (1) age ⬍ 70 years old, (2) elective CABG surgery, (3) left ventricular ejection fraction ⬎ 40%, (4) planned grafting of the left internal mammary artery (LIMA) to the left anterior descending artery, (5) planned nonsequential grafting using a saphenous vein to a right-sided coronary artery, (6) absence of myocardial infarction within the previous 6 months, and (7) hemodynamic stability on separation from cardiopulmonary bypass (CPB) without the use of a vasoactive agent. The patients received lorazepam, 0.02 to 0.03 mg/kg orally, as a premedicant together with their concurrent medication (Table 1) 2 hours preoperatively. General anesthesia was induced with fentanyl, 15 to 20 g/kg, and propofol, 0.5 to 1 mg/kg, and maintained with isoflurane 0.5% to 1% end-tidal concentration and a propofol infusion (2 to 3 mg/kg/h). No volatile anesthetic agent was administered from the start of CPB until completion of the operation. Muscle relaxation was achieved using pancuronium, 0.1 mg/kg. Monitors included electrocardiography (leads II and V5 with automated ST analysis, DATEX AS3) and arterial and central venous pressures. Positive-pressure ventilation was adjusted to maintain end-tidal carbon dioxide in the normal range (35 to 40 mmHg). The LIMA was dissected free of overlying connective tissue to facilitate accurate placement of the probe. Patients weaned from CPB without vasodilator or inotropic support were assigned to the fenoldopam or placebo groups (according to a random allocation). On confirmation of adequacy of the reversal of heparin effects with protamine, an infusion of fenoldopam, 0.1 g/kg/min, or placebo (normal saline) was administered through a central infusion port by a blinded investigator. The 50-mL syringes were prepared and coded by the hospital pharmacy. Immediately before and at 5-minute intervals for 15 minutes after starting the infusion, blood flow was measured in the LIMA and one saphenous vein graft using a transit time ultrasonic flow probe (Linton Instrumentation, Norfolk UK). The flow waveform pattern was recorded continuously and analyzed (Fig 1). To ensure that there was no
Journal of Cardiothoracic and Vascular Anesthesia, Vol 15, No 1 (February), 2001: pp 72-76
FENOLDOPAM AND CORONARY CONDUIT BLOOD FLOW
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Table 1. Medication Taken by Participating Patients Preoperatively
Nitrates -Adrenoceptor antagonists Calcium antagonists Converting enzyme inhibitors
Placebo (n ⫽ 15)
Fenoldopam (n ⫽ 16)
11 12 4 3
13 10 5 2
reactive hyperemia caused by the placement of the probe on the vessel, stabilization of 30 seconds was allowed before the start of the measurement. At each time point, the value recorded was the mean blood flow measured over 30 seconds. As each flow measurement was obtained, heart rate, mean arterial blood pressure, and central venous pressure were recorded. The number of patients in each group is based on the following: One-tailed Student’s t-test; ␣ ⫽ 0.05;  ⫽ 0.2 Effect size: 36.0 mL/min 䡠 20% ⫽ 7.2 mL/min Standardized effect size ⫽ 7.2/4.1 ⫽ 1.7 Minimum sample size ⫽ 12/group Demographic data, hemodynamic data, and baseline (preinfusion) blood flows were analyzed using unpaired Student’s t-tests. Coronary conduit blood flow was analyzed by repeated measures analysis of variance using group as the between-subjects factor and time as the within-subject factor and Dunnett’s test where appropriate; p ⬍ 0.05 was considered statistically significant. RESULTS
Of 33 patients recruited in this study, 2 required inotropic support on separation from CPB and were excluded from the study. The 2 groups were similar in terms of age, body weight, height, body surface area, sex, left ventricular ejection fraction, and number of grafts performed (Table 2). The duration of anesthesia, surgery, CPB, aortic cross-clamp time, fluid administration, and intraoperative blood loss were similar in the 2 groups (Table 3). Before starting the study infusion, heart rate, mean arterial pressure, and central venous pressure were sim-
Fig 1. Flow waveform recording of left internal mammary artery (LIMA) and saphenous vein (SV) blood flow as measured by the transit time ultrasonic flow probe.
Table 2. Demographic Data
Age (yr) Height (cm) Weight (kg) BSA (m2) Sex (female/male) Left ventricular ejection fraction (%) No. vessel grafts
Placebo (n ⫽ 15)
Fenoldopam (n ⫽ 16)
61 (8) 170 (9) 77 (16) 1.86 (0.2) 4/11
60 (9) 172 (10) 75 (11) 1.89 (0.2) 4/12
40 3.4 (0.8)
40 3.5 (0.5)
NOTE. Data are mean (SD). Abbreviation: BSA, body surface area.
ilar in the 2 groups (Figs 2, 3, and 4). Administration of fenoldopam did not alter heart rate, mean arterial pressure, or central venous pressure (Figs 2, 3, and 4). The coronary perfusion pressure was similar in both groups at each of the 4 time points in the study (Fig 5). During the study period, electrocardiogram signs of myocardial ischemia (defined as 1 mm ST depression at 60 msec after the J point if down-sloping or horizontal and ⬎2 mm if up-sloping) were not observed. In¯ ⫾ ternal mammary artery (32 ⫾ 13 and 30 ⫾ 12 mL/min) (X SD) coronary conduit blood flow in the placebo and fenoldopam groups was similar at baseline. Neither the internal mammary artery nor the saphenous vein graft flow changed in the placebo group during the study period (Figs 6). A minor increase in LIMA blood flow (which did not reach statistical significance) was observed during the 15-minute study period (30 ⫾ 12 to 35 ⫾ 10 mL/min) (Fig 7) in the patients who received fenoldopam. DISCUSSION
The most important finding of this study is that fenoldopam (0.1 g/kg/min) administered by continuous intravenous infusion after separation from CPB did not produce a clinically
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HALPENNY ET AL
Table 3. Study Parameters Placebo (n ⫽ 15)
Duration of anesthesia (min) Duration of surgery (min) Duration of extracorporeal circulation (min) Duration of aortic crossclamping (min) Crystalloids (mL) Colloid (mL) Blood/components (U) Blood loss (mL)
Fenoldopam (n ⫽ 16)
335 (42) 258 (44)
345 (50) 274 (48)
101 (24)
103 (15)
73 (21) 2893 (633) 2688 (443) 3 (4) 2342 (886)
75 (13) 2903 (496) 2828 (582) 2 (3) 2523 (1070)
NOTE. Data are mean (SD).
Fig 2. Heart rate (beats/min [bpm]) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam (n ⴝ 16).
Fig 3. Mean arterial blood pressure (mmHg) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam (n ⴝ 16).
significant increase in either LIMA or saphenous vein coronary conduit blood flow. Although administration of fenoldopam in this low dose was not associated with adverse hemodynamic effects, it is unlikely that the modest trend toward increased flow through the LIMA graft during the 15-minute study period confers a real clinical benefit. The magnitudes of measured blood flow in this study in the placebo group for LIMA (32 ⫾ 13 mL/min) and for saphenous vein graft (33 ⫾ 13 mL/min) were similar to the corresponding ultrasonically measured values (34 ⫾ 2.5 and 33 ⫾ 2.4 mL/ min) reported by Canver et al.13 The interpatient variation in flow was considerably greater than in Canver’s study, however, decreasing the likelihood of identifying a fenoldopam-related change in flow. Nonpatient factors that may account for this variation include use of a probe of inappropriate size or failure to obtain adequate contact between the probe and the vessel wall. Other factors that may have decreased the likelihood of identifying an effect of fenoldopam on conduit blood flow, if
Fig 4. Central venous pressure (cm H2O) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam.
one truly exists, include (1) the administration of a single and relatively low dose; (2) a short (15-minute) study period; (3) measurement of blood flow shortly after the start of a fenoldopam infusion (5, 10, and 15 minutes), rather than the likely achievement of steady-state concentration (approximately 3.2 g/mL) from the start of a fenoldopam infusion at 0.1 g/kg/ min in 20 minutes (ie, 4 ⫻ elimination half-life ⫽ 5 minutes)7; and (4) administration of fenoldopam at a time (immediately after separation from CPB) when systemic concentrations of endogenous catecholamines and thromboxane A2 (potent coronary vasoconstrictors) are markedly elevated.14,15 Measurement of blood flow in the anastomosed LIMA and saphenous vein conduit after separation from CPB reflects the clinical setting more accurately than does measurement of free flow (before distal anastomosis) as previously reported.16,17 This point is particularly important in assessing a systemically administered drug, which mediates its effects on graft flow primarily on the coronary resistance arterioles rather than on the conduit itself. Goldberg et al18 classified the peripheral dopamine receptors into 2 groups, the DA1 and DA2 subtypes, on the basis of synaptic localization. DA1 receptors are located postsynaptically on smooth muscle cells in the peripheral vasculature as well as in the renal, mesenteric, and coronary vasculature; in the proximal tubule; and in the cortical collecting ducts of nephrons.8,18 DA1 receptors activate adenylate cyclase, causing smooth muscle relaxation, systemic vasodilation, and increased regional blood flow. In renal tubules, DA1 receptors cause sodium and water excretion.19 Fenoldopam mesylate, a benzazepine derivative of the endogenous catecholamine transmitter dopamine, is a highly selective DA1-receptor agonist.7 Fenoldopam has no DA2, ␣-adrenergic, or -adrenergic agonist activity.7 Fenoldopam has been used
Fig 5. Coronary perfusion pressure (mmHg) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam (n ⴝ 16).
FENOLDOPAM AND CORONARY CONDUIT BLOOD FLOW
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Fig 6. Coronary blood flow (mL/min) in the left internal mammary artery in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. ■, placebo (n ⴝ 15); 䊐, fenoldopam (n ⴝ 16).
safely in clinical practice as an antihypertensive agent since 1981. In the present study, the highest dose possible of fenoldopam (0.1 g/kg/min) that had in previous studies been shown not to induce an antihypertensive effect was chosen. No significant changes in heart rate and blood pressure resulted from administration of fenoldopam, 0.1 g/kg/min, in this study. This finding is consistent with the findings of Murphy et al,20 who examined the effects of intravenous infusion of fenoldopam (using an increasing dose regimen) to patients with uncomplicated essential hypertension. In only 1 of the 17 patients studied did fenoldopam, 0.1 g/kg/min, decrease diastolic blood pressure by ⬎10 mmHg.20 In that study, heart rate increased in proportion to the decrease in systemic blood pressure. During infusion of fenoldopam, 0.1 g/kg/min, to healthy volunteers, no change in diastolic blood pressure was observed.21 In vitro and in vivo studies have shown the existence of DA1 receptors in coronary vasculature.8-10 Kopia and Valocik22 showed in a dog model that direct, dopamine-mediated coronary vasodilation occurs by stimulation of a vascular receptor of the DA1 subtype, inducing a pronounced increase in coronary blood flow. However, Zhao et al23,24 indicated that primary dopaminergic coronary vasodilation was unlikely to be of functional significance. Wang et al25 compared the adenylate
Fig 7. Saphenous vein blood flow (mL/min) in the left internal mammary artery in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. ■, placebo (n ⴝ 15); 䊐, fenoldopam (n ⴝ 16).
cyclase–stimulating effects of fenoldopam in coronary and renal arteries in an attempt to assess the functional significance of coronary DA1 receptors. Fenoldopam increased cyclic adenosine monophosphate production in coronary and renal arteries. The magnitude of the increase was much greater in renal arteries than in coronary arteries, however. This situation was attributed to a greater number of DA1 receptor sites in the renal vessels.25 It was reported in a dog model that fenoldopam significantly increased renal blood flow but had no dilating activity in the coronary vasculature at the same dose.26 The results of the present study are consistent with those of Wang et al25 and Lang and Woodman.26 It appears that if a clinical role does exist for DA1-receptor agonists in improving postCABG coronary conduit blood flow, patient and dose selection and timing of administration would be crucial in maximizing the benefit of a modest pharmacologic effect. In conclusion, these findings indicate that fenoldopam (administered in the manner and dose described) did not influence coronary conduit blood flow to a clinically significant extent. The modest trend toward increased LIMA coronary conduit blood flow may indicate that further studies are warranted to determine the effects of this drug administered at a higher dose and for a greater duration.
REFERENCES 1. Cameron A, Davis KB, Green G, Schaff HV: Coronary bypass surgery with internal-thoracic-artery grafts— effects on survival over a 15-year period. N Engl J Med 334:216-219, 1996 2. Lytle BW, Loop FD, Cosgrove DM, et al: Long-term (5 to 12 years) serial studies of internal mammary artery and saphenous vein coronary grafts. J Thorac Cardiovasc Surg 89:248-258, 1985 3. Singh RN, Sosa JA, Green GE: Long-term fate of the internal mammary and saphenous vein grafts. J Thorac Cardiovasc Surg 86: 359-363, 1983 4. Okies JE, Page S, Bigelow JC, et al: The left internal mammary artery: The graft of choice. Circulation 70:213-221, 1984 5. Jett GK, Arcidi JM, Lynne M, et al: Vasoactive drug effects on blood flow in internal mammary artery and saphenous vein grafts. J Thorac Cardiovasc Surg 94:2-11, 1987 6. Sarabu MR, McClung JA, Fass A, Reed GE: Early postoperative spasm in the left internal mammary artery bypass grafts. Ann Thorac Surg 44:195-200, 1987 7. Brogden RN, Markham A: Fenoldopam: A review of its pharmacodynamic and pharmacokinetic properties and intravenous clinical potential in the management of hypertensive urgencies and emergencies. Drugs 54:634-650, 1997
8. Ozono R, O’Connell DP, Wang ZQ, et al: Localisation of the dopamine D1 receptor protein in the human heart and kidney. Hypertension 30:725-729, 1997 9. Amenta F: Light microscope autoradiography of peripheral dopamine receptor subtypes. Clin Exp Hypertens 19:27-41, 1997 10. Goldberg LI: Dopamine receptors and hypertension: Physiologic and pharmacological implications. Am J Med 77:37-44, 1984 11. Hughes AD, Sever PS: Action of fenoldopam, a selective (DA1) receptor agonist, on isolated human arteries. Blood Vessels 26:119127, 1989 12. Shi Y, Zalewski A, Bravette B, et al: Selective dopamine-1 receptor agonist augments regional myocardial blood flow: Comparison of fenoldopam and dopamine. Am Heart J 124:418-423, 1992 13. Canver CC, Cooler SD, Murray AL, et al: Clinical importance of measuring coronary graft flows in the revascularised heart: Ultrasonic or electromagnetic? J Cardiovasc Surg 38:211-215, 1997 14. Reeves JG, Karp RB, Buttner EE, et al: Neuronal and adrenomedullary catecholamine release in response to cardiopulmonary bypass in man. Circulation 66:49-55, 1982
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15. Teoh KH, Fremes SE, Weisel RD, et al: Cardiac release of prostacyclin and thromboxane A2 during coronary revascularization. J Cardiovasc Surg 93:120-126, 1987 16. Izzat MB, West RR, Ragoonanan C, Angelini GD: Effect of systemic vasodilators on internal mammary artery flow. J Thorac Cardiovasc Surg 108:82-85, 1994 17. Cracowski JL, Chavanon O, Durand M, et al: Effect of low-dose positive inootropic drugs on human internal mammary artery flow. Ann Thorac Surg 64:1742-1746, 1997 18. Goldberg LI, Kohli JD, Glock D: Conclusive evidence for two subtypes of peripheral dopamine receptors, in Woodruff GN, Poat JA, Roberts PJ (eds): Dopaminergic Systems and Their Regulation. London, Macmillan, 1986, pp 195-212 19. Mathur VS, Swan SK, Lambrecht LJ, et al: The effects of fenoldopam, a selective dopamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects. Crit Care Med 27:1832-1837, 1999 20. Murphy MB, McCoy CE, Weber RR, et al: Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine1 agonist fenoldopam. Circulation 76:1312-1318, 1987
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21. Girbes ARJ, Smit AJ, Meijer S, Reitsma WD: Renal and endocrine effects of fenoldopam and metoclopramide in normal man. Nephron 56:179-185, 1990 22. Kopia GA, Valocik RE: Demonstration of a specific-1 receptormediated coronary vasodilation in the anesthetised dog. J Pharmacol Exp Ther 248:215-221, 1989 23. Zhao RR, Fennell WH, Abel FL: Effects of dopamine D1- and dopamine D2-receptor agonists on coronary and peripheral hemodynamics. Eur J Pharmacol 190:193-202, 1990 24. Zhao RR, Wang PH, Zhang WF, Fennell WH: Analysis of the effects of dopamine-1 and dopamine-2 receptor agonists on coronary flow. Methods Find Exp Clin Pharmacol 14:5-11, 1992 25. Wang WZ, Zhao RR, Qin FZ: Comparison of the effects of dopamine1- and dopamine2-receptor agonists on the cAMP generating system in canine coronary and renal arteries. Methods Find Exp Clin Pharmacol 16:691-696, 1994 26. Lang WJ, Woodman OL: Comparison of the vasodilator action of dopamine and dopamine agonists in the renal and coronary beds of the dog. Br J Pharmacol 77:23-28, 1982
Heart rate, blood pressure, and central venous pressure were documented at these time points. Administration of fenoldopam, 0.1 g/kg/min, did not alter heart rate or blood pressure. A small, nonsignificant increase in LIMA blood flow occurred during the 15-minute study period (30 ⴞ 12 to 35 ⴞ 10 mL/min) in patients who received fenoldopam. No significant changes occurred in the placebo group. Conclusions: The findings indicate that fenoldopam, 0.1 g/kg/min, did not influence coronary conduit blood flow to a clinically significant extent. The small increase in LIMA blood flow may be of greater importance in high-risk patients or in the prevention of coronary arterial spasm. Copyright © 2001 by W.B. Saunders Company
S
hypothesis, a prospective, randomized, double-blind, placebocontrolled trial was performed to assess the effect of fenoldopam on coronary conduit blood flow after anastomosis to the distal coronary circulation.
APHENOUS VEINS and internal mammary arteries are used as conduits in patients undergoing coronary revascularization.1 In terms of long-term patency, the internal mammary artery is superior to the saphenous vein graft.2-4 The internal mammary artery is a dynamic coronary graft, whereas the saphenous vein graft is passive. Potential exists for pharmacologically induced vasodilation or vasoconstriction of the artery.5 It is likely that a selective coronary artery vasodilator would increase total myocardial oxygen delivery after coronary artery bypass graft (CABG) surgery, a time of risk for ischemia-related adverse events. Perioperative internal mammary artery spasm is associated with morbidity and mortality, and its prevention is a reasonable clinical objective in the postoperative period.6 Fenoldopam is a highly selective agonist at peripheral dopamine (DA1) receptors.7 The presence of DA1 receptors in human coronary and mammary arteries, and in saphenous vein smooth muscle, has been shown using immunocytochemical techniques.8,9 Agonist activity at DA1 receptors results in smooth muscle relaxation and vasodilation.10 The precise role and functional significance of these receptors in the coronary circulation have not been defined, however. In vitro studies have shown that fenoldopam relaxes precontracted human coronary arteries.11 In a dog model, fenoldopam increased myocardial blood flow in normal and ischemic border myocardium.12 It was hypothesised that fenoldopam, 0.1 g/kg/min, may increase the coronary conduit blood flow after CABG surgery through its agonist activity at DA1 receptors. To test this
From the Departments of Anesthesia, Intensive Care Medicine, and Surgery, Cork University Hospital, Wilton, Cork, Ireland. Supported in part by Neurex/Elan Pharmaceutical. Address reprint requests to Michele Halpenny, MRCPI, FFARCSI, 3 Waltham, Clonfadda Wood, Mount Merrion Avenue, Blackrock, Co. Dublin, Ireland. Copyright © 2001 by W.B. Saunders Company 1053-0770/01/1501-0015$35.00/0 doi:10.1053/jcan.2001.20374 72
KEY WORDS: coronary artery bypass, dopamine receptors, fenoldopam, internal mammary artery, saphenous vein
METHODS The protocol was approved by the ethics committee of the Cork Teaching Hospitals and by the Irish Medicines Board. Written informed consent was obtained from study patients. Criteria for inclusion in the study were (1) age ⬍ 70 years old, (2) elective CABG surgery, (3) left ventricular ejection fraction ⬎ 40%, (4) planned grafting of the left internal mammary artery (LIMA) to the left anterior descending artery, (5) planned nonsequential grafting using a saphenous vein to a right-sided coronary artery, (6) absence of myocardial infarction within the previous 6 months, and (7) hemodynamic stability on separation from cardiopulmonary bypass (CPB) without the use of a vasoactive agent. The patients received lorazepam, 0.02 to 0.03 mg/kg orally, as a premedicant together with their concurrent medication (Table 1) 2 hours preoperatively. General anesthesia was induced with fentanyl, 15 to 20 g/kg, and propofol, 0.5 to 1 mg/kg, and maintained with isoflurane 0.5% to 1% end-tidal concentration and a propofol infusion (2 to 3 mg/kg/h). No volatile anesthetic agent was administered from the start of CPB until completion of the operation. Muscle relaxation was achieved using pancuronium, 0.1 mg/kg. Monitors included electrocardiography (leads II and V5 with automated ST analysis, DATEX AS3) and arterial and central venous pressures. Positive-pressure ventilation was adjusted to maintain end-tidal carbon dioxide in the normal range (35 to 40 mmHg). The LIMA was dissected free of overlying connective tissue to facilitate accurate placement of the probe. Patients weaned from CPB without vasodilator or inotropic support were assigned to the fenoldopam or placebo groups (according to a random allocation). On confirmation of adequacy of the reversal of heparin effects with protamine, an infusion of fenoldopam, 0.1 g/kg/min, or placebo (normal saline) was administered through a central infusion port by a blinded investigator. The 50-mL syringes were prepared and coded by the hospital pharmacy. Immediately before and at 5-minute intervals for 15 minutes after starting the infusion, blood flow was measured in the LIMA and one saphenous vein graft using a transit time ultrasonic flow probe (Linton Instrumentation, Norfolk UK). The flow waveform pattern was recorded continuously and analyzed (Fig 1). To ensure that there was no
Journal of Cardiothoracic and Vascular Anesthesia, Vol 15, No 1 (February), 2001: pp 72-76
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Table 1. Medication Taken by Participating Patients Preoperatively
Nitrates -Adrenoceptor antagonists Calcium antagonists Converting enzyme inhibitors
Placebo (n ⫽ 15)
Fenoldopam (n ⫽ 16)
11 12 4 3
13 10 5 2
reactive hyperemia caused by the placement of the probe on the vessel, stabilization of 30 seconds was allowed before the start of the measurement. At each time point, the value recorded was the mean blood flow measured over 30 seconds. As each flow measurement was obtained, heart rate, mean arterial blood pressure, and central venous pressure were recorded. The number of patients in each group is based on the following: One-tailed Student’s t-test; ␣ ⫽ 0.05;  ⫽ 0.2 Effect size: 36.0 mL/min 䡠 20% ⫽ 7.2 mL/min Standardized effect size ⫽ 7.2/4.1 ⫽ 1.7 Minimum sample size ⫽ 12/group Demographic data, hemodynamic data, and baseline (preinfusion) blood flows were analyzed using unpaired Student’s t-tests. Coronary conduit blood flow was analyzed by repeated measures analysis of variance using group as the between-subjects factor and time as the within-subject factor and Dunnett’s test where appropriate; p ⬍ 0.05 was considered statistically significant. RESULTS
Of 33 patients recruited in this study, 2 required inotropic support on separation from CPB and were excluded from the study. The 2 groups were similar in terms of age, body weight, height, body surface area, sex, left ventricular ejection fraction, and number of grafts performed (Table 2). The duration of anesthesia, surgery, CPB, aortic cross-clamp time, fluid administration, and intraoperative blood loss were similar in the 2 groups (Table 3). Before starting the study infusion, heart rate, mean arterial pressure, and central venous pressure were sim-
Fig 1. Flow waveform recording of left internal mammary artery (LIMA) and saphenous vein (SV) blood flow as measured by the transit time ultrasonic flow probe.
Table 2. Demographic Data
Age (yr) Height (cm) Weight (kg) BSA (m2) Sex (female/male) Left ventricular ejection fraction (%) No. vessel grafts
Placebo (n ⫽ 15)
Fenoldopam (n ⫽ 16)
61 (8) 170 (9) 77 (16) 1.86 (0.2) 4/11
60 (9) 172 (10) 75 (11) 1.89 (0.2) 4/12
40 3.4 (0.8)
40 3.5 (0.5)
NOTE. Data are mean (SD). Abbreviation: BSA, body surface area.
ilar in the 2 groups (Figs 2, 3, and 4). Administration of fenoldopam did not alter heart rate, mean arterial pressure, or central venous pressure (Figs 2, 3, and 4). The coronary perfusion pressure was similar in both groups at each of the 4 time points in the study (Fig 5). During the study period, electrocardiogram signs of myocardial ischemia (defined as 1 mm ST depression at 60 msec after the J point if down-sloping or horizontal and ⬎2 mm if up-sloping) were not observed. In¯ ⫾ ternal mammary artery (32 ⫾ 13 and 30 ⫾ 12 mL/min) (X SD) coronary conduit blood flow in the placebo and fenoldopam groups was similar at baseline. Neither the internal mammary artery nor the saphenous vein graft flow changed in the placebo group during the study period (Figs 6). A minor increase in LIMA blood flow (which did not reach statistical significance) was observed during the 15-minute study period (30 ⫾ 12 to 35 ⫾ 10 mL/min) (Fig 7) in the patients who received fenoldopam. DISCUSSION
The most important finding of this study is that fenoldopam (0.1 g/kg/min) administered by continuous intravenous infusion after separation from CPB did not produce a clinically
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HALPENNY ET AL
Table 3. Study Parameters Placebo (n ⫽ 15)
Duration of anesthesia (min) Duration of surgery (min) Duration of extracorporeal circulation (min) Duration of aortic crossclamping (min) Crystalloids (mL) Colloid (mL) Blood/components (U) Blood loss (mL)
Fenoldopam (n ⫽ 16)
335 (42) 258 (44)
345 (50) 274 (48)
101 (24)
103 (15)
73 (21) 2893 (633) 2688 (443) 3 (4) 2342 (886)
75 (13) 2903 (496) 2828 (582) 2 (3) 2523 (1070)
NOTE. Data are mean (SD).
Fig 2. Heart rate (beats/min [bpm]) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam (n ⴝ 16).
Fig 3. Mean arterial blood pressure (mmHg) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam (n ⴝ 16).
significant increase in either LIMA or saphenous vein coronary conduit blood flow. Although administration of fenoldopam in this low dose was not associated with adverse hemodynamic effects, it is unlikely that the modest trend toward increased flow through the LIMA graft during the 15-minute study period confers a real clinical benefit. The magnitudes of measured blood flow in this study in the placebo group for LIMA (32 ⫾ 13 mL/min) and for saphenous vein graft (33 ⫾ 13 mL/min) were similar to the corresponding ultrasonically measured values (34 ⫾ 2.5 and 33 ⫾ 2.4 mL/ min) reported by Canver et al.13 The interpatient variation in flow was considerably greater than in Canver’s study, however, decreasing the likelihood of identifying a fenoldopam-related change in flow. Nonpatient factors that may account for this variation include use of a probe of inappropriate size or failure to obtain adequate contact between the probe and the vessel wall. Other factors that may have decreased the likelihood of identifying an effect of fenoldopam on conduit blood flow, if
Fig 4. Central venous pressure (cm H2O) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam.
one truly exists, include (1) the administration of a single and relatively low dose; (2) a short (15-minute) study period; (3) measurement of blood flow shortly after the start of a fenoldopam infusion (5, 10, and 15 minutes), rather than the likely achievement of steady-state concentration (approximately 3.2 g/mL) from the start of a fenoldopam infusion at 0.1 g/kg/ min in 20 minutes (ie, 4 ⫻ elimination half-life ⫽ 5 minutes)7; and (4) administration of fenoldopam at a time (immediately after separation from CPB) when systemic concentrations of endogenous catecholamines and thromboxane A2 (potent coronary vasoconstrictors) are markedly elevated.14,15 Measurement of blood flow in the anastomosed LIMA and saphenous vein conduit after separation from CPB reflects the clinical setting more accurately than does measurement of free flow (before distal anastomosis) as previously reported.16,17 This point is particularly important in assessing a systemically administered drug, which mediates its effects on graft flow primarily on the coronary resistance arterioles rather than on the conduit itself. Goldberg et al18 classified the peripheral dopamine receptors into 2 groups, the DA1 and DA2 subtypes, on the basis of synaptic localization. DA1 receptors are located postsynaptically on smooth muscle cells in the peripheral vasculature as well as in the renal, mesenteric, and coronary vasculature; in the proximal tubule; and in the cortical collecting ducts of nephrons.8,18 DA1 receptors activate adenylate cyclase, causing smooth muscle relaxation, systemic vasodilation, and increased regional blood flow. In renal tubules, DA1 receptors cause sodium and water excretion.19 Fenoldopam mesylate, a benzazepine derivative of the endogenous catecholamine transmitter dopamine, is a highly selective DA1-receptor agonist.7 Fenoldopam has no DA2, ␣-adrenergic, or -adrenergic agonist activity.7 Fenoldopam has been used
Fig 5. Coronary perfusion pressure (mmHg) in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. }, placebo (n ⴝ 15); ■, fenoldopam (n ⴝ 16).
FENOLDOPAM AND CORONARY CONDUIT BLOOD FLOW
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Fig 6. Coronary blood flow (mL/min) in the left internal mammary artery in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. ■, placebo (n ⴝ 15); 䊐, fenoldopam (n ⴝ 16).
safely in clinical practice as an antihypertensive agent since 1981. In the present study, the highest dose possible of fenoldopam (0.1 g/kg/min) that had in previous studies been shown not to induce an antihypertensive effect was chosen. No significant changes in heart rate and blood pressure resulted from administration of fenoldopam, 0.1 g/kg/min, in this study. This finding is consistent with the findings of Murphy et al,20 who examined the effects of intravenous infusion of fenoldopam (using an increasing dose regimen) to patients with uncomplicated essential hypertension. In only 1 of the 17 patients studied did fenoldopam, 0.1 g/kg/min, decrease diastolic blood pressure by ⬎10 mmHg.20 In that study, heart rate increased in proportion to the decrease in systemic blood pressure. During infusion of fenoldopam, 0.1 g/kg/min, to healthy volunteers, no change in diastolic blood pressure was observed.21 In vitro and in vivo studies have shown the existence of DA1 receptors in coronary vasculature.8-10 Kopia and Valocik22 showed in a dog model that direct, dopamine-mediated coronary vasodilation occurs by stimulation of a vascular receptor of the DA1 subtype, inducing a pronounced increase in coronary blood flow. However, Zhao et al23,24 indicated that primary dopaminergic coronary vasodilation was unlikely to be of functional significance. Wang et al25 compared the adenylate
Fig 7. Saphenous vein blood flow (mL/min) in the left internal mammary artery in placebo and fenoldopam groups before infusions and at 5, 10, and 15 minutes after starting infusions. ■, placebo (n ⴝ 15); 䊐, fenoldopam (n ⴝ 16).
cyclase–stimulating effects of fenoldopam in coronary and renal arteries in an attempt to assess the functional significance of coronary DA1 receptors. Fenoldopam increased cyclic adenosine monophosphate production in coronary and renal arteries. The magnitude of the increase was much greater in renal arteries than in coronary arteries, however. This situation was attributed to a greater number of DA1 receptor sites in the renal vessels.25 It was reported in a dog model that fenoldopam significantly increased renal blood flow but had no dilating activity in the coronary vasculature at the same dose.26 The results of the present study are consistent with those of Wang et al25 and Lang and Woodman.26 It appears that if a clinical role does exist for DA1-receptor agonists in improving postCABG coronary conduit blood flow, patient and dose selection and timing of administration would be crucial in maximizing the benefit of a modest pharmacologic effect. In conclusion, these findings indicate that fenoldopam (administered in the manner and dose described) did not influence coronary conduit blood flow to a clinically significant extent. The modest trend toward increased LIMA coronary conduit blood flow may indicate that further studies are warranted to determine the effects of this drug administered at a higher dose and for a greater duration.
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