Eur J Cardiothorac Surg 2006;30:324-328
© 2006 Elsevier Science NL
Effects of milrinone on blood flow of the Y-graft composed with the radial and the internal thoracic artery in patients with coronary artery disease
Sungwon Naa,
Young Jun Oha,b,
Yon Hee Shima,b,
Yong Woo Honga,b,c,
Seo Ouk Banga,b,
Young Lan Kwaka,b,c,*
a Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Ku, Seoul 120-725, South Korea
b Anesthesia and Pain Research Institute, South Korea
c Yonsei Cardiovascular Research Institute, South Korea
Received 15 February 2006;
received in revised form 5 April 2006;
accepted 20 April 2006.
* Corresponding author. Address: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Ku, Seoul 120-725, South Korea. Tel.: +82 2 2228 8513; fax: +82 2 364 2951. (Email: ylkwak{at}yumc.yonsei.ac.kr).
 |
Abstract
|
|---|
Objective: Milrinone has been known to dilate the internal thoracic artery (ITA) and the radial artery (RA). The effect of milrinone, however, on each graft is unclear when the left ITA (LITA) and the RA form a Y-graft. This study evaluated the changes in blood flow of a composite Y-graft in response to milrinone. Methods: Thirty-two patients undergoing an isolated coronary artery bypass graft surgery were included in this study. A Y-graft was created with an in situ LITA and free RA graft attached to the proximal side of the LITA. Graft flow was measured by opening the graft end for 30 s, and is expressed in ‘ml/min’. Graft flow and hemodynamic data were recorded before and 10 min after intravenous milrinone (50 µg/kg) administration. Results: Milrinone significantly increased the RA graft flow, measured while the LITA graft end was clamped, and total Y-graft flow. Respective graft flows were not increased by milrinone when both clamps were released simultaneously, in spite of a significant decrease in the resistance of both grafts. The ratio of flows through the RA and the LITA grafts was not changed by milrinone. Conclusion: Milrinone significantly reduced RA and LITA resistances and increased the total Y-graft flow. Milrinone might dilate each individual arterial graft to a different degree. Milrinone did not, however, change the flow ratio through the RA to LITA grafts when they were measured simultaneously. Therefore, it would not significantly divert graft flow to one side in a composite Y-graft.
Key Words: Milrinone • Y-graft • Radial artery • Internal thoracic artery • Graft blood flow
|
1. Introduction
|
|---|
As an arterial graft has a long-term patency superior to that of the saphenous vein [1,2], total arterial revascularization in coronary artery bypass graft surgery has been increased. The growing use of the left internal thoracic artery (LITA) in a Y configuration with the radial artery (RA) allows maximal arterial graft economy, sufficient graft length, and has been employed with excellent clinical results [3]. One caveat is that the RA possesses a pronounced medial layer and is known to be highly vasoreactive [4,5]. The internal thoracic artery (ITA), on the other hand, possesses a thin medial layer with few smooth muscle cells and has little vasoreactivity [6]. Various procedures, such as no touch technique [7], topical or systemic vasodilator injection [8,9], and maintaining graft intraluminal pressure have been attempted to prevent vasospasm.
Milrinone, a phosphodiesterase inhibitor, is an inotropic agent with vasodilatory activity [10]. A few studies have demonstrated that milrinone can have a vasorelaxant effect on RA [4], ITA [11,12], and the coronary vasculature itself [13]. Those studies, however, evaluated the effect of milrinone on independent arterial grafts and not on a composite Y-graft. In a Y-graft composed of the LITA and the RA, that have different anatomical characteristics, both grafts compete for the proximal LITA flow and milrinone could affect both grafts differently. Thus, we evaluated the effect of milrinone on the LITA and RA graft flows individually and as a Y-graft.
|
2. Materials and methods
|
|---|
This study was approved by the Institutional Review Board and all participants provided written informed consent. Thirty-two patients undergoing elective coronary artery bypass graft surgery participated in this study. The surgery was performed with an arterial composite Y-graft, in which a free RA graft was attached to the proximal portion of the LITA. All Y-grafts were created by the same surgeon to minimize any bias associated with surgical skill. Patients with peripheral vascular disease, chronic renal or hepatic disease, coagulopathy, a platelet count less than 100,000 µl–1, hemoglobin less than 12 g/dl, significant dysrrhythmia or a left ventricular ejection fraction less than 40% were excluded from the study. Patients who were on inotropic agent were excluded, too.
All regular cardiovascular medications, except diuretics and digitalis, were continued up until the morning of surgery. Patients were premedicated with intramuscular morphine (0.05–0.1 mg/kg). Five electrocardiogram leads were placed, and leads II and V5 were continuously monitored. Arterial pressure was monitored by a RA catheter placed in the dominant hand. A pulmonary artery catheter (Swan-Ganz CCOmbo-CCO/SvO2
®, Edwards Lifesciences LLC, Irvine, CA, USA) was inserted in the right internal jugular vein to monitor several cardiac performance parameters continuously, including: central venous pressure (CVP), pulmonary artery pressure (PAP), cardiac output (CO) and right ventricular volumetric parameters. Anesthesia was induced with intravenous injection of 1.5–2.5 mg of midazolam, 1.5–3.0 µg/kg of sufentanil, and 50 mg of rocuronium. Anesthesia was maintained with intravenous infusion of sufentanil (0.5–1.5 µg/(kg h)) and inhalation of 0.4–0.6% isoflurane, 60% oxygen and air. Cardiac performance was also monitored by transesophageal echocardiography after anesthesia induction.
All patients were explored through median sternotomy. The LITA was harvested with a pedicle using diathermy and hemoclips to control the side branches. The RA was harvested without skeletonization. To minimize vasospasm, papaverine was injected into the adventitia of the internal thoracic artery graft and the harvested radial artery was also treated with diluted papaverin and heparin. Mechanical dilation was not applied. After the RA harvest and LITA dissection, heparin (150 U/kg) was injected intravenously. The RA was anastomosed to the proximal part of LITA after confirming that the activated clotting time was over 300 s.
The Y-graft was constructed, and respective graft free flow rates were measured directly with no resistance. Blood was collected for 30 s and the graft flow was calculated from the collected volume and expressed in ‘ml/min’. The RA flow (RA-fl1) and LITA flow (LITA-fl1) were measured while the opposite graft was clamped. Next graft flows were measured simultaneously but separately by releasing both vascular clamps (RA-fl2 and LITA-fl2). The total Y-graft flow was the sum of RA-fl2 and LITA-fl2. The order in which flow rates were measured was determined by a computer-generated random number table.
During this process, the anesthesiologist collected hemodynamic data, including: cardiac index (CI), heart rate (HR), mean arterial pressure (MAP), mean PAP (MPAP), CVP, and pulmonary capillary wedge pressure (PCWP). Rate-pressure product (RPP, HR x systolic blood pressure), resistance of each graft blood flow (MAP/graft flow), systemic vascular resistance (SVRI), and pulmonary vascular resistance (PVRI) were calculated from known data (pre-milrinone).
Milrinone (50 µg/kg, Primacor® Sanofi-Synthelabo Korea, Seoul, Korea) was then administered intravenously for 10 min. The graft flow measurements (RA-fl1, LITA-fl1, RA-fl2, LITA-fl2) and hemodynamic variables were repeated as described above 10 min after milrinone injection (post-milrinone). Graft resistances were calculated as follows: RA-resist1 = MAP/RA-fl1, LITA-resist1 = MAP/LITA-fl1, RA-resist2 = MAP/RA-fl2, LITA-resist2 = MAP/LITA-fl2, total resistance = MAP/total Y-graft flow. Blood for flow measurements was collected by Cell Saver (Cell Saver® 5 System, Haemonetics, Braintree, MA, USA) and retransfused after surgery. To minimize the effect anesthetics and hemodynamics might have on the data, anesthetic settings (the concentration of inhaled anesthetics and the infusion rate of intravenous anesthetics) and fluid administration rate were not changed and no vasoactive drug was used during the data collection process.
Statistical analysis was performed with SPSS 11.5 (SPSS Inc., LS, USA). All data are presented as mean ± standard deviation or number of patients (%). Continuous data were compared by a paired t-test. Wilcoxon signed rank test was used when the results did not show normal distribution. The normality of continuous data was analyzed by Kolmogorov–Smirnov test. p
< 0.05 was considered statistically significant.
|
3. Results
|
|---|
The demographic data, preoperative medication, comorbid diseases, and coronary angiographic findings are presented in Table 1
.
Milrinone increased HR, CI, and RPP but did not change MAP, MPAP, or PVRI. Milrinone administration resulted in a statistically significant decrease in CVP and SVRI (Table 2
).
The RA graft flow with the LITA graft clamped (RA-fl1) and total Y-graft flow were significantly increased after milrinone administration. The LITA graft flow with the RA graft clamped (LITA-fl1), however, was not significantly changed with milrinone. Furthermore, milrinone did not significantly increase the simultaneously measured LITA and RA graft flows (LITA-fl2 and RA-fl2). RA-fl1 was significantly greater than LITA-fl1 both before and after milrinone administration. The graft flow divided by cardiac output (proportion of graft flow in cardiac output) only significantly increased for RA-fl1 after milrinone administration. The ratio of RA-fl2 to LITA-fl2 and the individual graft flows divided by total Y-graft flow were not significantly changed by milrinone (Table 3
).
All resistances (RA-resist1, LITA-resist1, RA-resist2, LITA-resist2, and total resistance) decreased significantly after milrinone administration though the RA-resist2 to LITA-resist2 ratio did not change (Table 4
).
The Kolmogorov–Smirnov normality test found all continuous data, except RA-resist2 and RA-resist2/LITA-resist2 before milrinone administration to be normal. Upon applying the Wilcoxon signed rank test, RA-resist2 was found to significantly decreased after milrinone administration as compared to before milrinone administration (p
= 0.012).
|
4. Discussion
|
|---|
In a composite Y-graft, created with the RA and the LITA, milrinone increased the free blood flow of the RA graft with the LITA graft clamped and total Y-graft flow. Milrinone, however, did not significantly change the RA and LITA flows, with respect to one another, and the RA to LITA flow ratio when both arterial graft flows were measured simultaneously. From these results, milrinone would not divert graft flow to one side of a Y-graft.
Coronary blood flow is closely matched to myocardial oxygen demand [14]. There is a report that Y-graft blood flow was also significantly increased in response to increased myocardial oxygen demand (MvO2), in which MvO2 was represented as RPP [15]. As blood pressure affects both graft flow and MvO2 simultaneously, it may be inappropriate to assume that RPP is the only factor affecting Y-graft flow. There is a possibility that not only myocardial metabolism but also the vascular tone of the grafts regulate the Y-graft flow because the Y-graft is subject to a different neurohumoral milieu from native coronary vasculature. It is not well established what effect hemodynamics have on flow through a composite arterial Y-graft.
The RA is a limb artery and it is more spastic than other types of arteries [16]. After RA was reintroduced using as a conduit for coronary revascularization [17], it has been reported to have a long-term patency superior to that of the saphenous vein [2]. The RA is very susceptible to vasospasm, however, due to its pronounced medial layer [4,5]. Therefore, vasodilator administration, especially calcium channel blockers, has been used to prevent vasospasm [18]. In contrast, ITA, a somatic artery, is less vasoreactive than the RA due to its thin medial layer with few smooth muscle cells [16]. The ITA dilates in response to milrinone and does not constrict in response to norepinephrine [19].
We hypothesized that milrinone, an inodilator, would increase Y-graft flow by reducing grafts vascular tone and/or increasing CO but its effect on them might be different due to anatomical differences and competition for proximal LITA blood flow between the two grafts. Although, studies have demonstrated that milrinone has a vasodilatory effect on the RA [4] and ITA [11,12], it was unclear how this drug would affect the Y-graft in vivo. In contrast to previous studies, that reported that milrinone dilated the ITA more than the RA [20–22], we observed a more prominent vasodilatory effect in the RA graft in this study. This discrepancy may result from different experimental conditions. Most previous studies have investigated milrinone's effect on precontracted arteries in vitro or on graft flow after a cardiopulmonary bypass, which raise vascular tone. We, on the other hand, investigated a Y-graft flow without vasoconstrictor pretreatment. The baseline condition of an arterial graft affected the graft's response to drug treatment [21].
In this study, the free RA flow (RA-fl1) was greater than the free LITA flow (LITA-fl1) both before and after milrinone administration. This may be due to a greater RA diameter than that of the ITA [23]. Furthermore, milrinone increased the RA-fl1, although it failed to increase the LITA-fl1. The increase of RA flow/CO ratio after milrinone administration indicated that the increase in RA graft flow did not just result from increased CO. From these results, there is a concern that milrinone may divert blood flow from the proximal LITA to the RA graft, rather than the LITA graft, in a Y-graft. This could be a serious issue because the LITA is usually anastomosed to the coronary artery that perfuses the most critical myocardial region. As a composite Y-graft was reported to provide a 2.3-fold flow reserve to the coronary vascular bed through the grafts [24], there is a possibility that milrinone can divert more proximal LITA flow to the RA side than the LITA side of a composite Y-graft with concomitant increase in MvO2. Both RA and LITA grafts flows and flow ratio of RA to the LITA, however, were not significantly changed by milrinone when blood flowed through both grafts simultaneously. Thus, milrinone is not likely to cause graft flow diversion from the LITA to the RA in clinical situation. It is important to consider that milrinone can cause hypotension occasionally and the LITA graft flow is dependent on the perfusion pressure, although systemic blood pressure was not changed with milrinone in this study. Hypotension and use of a vasopressor could affect respective graft flow but it was not evaluated in this study. In a Y-graft, the proximal portion of the LITA might be the flow-limiting segment of the RA graft [24], and likely causes no significant increase in RA-fl2 and LITA-fl2, despite a significant increase in total Y-graft flow after milrinone administration. Each graft flow is expected to be statistically significant with greater sample size.
There are some limitations to this study. First, this study investigated the effect of milrinone on the free RA and the LITA without the effect of MvO2. Milrinone would, therefore, differently affect bypassed RA and LITA grafts flows, which are regulated by MvO2, than what we observed. Nevertheless, design of this study is thought to be closer to a clinical situation than other previous studies on composite Y-graft flow using LITA and RA. Second, application of the vascular clamps to measure graft flow, could damage the grafts. It could affect later measurements and attenuate milrinone's vasodilatory effect. These vessel manipulations did no harm to the patients since the distal portion of both grafts were excised before graft anastomosis.
In conclusion, milrinone increased total Y-graft flow with a non-significant increase in flows through both grafts. Although milrinone increased the RA graft flow but not LITA graft flow in a composite Y-graft when the other graft was clamped, it resulted in identical changes to the RA and LITA graft flows when blood flowed through both grafts. And it is not likely to significantly divert Y-graft flow toward the RA graft in clinical situation.
|
Footnotes
|
|---|
This article was presented in part at the 50th Annual Meeting of the Korean Society of Anesthesiologists in Cheju, Korea, November 17–19, 2005.
|
References
|
|---|
- Cooper GJ, Underwood MJ, Deverall PB. Arterial and venous conduits for coronary artery bypass. A current review. Eur J Cardiothorac Surg 1996;10:129-140.[Abstract]
- Zacharias A, Habib RH, Schwann TA, Riordan CJ, Durham SJ, Shah A. Improved survival with radial artery versus vein conduits in coronary bypass surgery with left internal thoracic artery to left anterior descending artery grafting. Circulation 2004;109:1489-1496.[Abstract/Free Full Text]
- Royse AG, Royse CF, Raman JS. Exclusive Y graft operation for multivessel coronary revascularization. Ann Thorac Surg 1999;68:1612-1618.[Abstract/Free Full Text]
- He GW, Yang CQ. Vasorelaxant effect of phosphodiesterase inhibitor milrinone in the human radial artery used as coronary bypass graft. J Thorac Cardiovasc Surg 2000;119:1039-1045.[Abstract/Free Full Text]
- Chardigny C, Jebara VA, Acar C, Descombes JJ, Verbeuren TJ, Carpentier A, Fabiani JN. Vasoreactivity of the radial artery: comparison with the internal mammary and gastroepiploic arteries with implications for coronary artery surgery. Circulation 1993;88:II115-II127.
- van Son JA, Smedts F. Histology of arterial conduits as a predictor of their long-term patency as coronary bypass conduits. Eur J Cardiothorac Surg 1993;7:277-278.[CrossRef][Medline]
- Galvin IF. Mammary artery grafts: a new no-touch technique for anastomosis. Ann Thorac Surg 1991;51:500-503.[Abstract]
- He GW, Buxton BF, Rosenfeldt FL, Angus JA, Tatoulis J. Pharmacologic dilitation of the internal mammary artery during coronary bypass grafting. J Thorac Cardiovasc Surg 1994;107:1440-1444.[Abstract/Free Full Text]
- Cooper GJ, Wilkinson GA, Angelini G. Overcoming perioperative spasm of the internal mammary artery: which is the best vasodilator?. J Thorac Cardiovasc Surg 1992;104:465-468.[Abstract]
- Alousi AA, Stankus GP, Stuart JC, Walton LH. Characterization of the cardiotonic effects of milrinone, a new and potent cardiac bipyridine, on isolated tissues from several animal species. J Cardiovasc Pharmacol 1983;5:804-811.[Medline]
- Salmenpera MT, Levy JH. The in vitro effects of phosphodiesterase inhibitors on the human internal mammary artery. Anesth Analg 1996;82:954-957.[Abstract]
- Liu JJ, Doolan LA, Xie B, Chen JR, Buxton BF. Direct vasodilator effect of milrinone, an inotropic drug, on arterial coronary bypass grafts. J Thorac Cardiovasc Surg 1997;113:108-113.[Abstract/Free Full Text]
- Monrad ES, Baim DS, Smith HS, Lanoue A, Brauwald E, Grossman W. Effects of milrinone on coronary hemodynamics and myocardial energetics in patients with congestive heart failure. Circulation 1985;71:972-979.[Abstract/Free Full Text]
- Sethna DH, Moffitt EA. An appreciation of the coronary circulation. Anesth Analg 1986;65:294-305.[Free Full Text]
- Lemma M, Mangini A, Gelpi G, Innorta A, Spina A, Antona C. Analysis of Y-graft blood flow and flow reserve in conditions of increased myocardial oxygen consumption. Ital Heart J 2004;5:290-294.[Medline]
- He GW. Arterial grafts for coronary artery bypass grafting: biological characteristics, functional classification, and clinical choice. Ann Thorac Surg 1999;67:277-284.[Abstract/Free Full Text]
- Acar C, Jebara VA, Portoghese M, Beyssen B, Pagny JY, Grare P, Chachques JC, Fabiani JN, Deloche A, Guermonprez JL. Revival of the radial artery for coronary artery bypass grafting. Ann Thorac Surg 1992;54:652-659.[Abstract]
- He GW, Yang CQ. Comparative study on calcium channel antagonists in the human radial artery: clinical implications. J Thorac Cardiovasc Surg 2000;119:94-100.[Abstract/Free Full Text]
- Gitter R, Anderson Jr. JM, Jett GK. Influence of milrinone and norepinephrine on blood flow in canine internal mammary artery grafts. Ann Thorac Surg 1996;61:1367-1371.[Abstract/Free Full Text]
- Zabeeda D, Medalion B, Jackobshvilli S, Ezra S, Schachner A, Cohen AJ. Comparison of systemic vasodilators: effects on flow in internal mammary and radial arteries. Ann Thorac Surg 2001;71:138-141.[Abstract/Free Full Text]
- Wei W, Yang CQ, Furnary A, He GW. Greater vasopressin-induced vasoconstriction and inferior effects of nitrovasodilators and milrinone in the radial artery than in the internal thoracic artery. J Thorac Cardiovasc Surg 2005;129:33-40.[Abstract/Free Full Text]
- Onomoto M, Tsuneyoshi I, Yonetani A, Suehiro S, Matsumoto K, Sakata R, Kanmura Y. Differential pharmacologic sensitivities of phosphodiesterase-3 inhibitors among human isolated gastroepiploic, internal mammary, and radial arteries. Anesth Analg 2005;101:950-956.[Abstract/Free Full Text]
- Chamiot-Clerc P, Copie X, Renaud JF, Safar M, Girerd X. Comparative reactivity and mechanical properties of human isolated internal mammary and radial arteries. Cardiovasc Res 1998;37:811-819.[Abstract/Free Full Text]
- Royse AG, Royse CF, Groves KL, Yu G. Blood flow in composite arterial grafts and effect of native coronary flow. Ann Thorac Surg 1999;68:1619-1622.[Abstract/Free Full Text]
Top
Abstract
1. Introduction
