Intraoperative perfusion contrast echocardiography

J

THORAC CARDIOVASC SURG 1990;99:536-42

Intraoperative perfusion contrast echocardiography Initial experience during coronary artery bypass grafting Intraoperath'e evaluation of the effectiveness of myocardial revascularization bas been limited by an inability to assess regional myocardial perfusion. Microbubbles of sonicated diatrizoate sodium and diatrizoate meglumine (Renografin) have been an effective echocardiograpbic contrast agent and have been employed clinically during cardiac catheterization. This recent development in contrast-enhanced two-dimemional echocardiography permits real-time imaging of trammural myocardial blood flow but bas not been evaluated in the operating room. This study represents the initial surgical application of this directed technique and was designed to evaluate the safety and efficacy of intraoperative perfusion contrast echocardiography in assessing the results of coronary artery bypass grafting. Twenty men with significant coronary artery disease ranging in age from 49 to 73 years were studied. Direct contrast agent injection into completed saphenous vein bypass grafts caused the myocardium supplied by each graft to be weD delineated and provided a tomograpbic view of contrast distribution. The enhanced region was weD correlated with the size and distribution of the native vessel. Rapid contrast washout «20 seconds) indicated satisfactory regional perfusion. Contrast echocardiography prolonged the operation less than 10 minutes and did not result in any perioperative complications.

J. Scott Kabas, MD, Joseph Kisslo, MD, Conrad L. Flick, MD, Scott H. Johnson, MD, Damian M. Craig, BS, Thomas E. Stanley, MD, and Peter K. Smith, MD, Durham. NiC.

IdeallY, intraoperative evaluation of coronary artery bypass grafting would be performed by methods that assure the following: I. Graft and anastomotic sites are unobstructed. 2. Appropriate anastomotic sites are selected (distal to significant stenoses in significant arteries). 3. Adequate transmural reperfusion is established.

Although methods such as probing anastomoses, stripping grafts, measuring graft blood flow, and even highfrequency echocardiographic imaging of anastomotic

From the Duke University Medical Center, Department of Surgery, Durham, N.C. Supported by National Heart, Lung, and Blood Institute Grants K04HL02051 and ROI-HL4J087, North Carolina Affiliate of the American Heart Association Grant 1988-89-A-04, and by a grant from the Warren W. Hobbie Charitable Trust of Roanoke, Virginia. Presented in part at the American College of Surgeons 74th Clinical Congress, Surgical Forum, Chicago, 1988. Received for publication March 13, 1989. Accepted for publication May 22, 1989.

Addr~ for reprints: Peter K. Smith, MD, Box 3442, Duke University Medical Center, Durham, NC 27710.

12/1/15642

536

sites have evolved, there is no practical, safe method to evaluate regional myocardial perfusion provided by bypass grafts. The emergence of intraoperative two-dimensional echocardiography and the employment of evolving intravascular contrast techniques (injected microbubbles) have made ultrasound imaging an attractive new method for assessing the magnitude and geometry of regional perfusion during surgical revascularization. Such information, obtained in real-time, could be used to improve intraoperative decision making. Goldman and Mindich I first observed the spontaneous contrast effect of cardioplegic solution infusion during coronary artery bypass grafting and used this information to estimate hypoperfused areas of myocardium to direct the sequence of bypass grafting. These observations, probably resulting from microbubbles created by microcavitation in administered cardioplegic solution, have resulted in attempts to make smaller bubbles to more efficiently transit the microcirculation. One such approach is the intentional production of smaller microbubbles «10 J,Lm diameter) through the sonication of diatrizoate sodium and diatrizoate meglumine (Renografin 76). This imparts high frequency ultrasonic energy to a liquid medium and creates microbubbles that have flow characteristics similar to red

Volume 99 Number 3 March 1990

blood cells. 2-4 Intracoronary microbubble injection produces a rapid increase in myocardial echogenicity followed by a gradual return to baseline intensity as contrast is washed from the myocardium. Other investigators have correlated contrast intensity and transit times with myocardial blood flow in animal preparations."!" In the laboratory setting contrast echocardiography has been employed to estimate coronary flow reserve and to define areas of underperfused or infarcted myocardium." 11-18 The intracoronary injection of sonicated Renografin has been performed in humans during cardiac catheterization and after coronary angioplasty.lv-" This study was performed to test the hypotheses that echocardiographic perfusion imaging could be rapidly and safely performed intraoperatively and that such images would reveal preliminary information regarding the transmural distribution of new blood flow provided by revascularization.

Material and methods After Institutional Review Board approval and individual patient consent had been obtained, 20 men whose ages ranged from 49 to 73 years from the Asheville Veterans Administration and Duke University Medical Centers were entered into the study protocol. All patients had substantial coronary artery disease documented by recent cardiac catheterization. Patient conditions necessary for study enrollment included stable hemodynamics, normal renal and neurologic function, and the absence of an allergic reaction to Renografin or other iodinated products. All patients underwent coronary artery bypass grafting with reversedsaphenous vein and internal mammary artery. Only saphenous vein grafts were studied. The contrast agent was prepared by the method of Keller and associates" with commercially available sterile Renografin 76. Sonication for 30 seconds created highly reflective,gaseous microbubbles with an average diameter of 4.5 lIm. A considerable amount of training and practice was undertaken to reproducibly create microbubbles of consistent concentration and size distribution (confirmed by light microscopy). This is necessary, as it is not practical to evaluate the contrast agent before its use because of its short ( 100 seconds) half-life. A gas-sterilized Branson sonifier (Heat Systems, Branson Ultrasonics Corp., Danbury, Conn.) was mounted under aseptic conditions in the operating room. The probe of the sonication unit was positioned in an inverted syringe containing Renografin (8 mI). A small amount of air was introduced into the Renografin as the sonication probe was activated. Immediately after removing the syringe from the probe, sonicated Renografin was employed for contrast enhancement. Contrast injections were performed during the cardiopulmonary bypass period, while venous drainage was adjusted to minimize left ventricular ejection so that proximally ascending aortic flow was predominantly retrograde. Injection sites included the ascending aorta before and after bypass grafting, directly into each saphenous vein bypass graft after completion of proximal and distal anastomoses, and into the side arm of the cardioplegicsolution delivery system. After graft completion injections were performed during the late rewarming period to minimize interference with the conduct of the operation.

Intraoperative perfusion contrast echocardiography 5 3 7

Epicardial two-dimensional echocardiography with a handheld 3.5 or 5.0 MHz probe was performed just before and for 100 seconds after each contrast injection with an Aloka 880 scanner (Aloka Incorporated, Tokyo, Japan) (Asheville Veterans Administration Medical Center) or a Hewlett-Packard 7720 CF scanner (Hewlett-Packard Company, Palo Alto, Calif.) (Duke University Medical Center). Short-axis images of the left ventricle at the middle papillary muscle level were visually interpreted in real-time and stored on a Panasonic AG-6300 VHS recorder for later analysis. Optimum gain settings were established at the beginning of each study and were maintained constant throughout. Imaging planes were kept consistent by utilizing both echocardiographic and external anatomic landmarks. Detailed analysis of the echocardiographic images was performed retrospectively from videotape. Contrast washout times were determined from the visually defined onset of myocardial enhancement to the return of intensity to baseline. The quality of contrast enhancement was determined on a subjective scale of 0 to 4 by averaging the observations of three independent examiners. Enhancement was considered optimum when brightness in any myocardial region equaled that of the pericardium (normally the brightest target seen), and no acoustic attenuation was caused by the contrast agent. 0, No enhancement I, Minimum enhancement 2, Mild enhancement 3, Optimum enhancement 4, Excessive enhancement (acoustic attenuation apparent) Selected image sequences were displayed on a Sony PVM high resolution monitor and converted to digital form with a PC Vision Plus video image digitizer. Myocardial intensity enhancement was determined on suitable images with a Compaq 386 Deskpro microcomputer and software developed in our laboratory. J22

Results The echocardiographic effect of sonicated Renografin injected into a saphenous vein graft is demonstrated in Fig. I. A return to baseline image intensity occurred within 20 seconds in all cases. The region of contrast enhancement from this injection is displayed in Fig. 2. The area of revascularized myocardium, defined by contrast enhancement, correlated well with the size and distribution of the native coronary artery selected for bypass grafting. Contrast injections (l to 3 ml) made in the ascending aorta (before and after aortic crossclamping) resulted in inadequate echocardiographic contrast enhancement. Similarly, cardioplegic solution infusion (with standard methods employing a roller pump) resulted in inconsistent, minimum echocardiographic enhancement. For analysis the patients were divided into two groups (Table I). Group I, the initial seven patients, received I ml of contrast material through a 2a-gauge needle for all saphenous vein graft injections. In these patients the development of a safe (low contrast dose, small needle) technique that also provided image enhancement was the

The Journal of Thoracic and Cardiovascular

5 3 8 Kabas et al.

Surgery

Fig. I. Sequential diastolic images (approximately 5-second intervals) depicting contrast injection into a circumflex marginal graft (patient 14). The imaging plane is the left ventricular short-axis at the middle papillary level.The. ventricular septum is on the left, posterior left ventricle at the bottom. A, Control image obtained before contrast in- . jection. 8, Peak contrast enhancement of posterolateral left ventricle (arrow). C and D, Regional myocardial intensity gradually returns to baseline as contrast is washed out by graft and native coronary blood flow.

goal. Suboptimum echocardiographic results, the absence of study-related complications, and in vitro testing that revealed substantial microbubble disruption caused by the small diameter and relatively high resistance of a 20gauge needle dictated modifications in techniques. These changes consisted of an increase to 3 ml of contrast medium injected per graft and the use of an 18-gauge needle for all injections in group 2, the last 13 patients. A total of 49 saphenous vein grafts were performed in the 20 patients studied, 20 in group 1 and 29 in group 2. Repetitive injections to optimize the contrast effect were not employed. Echocardiographic study time averaged 5.33 ± 2.4 minutes with a range of 3.33 to 9.17 minutes in the seven patients of group 1. For group 2 the average time was 4.33 ± 1.16 minutes with a range of 2.7 to 6.3 minutes. In group 1, 1 ml of contrast medium administered through a 20-gauge needle produced myocardial en-

hancement in only three of the 20 grafts, although all grafts were determined to be functional (flow >30 ml/rnin) with electromagnetic flow probes. For the 20 grafts studied in group 1 the overall quality of injection was 0.2 ± 0.5 on our subjective scale. In the three injections that augmented myocardial intensity, average contrast washout time was 13.0 ± 1.7 seconds. In group 2, 3 ml of contrast medium administered through an I8-gauge needle produced myocardial enhancement in each of the 29 grafts studied, with an overall quality of 2.7 ± 0.6. The average washout time in group 2 was 14.3 ± 2.7 seconds.

Case report The following case study illustrates the results of direct saphenous vein graft injection. A 58-year-old man (patient 15) had substernal chest pain, and the 12-lead electrocardiogram indicated diaphragmatic myocardial infarction. Intravenous

Volume 99 Number 3 March 1990

Intraoperative perfusion contrast echocardiography 539

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Fig. 2. Computed image analysis of peak contrast effect (patient 14). Data points (0) represent average transmural pixel intensity over radial chords depicted in schematic short-axis image after subtraction of control pixel intensity. Geometry of enhancement is defined as more than 2 standard deviations increase in intensity [X], X2). The proportion of short-axis enhancement (X, - X,/IOO) is 0.24 in this case.

Table I. Descriptors of individualpatients studied Bypass grafts Patient

Group 1 1 2 3 4 5 6 7 Group 2 8 9 10 11 12 13 14 15 16 17 18 19 20

IMA

SVG

Creatinine (mgjdl) preop.fpostop.

POSlOp. day of discharge

EFO.44 EF 0.28 EF 0.55 EFO.40 EF 0.82 EFO.60 EF 0.67

1 1 1 1 0 0 1

3 3 3 5 3 1 2

1.7/1.5 1.2/1.2 1.0/1.2 1.4/1.4 1.1/1.0 1.1/1.1 1.2/1.3

11 9 14 9 9 10 15

2 YO, EF 0.52 3 YO, EF 0.58 3 YO, EF 0.52 2 YO, EF 0.43 3 YO, EF 0.42 3 YO, EF 0.43 2 YO, EF 0.50 2 YO, EF 0.32 2 YO, EF 0.51 2 YO, EF 0.52 I YO, EF 0.68 3 YO, EF 0.45 2 YO, EF 0.58

1 1 I I 1 1 0 0

2 2 3 2 3 2 2 3 2 I 2 3 2

1.0/0.9 1.4/1.3 1.1/ 1.4 1.1/0.9 1.0/1.0 2.1/1.9 1.0/1.0 1.0/0.9 0.9/0.9 1.1/ 1.2 1.0/1.2 1.1/1.2 1.4/2.0

12 11 10 9 7 8 6 7 7 7 7 7 9

Cardiac catheterization

3 YO, 3 YO, 3 YO, 3 YO, 2 YO, I YO, 2 YO,

I I 0 1 0

IMA. Internal mammary artery; SVG. saphenous vein graft; YD. vessels diseased; EF. ejection fraction.

5 4 0 Kabas et al.

The Journal of Thoracic and Cardiovascular Surgery

Fig. 3. Fogarty thrombectomy of right coronary artery. A largeamountof distal right coronary artery thrombus was extracted with a 2F Fogarty balloon catheter. streptokinase (I million units)wasadministered. Cardiaccatheterization revealed significant two-vessel disease that included a 95% proximal right coronary artery stenosis and a 75% left anteriordescending lesion. The ejection fraction was 32%. The patientthenunderwent coronary arterybypass grafting of these vessels forpostinfarction angina. At operation thrombosis ofthe right coronary artery (with distal extension) was discovered (Fig.3).The thrombus wasextracted with a 2F Fogarty balloon catheter,and a saphenous vein wasanastomosed to the arteriotomy site. Contrast injection (Fig. 4) demonstrated excellent enhancement of a largearea of posterior leftventricle and ventricular septum, indicating successful reperfusion of all distal coronary branches. Inotropic support was unnecessary in the perioperative period for this group of patients. Neither acute ischemic change nor heart block was noted on electrocardiogram, and no renal dysfunction could be attributed to the contrast agent. There were no infectious, hemorrhagic, or clinically apparent neurologic complications.

Fig. 4. Contrast agent was injected into the proximal end of thecompleted saphenous vein bypass graft.A,Short-axis image of the left ventricle is shown before injection. The ventricular septum isseen on the left,posterior leftventricle at the bottom. B,Marked enhancement of the Posterior leftventricle andventricular septum (arrows) indicates successful thrombectomy with reperfusion of all distal coronary branches.

Discussion

This work represents the initial surgical experience with directed intraoperative perfusion contrast echocardiography in evaluating the results of myocardial revascularization. The major finding of this study is that perfusion contrast echocardiography provides an immediate qualitative assessment of individual saphenous vein bypass graft function and can be used to demonstrate graft patency and the geometry of graft perfusion. The study minimally prolonged operation and resulted in no perioperative complications, thereby documenting the safety of

intraarterial contrast injections in the dosage employed. Accordingly, the requirement for investigational consent has been waived by our institutional review board. A reliable qualitative assessment of global short-axis myocardial perfusion through contrast injection into the ascending aorta, either before or after coronary grafting, was not realized in this study. This is partly the result of a self-imposed limit of 4 ml of Renografin per injection and partly due to dispersion of the agent into the systemic circulation.

Volume 99 Number 3 March 1990

In addition, we have demonstrated that a large bore (at least 18-gauge) catheter must be employed to prevent microbubble disruption and further diminution in microbubble concentration. This finding may preclude the direct use of this agent to study mammary artery graft function; none was studied in this series. Although an excellent qualitative assessment of myocardial revascularization was accomplished in this study, quantitation of myocardial perfusion, the ultimate goal of contrast echocardiography, was not possible.The primary limiting factors are nonlinearity of the video imaging system and the nonideal characteristics of contrast agents now available for human use. These problems may be overcome with advances in equipment and by the recent development of air-encapsulated albumin microspheres for contrast enhancement. Albumin microspheres are appropriately small, uniform in size, stable, and require no processing before injection. With albumin microspheres in animals, Keller and associates 10 closely correlated washout times with myocardial perfusion as determined with radioactive microspheres. Additional features of contrast echocardiography make this method potentially appealing for use during surgical revascularization. This imaging modality, unlike most, is capable of providing transmural data in real-time.F The contrast agent is transient, permitting an essentially unlimited number of sequential observations. Because echocardiography can also be used to assess regional wall motion, the correlation of regional myocardial function and perfusion may be possible. The availability of albumin microspheres, which are shelf-ready, combined with increasing use of intraoperative echocardiography (including the use of transesophageal ultrasound probes) will make this technique more practical. In conclusion, our initial experience with contrast echocardiography suggests that its intraoperative use is safe and that it can provide an immediate qualitative assessment of bypass grafting results. Graft patency and graft blood flow distribution can be evaluated. The availability of perfusion contrast agents provides another reason to employ intraoperative echocardiography and may result in or parallel its becoming an integral facet of cardiac surgery. REFERENCES I. Goldman ME, Mindich BP. Intraoperative cardioplegic contrast echocardiography for assessing myocardial perfusion during open heart surgery. J Am Coli Cardiol 1984; 4:1029-34. 2. Feinstein SB, Shah PM, Bing RJ, et al. Microbubble dynamics visualized in the intact capillary circulation. J Am Coli Cardiol 1984;4:595-600.

Intraoperative perfusion contrast echocardiography 5 4 1

3. Ten Cate FJ, Feinstein S, Zwehl W, et al. Two-dimensional contrast echocardiography. II. Transpulmonary studies. J Am Coli CardioI1984;3:21-7. • 4. Feinstein SB, Ong K, Staniloff HM, et al. Myocardial contrast echocardiography: examination of intracoronary injections, microbubble diameters, and video-intensity decay. Am J Physiol Imaging 1986;1:12-8. 5. Tei C, Kondo S, Meerbaum S, et al. Correlation of myocardial echo contrast disappearance rate ("washout") and severity of experimental coronary stenosis. J Am Coil Cardiol 1984;3:39-46. 6. Ong K, Maurer G, Feinstein S, Zwehl W, Meerbaum S, Corday E. Computer methods for myocardial contrast two-dimensional echocardiography. J Am ColI Cardiol 1984;3:1212-8. 7. Ten Cate FJ, Drury JK, Meerbaum S, et al. Myocardial contrast two-dimensional echocardiography: experimental examination at different coronary flow levels. J Am Coil Cardiol 1984;3:1219-26. 8. Maurer G, Ong K, Haendchen R, et al. Myocardial contrast two-dimensional echocardiography: comparison of contrast disappearance rates in normal and underperfused myocardium. Circulation 1984;69:418-29. 9. Nishimura RA, Rogers PJ, Holmes DR Jr, Gehrig DG, Bove AA. Assessment of myocardial perfusion by videodensitometry in the canine model. J Am ColI Cardiol 1987;9:891-9. 10. Keller MW, Spotnitz WD, Matthews TL, Glasheen WP, Watson DD, Kaul S. Quantitative intraoperative myocardial contrast echocardiography: implications for preventing perioperative infarction. Circulation 1988;78 (Pt 4):11567. II. Armstrong WF, Mueller TM, Kinney EL, Tickner EG, Dillon JC, Feigenbaum H. Assessment of myocardial perfusion abnormalities with contrast-enhanced two-dimensional echocardiography. Circulation 1982;66:166-73. 12. Kemper AJ, O'Boyle JE, Sharma S, et al. Hydrogen peroxide contrast-enhanced two-dimensional echocardiography: real-time in vivodelineation of regional myocardial perfusion. Circulation 1983;68:603-11. 13. Armstrong WF, West SR, Mueller TM, Dillon JC, Feigenbaum H. Assessment of location and size of myocardial infarction with contrast-enhanced echocardiography. J Am Coli Cardiol 1983;2:63-9. 14. Tei C, Sakamaki T, Shah PM, et al. Myocardial contrast echocardiography: a reproducible technique of myocardial opacification for identifying regional perfusion deficits. Circulation 1983;67:585-93. 15. Armstrong WF, West SR, Dillon JC, Feigenbaum H. Assessment of location and size of myocardial infarction with contrast-enhanced echocardiography. II. Application of digital imaging techniques. J Am Coli Cardiol 1984;4: 141-8. 16. Kaul S, Pandian NG, Okada RD, Pohost GM, Weyman AE. Contrast echocardiography in acute myocardial ischemia. I. In vivo determination of total left ventricular "area at risk." J Am Coli Cardiol 1984;4:1272-82.

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17. Taylor AL, Collins SM, Skorton DJ, Kieso RA, Melton J, Kerber RE. Artifactual regional gray level variability in contrast-enhanced two-dimensional echocardiographic images: effect on measurement of the coronary perfusion bed. J Am Coli Cardiol 1985;6:831-8. 18. Kaul S, Glasheen W, Ruddy TD, Pandian NG, Weyman AE, Okada RD. The importance of defining left ventricular area at risk in vivo during acute myocardial infarction: an experimental evaluation with myocardial contrast twodimensional echocardiography. Circulation 1987;75: 124960.

19. Lang RM, Feinstein SB, Feldman T, Neurmann A, Chua KG, Borow KM. Contrast echocardiography for evaluation

The Journal of Thoracic and Cardiovascular Surgery

of myocardial perfusion: effects of coronary angioplasty. J Am Coli Cardiol 1986;I :232-5. 20. Cheirif J, Zoghbi WA, Raizner AE, et al. Assessment of myocardial perfusion in humans by contrast echocardiography. I. Evaluation of regional coronary reserve by peak contrast intensity. J Am Coli Cardiol 1988;II :735-43. 21. Keller MW, Feinstein SB, Briller RA, Powsner SM. Automated production and analysis of echo contrast agents. J Ultrasound Med 1986;5:493-8. 22. Marcus ML, Wilson RF, White CWo Methods of measurement of myocardial blood flow in patients: a critical review. Circulation 1987;76:245-53.

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