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J Thorac Cardiovasc Surg 2004;127:1018-1025
© 2004 The American Association for Thoracic Surgery
Cardiopulmonary support and physiology |
a Department of Surgery, Division of Cardiothoracic Surgery, University of California, Los Angeles School of Medicine, Los Angeles, Calif, USA
Read at the Eighty-third Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 4-7, 2003.
Received for publication May 2, 2003; revisions received August 27, 2003; accepted for publication September 8, 2003.
* Address for reprints: Gerald D. Buckberg, MD, Division of Cardiothoracic Surgery, 62-258 Center for the Health Sciences, Los Angeles, CA 90095-1701, USA
gbuckberg{at}mednet.ucla.edu
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Abstract |
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METHODS: Twenty Yorkshire-Duroc pigs (31.8 ± 3.9 kg) underwent 15 minutes of mid-left anterior descending coronary artery ischemia in the beating heart. In 8 pigs, no protective measures were used. In 12 pigs, an aorta-coronary sinus shunt (with conventional cannulas) allowed retrograde perfusion during temporary ischemia; in 6 of these pigs, no leakage to the right atrium was ensured. Regional endocardial contraction was measured with sonomicrometer crystals. Systolic dysfunction (impaired regional shortening), diastolic dysfunction (contraction extending into early diastole), and coronary sinus nitric oxide and endothelin-1 levels were recorded.
RESULTS: Before ischemia, contraction did not extend into the diastolic interval. During ischemia, paradoxic bulging occurred in all hearts except in the occlusive coronary sinus shunt group (16% ± 6% of baseline, P < .01). Sixty minutes after ischemia, systolic segment shortening recovered 36% ± 24% without retrograde perfusion versus 56% ± 20% and 61% ± 14% with coronary sinus shunting (P < .05). Diastolic dysfunction (as percentage of diastolic time in contraction) was 38% ± 16% in the nontreated group versus 22% ± 22% and 9% ± 9% (P < .05) after shunting and occlusive shunting, respectively. This correlated with a left ventricular end-diastolic pressure increase of 4 mm Hg in the ischemic group versus no change in the retrograde perfusion groups. Nitric oxide decreased 15% without shunting and increased 8% after occlusive coronary sinus shunting (P < .05).
CONCLUSIONS: Retrograde coronary sinus perfusion during simulated off-pump coronary revascularization diminishes systolic and diastolic dysfunction. An aortic-coronary sinus shunt is a rapid, recognized approach that can improve myocardial muscle and endothelial safety during off-pump coronary artery bypass grafting.
Another alternative is retrograde coronary perfusion, because coronary sinus (CS) cannulation is routinely used in on-pump coronary artery bypass grafting (CABG), and early promising clinical results have been reported in high-risk patients.4
This study tested whether continuous retrograde coronary perfusion during a simulated 15-minute time frame (to match the interval for a distal graft by simple connection of antegrade and retrograde CS cannulas) could prevent resultant systolic and diastolic dysfunction.
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Material and methods |
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Twenty-two Yorkshire-Duroc pigs (31.8 ± 3.9 kg) of either sex were premedicated (ketamine 15 mg/kg, diazepam 0.5 mg/kg intramuscularly) and anesthetized (pentobarbital 30 mg/kg intravenously and subsequent bolus injections of sodium pentobarbital). Support with a volume-controlled ventilator (Servo 900C, Siemens-Elema, Solna, Sweden) was started after tracheostomy and endotracheal intubation. The femoral artery and vein were cannulated, and arterial blood gases were measured to keep oxygen tension, carbon dioxide tension, and pH values within the normal range. A balloon-tipped catheter (Model 132F5, Baxter Healthcare Corp, Irvine, Calif) was advanced into the pulmonary artery through a jugular vein to measure pulmonary artery and wedge pressures, and cardiac output was measured by the thermodilution technique.
The pericardium was incised after a median sternotomy, and a solid-state pressure transducer-tipped catheter (Model MPC-500, Millar Instruments, Inc, Houston, Tex) was inserted through the apex to monitor left ventricular pressure (LVP). A segment of the left anterior descending (LAD) coronary artery, distal of the first major diagonal branch, was circumferentially dissected. A 3-0 Prolene suture in between 2 Teflon pledgets was placed surrounding the LAD, leaving the LAD coronary vein free. A cardioplegia cannula was inserted into the ascending aorta, and a retrograde cardioplegia cannula was introduced transatrially into the CS. In the treated groups, both cannulas were connected by a
-inch polyvinyl chloride tube through Luer connections. The line was clamped until the start of myocardial ischemia (Figure 1).
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Hemodynamic measurements
LVP was electronically differentiated to obtain dP/dt, the first derivative of LVP. The cardiac cycle was defined automatically using dP/dt. Systole began 40 milliseconds before peak positive dP/dt and ended 20 milliseconds before peak negative dP/dt, as previously defined by other groups.5,6
Two 2-mm ultrasonic microtransducer crystals (Sonometrics, London, Ontario, Canada) were placed in the endocardial side of the anterior free wall of the left ventricle supplied by the LAD artery. Adequacy of LAD crystal placement was checked with 40-second LAD occlusion during the equilibration period. A control measurement consisted of crystals in the muscle supplied by the left circumflex coronary artery. Data were recorded digitally with acquisition hardware and software (Sonometrics). Systolic shortening was defined as the change in segment length between the start and end of systole. Diastole was defined as the time that LVP decreased below aortic diastolic pressure or the origin of the isovolumetric interval. The percentage of systolic shortening was calculated as the ratio in percent between systolic shortening and end-diastolic length. Contraction during the first part of diastole was analyzed by the percentage of time of diastole in which contraction is in effect.
Cardiac output was determined by 4 central venous injections of 3 mL of 4°C saline solution. Left ventricular stroke work index (LVSWI) was calculated by the following formula: LVSWI = (mean arterial pressure – left auricular pressure) x cardiac output x 0.0136 x heart rate–1 x weight–1.
CS blood analysis
Myocardial injury was determined by analyzing CS blood samples taken 5 minutes before and 30 and 60 minutes after the onset of myocardial ischemia.
As a marker of oxidant-mediated lipid peroxidation, conjugated diene (CD) levels were determined spectrophotometrically in CS plasma after chloroform-methanol 2:1 (vol/vol) extraction as previously described.7 CD concentration was expressed as absorbance (A) at a wavelength of 240 nm per 0.5 mL plasma.
Myocardial damage was determined by measuring plasmatic creatine kinase fraction MB (units/liter) by an ultraviolet-spectrophotometric method (Sigma Chemical Co, St Louis, Mo), as recommended by the German Society for Clinical Chemistry.
Nitric oxide (NO) (micromoles/liter) was determined as its spontaneous oxidation products, nitrite and nitrate, which were converted to NO and quantitated by a chemiluminescence assay using a nitrogen oxides analyzer (DASIBI Environmental Corp, Model 2108, Glendale, Calif).
Endothelin (ET)-1 levels (picograms/milliliter) were determined after sample purification (Ethyl C2 Amprep minicolumns, Amersham Pharmacia Biotech, Piscataway, NJ) by an enzyme immunometric assay (ACETM EIA kit, Cayman Chemical Company, Ann Arbor, Mich) based on a double-antibody "sandwich" technique.
Myocardial biopsy
At the end of the experiment, the pigs were killed by bolus injections of pentobarbital 250 mg followed 1 minute later by 15 mL of cold hyperkalemic blood (KCl, 30 mEq/L). With the LAD and the ascending aorta crossclamped, 60 mL of methicillin blue were injected through the aortic root into the coronary arteries to stain the non-ischemic myocardium. The ischemic myocardium was calculated as the percentage of dry weight between ischemic and non-ischemic myocardium.
Statistical analysis
Statistical analysis of data within and between groups was performed with multiple analysis of variance followed by the Student t test with Tukey-Kramer correction for multiplicity. Data are expressed as mean ± SD.
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Results |
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TopAbstractMaterial and methodsResultsDiscussionConclusionDiscussionReferences |
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Fifteen minutes of mid-LAD occlusion produced an ischemic zone of 27% ± 4% and 3% ± 2% of left and right ventricles, respectively, without differences among groups. In unprotected ischemia, bulging of the anterior wall occurred within seconds after LAD clamping, and each pig had at least 1 episode of ventricular fibrillation successfully treated by 10 J defibrillation. A 5-mg lidocaine bolus injection was only used to prevent further fibrillation. However, 7 of the 8 pigs had ventricular fibrillation during reperfusion, despite the lidocaine supplement. Mean arterial and left atrial pressures remained constant during the procedure, but cardiac output decreased by 17% ± 20% at 30 minutes and by 34% ± 27% at 60 minutes, causing LVSWI to decrease to 67% ± 26% and 58% ± 18% of baseline in the postischemia period (Table 1). Left ventricle end-diastolic pressure (LVEDP) increased from 8 ± 3 mm Hg to 12 ± 7 mm Hg during ischemia and remained high after 1 hour of reperfusion (12 ± 5 mm Hg at 60 minutes).
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Bulging during ischemia persisted with the self-inflated retrograde cannula, whereas some active contraction was retained at the percentage of systolic shortening (16% ± 6% of baseline, P < .01) (Figure 2) when the manually inflated balloon was used. Ventricular fibrillation occurred in the CS-shunt groups in 5 of 6 hearts in each group, with no difference compared with the ischemic group, although 3 and 4 hearts in the non-occlusive and occlusive shunt groups, respectively, fibrillated only at reperfusion. Table 1 shows the hemodynamic variables, documenting a comparable approximate 20% decrease in cardiac output in both shunted groups but a slightly (but not statistically different) better maintenance of LVSWI (26% vs 18%) in the manually inflated retrograde shunt group. This retrograde perfusion allowed a lower LVEDP than in the groups with unprotected ischemia (6 ± 2 mm Hg in the non-occlusive shunt group and 8 ± 1 mm Hg in the occlusive shunt group vs 12 ± 7 mm Hg in the unprotected ischemia group at 60 minutes, P = .06)
Retrograde perfusion during ischemia improved recovery of the percentage of systolic shortening after reperfusion (Figure 2) to a relatively comparable level (
50%) 15 minutes after reflow in both the self-inflated and manually inflated CS cannula. This contrasts with less than 20% systolic shortening without retrograde perfusion. This improvement was sustained, recovering to approximately 60% systolic shortening at 1 hour in both shunted groups.
Although systolic contraction was detected during the first part of diastole in the CS shunt groups (Figure 2), the percentage of diastolic time was reduced to 22% ± 22% with the non-occlusive CS shunt at 60 minutes and to 9% ± 9% with the occlusive retrograde shunt. These levels of diastolic dysfunction were less (P < .05) than in untreated hearts at 60 minutes after reperfusion.
CS creatine kinase-MB was 59% ± 33% greater than baseline in the untreated group compared with 56% ± 51% in the non-occlusive CS shunt group and 37% ± 7% in the occlusive CS shunt group (no statistical significance was found).
CD levels were similar (34% ± 16%, 32% ± 15%) in the untreated and non-occlusive shunt groups, respectively, after 60 minutes of reperfusion but decreased (24% ± 3%) when the occlusive CS shunt was used (P < .05).
NO levels in CS plasma decreased to 13% ± 15% below baseline values without retrograde shunting after 30 minutes of reperfusion (Figure 4), whereas NO levels were maintained in the non-occlusive CS shunt group and increased to 9% ± 8% at 30 minutes after reperfusion (P < .05).
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Discussion |
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TopAbstractMaterial and methodsResultsDiscussionConclusionDiscussionReferences |
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An alternate method is retrograde CS perfusion, which is currently a frequently used technique of delivering cardioplegic solutions during CABG. This study defines the benefit of this technique in limiting systolic and diastolic dysfunction after temporary coronary occlusion. This protective method is most effective for the left ventricle because of impaired right ventricular perfusion.10 Retrograde flow may be even more useful in beating heart surgery without bypass, because myocardial oxygen demands are high and cardioplegic protection is not possible.
The strategy for ensuring CS flow is important in the beating heart, because adequate perfusion pressure is needed to ensure nourishment during cardiac work. For example, a self-inflating retrograde cannula has an irregular wall allowing some leakage back into the right atrium, which can lessen CS pressure and possibly impair perfusion. For that reason, we tested both the self-inflating balloon (permitting some backflow into the right atrium) and manually inflating balloon (limiting backflow). We found a higher CS pressure (79 vs 42 mm Hg) and less diastolic dysfunction with the occlusive balloon. Retroperfusion during ischemia has been shown to be beneficial in previous reports.11-13 The importance of sustaining perfusion pressure in salvaging ischemic tissue is evident in experimental studies of retrograde venous perfusion during pressure-controlled intermittent coronary occlusion.11 The background for this method comes from clinical retroperfusion for circulatory support during failed percutaneous transluminal coronary angioplasty procedures as a rapid way to restore flow before emergency extracorporeal circulation and CABG.12 These reports led others to test this method successfully in patients undergoing OPCAB,13 and our study quantifies this benefit.
Fifteen minutes of regional no-flow ischemia is the classic method of inducing systolic stunning, as defined by Braunwald and Kloner.14 This is usually the time interval in which coronary artery flow is compromised during OPCAB. Simultaneously, such stunning leads to prolongation of systole into the diastolic interval,15 thus impairing relaxation and rendering the heart more turgid to limit suction and increasing end-diastolic pressure as the result of stiffening from this mechanism. Our studies codify such severe systolic and diastolic dysfunction in this swine model. Systolic dysfunction was evidenced by the persistent regional impaired contractility 60 minutes after reperfusion (Figures 5 and 6 ). Additionally, contraction extended into early diastole, thereby confirming that impaired postsystolic shortening is a marker of early myocardial stunning.16
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Continuous retrograde perfusion during LAD occlusion significantly improved excitation-contraction mismatch and reduced systolic and diastolic dysfunction. We recognize that retrograde perfusion was not sufficient because ischemic-induced ventricular fibrillation occurred in shunted studies and contractile function did not return to normal after 60 minutes of reperfusion. Nevertheless, postischemic systolic shortening was significantly higher in retrograde perfused hearts than in control hearts. Moreover, the occlusive coronary shunt prevented bulging during ischemia and, more important, nearly obliterated diastolic dysfunction in comparison with the untreated and non-occlusive shunt groups. We suspect that the improved diastolic function, with prevention of extended contraction, caused the avoidance of increased LVEDP during reperfusion, a numeric reading that may be a marker of improved suction and greater compliance.
We suspect that endothelial protection may have been afforded by retrograde perfusion during ischemia, because release of NO was significantly higher in the retrograde perfusion group versus the untreated group. Further studies are needed to verify these hypotheses.
Critique of the experimental model
Our experimental design studied ischemia in juvenile pig hearts without coronary artery disease, so generalization of our data must be performed cautiously. Our model differs from those including patients with extensive coronary artery disease, in whom collateral flow develops and limits the extent of ischemia after sudden LAD occlusion. Nevertheless, our method of retrograde perfusion may parallel patients with moderate single-vessel stenosis and limited collateral flow.
Retraction of the heart (as is performed in OPCAB) may impair CS catheter flow, mainly when it is performed by compression of the myocardial wall. We did not use retraction techniques in our study.
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Conclusion |
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Discussion |
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TopAbstractMaterial and methodsResultsDiscussionConclusionDiscussionReferences |
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The Emory group has done a lot with perfusion-assisted distal assist, and I was wondering if you could apply your idea to putting in a catheter and applying distal perfusion through a partial shunt?
Dr Castella. We provided a simultaneous flow rate for antegrade and retrograde perfusion in the past and did not see edema in those studies. Edema formation was not evaluated in the current experiments, but it is not expected with simultaneous perfusion, since coronary venous drainage is via the thebesian veins that empty into the ventricles.
We would be interested in seeing if our retrograde perfusion studies, done during ischemia, can amend the antegrade studies at Emory, which are done after the region is grafted.
Dr Nilas Young (Sacramento, Calif). It is the rare patient presenting for OPCAB with a single-vessel disease. Much more commonly, patients have multivessel disease and are at higher risk for major coronary artery occlusion during the case. Have you taken this model another step further to have a multidisease or preinfarction model, or do you plan on doing that?
Dr Castella. You are correct, but the results would be magnified with multivessel disease, since the systolic and diastolic dysfunction would be avoided in several areas. This refers to all other regions than segments perfused by the right coronary artery, where retrograde perfusion is limited, due to problems in distribution.
Dr Jakob Vinten-Johansen (Atlanta, Ga). Can you achieve the same goal by just occluding the CS and then perfusing ostensibly with deoxygenated blood (CS blood), or do you need the arterial component of that? Because essentially you're admixing both venous coronary effluent and arterial blood.
Dr Castella. We cannot answer your question directly, but the preservation of systolic and diastolic function relates to oxygenated perfusion, since the coronary sinus PO2 is very low. Evidence of the oxygenated supply was shown when the artery was opened, as our previous use of internal thoracic artery anastomosis during regional ischemia showed bright red retrograde return coming from the distal vessel.
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This article has been cited by other articles:
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  H. S. Bedi Clinical efficacy of retrograde coronary sinus perfusion in off-pump surgery J. Thorac. Cardiovasc. Surg., February 1, 2005; 129(2): 476 - 477. [Full Text] [PDF]
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