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J Thorac Cardiovasc Surg 1998;115:226-230
© 1998 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

Optimal flow rates for integrated cardioplegia

From the Division of Cardiovascular Surgery and the Department ofClinical Biochemistry; The Toronto Hospital and the University of Toronto.Toronto, Ontario, Canada.

Presented in part at the Sixty-ninty Scientific Sessions of theAmerican Heart Association, New Orleans, La., Nov. 9–13, 1996

Received for publication Nov. 29, 1996; revisions requested March7, 1997; revisions received August 27, 1997; accepted for publication Sept.16, 1997 Address for reprints: Richard D. Weisel, MD, EN 14–215, TheToronto Hospital, Toronto, Ontario, Canada M5G 2C4.

Abstract

Background: Antegrade cardioplegicdelivery may be impaired by coronary occlusions, whereas retrograde deliveryof cardioplegic solution may be inhomogeneous, leading to an accumulationof lactate and hydrogen ions, the products of anaerobic metabolism. Integratedcardioplegia using continuous retrograde cardioplegia and antegrade infusionsinto completed vein grafts washes out metabolites accumulated in regions inadequatelyperfused by retrograde cardioplegia alone. To determine the flow rates requiredto achieve the greatest washout, we compared a high flow rate (200 ml/min) to a lowflow rate (100 ml/min).
Methods: Twenty patientsscheduled for isolated coronary bypass surgery were prospectively randomizedto compare two flow rates for integrated cardioplegic protection using tepid(29° C) blood cardioplegia. Arterial and coronary sinus blood sampleswere collected to evaluate myocardial metabolism. After antegrade arrest,cardioplegic solution was delivered by coronary sinus perfusion and simultaneousinfusions into each completed vein graft at either high or low flow.
Results: Increasing from low to high flow increased the washout of lactate and hydrogenions during the aortic crossclamp period. Two hours after crossclamp removal,ventricular function was better in the highflow group.
Conclusions: Tepid retrogradecardioplegia resulted in an accumulation of toxic metabolites. The additionof antegrade vein graft infusions at a flow rate of 100 ml/min resulted ina washout of these metabolites. A flow rate of 200 ml/min further improvedthis washout and resulted in improved ventricular function. An integratedapproach to myocardial protection using a flow rate of 200 ml/min may improvethe results of coronary bypass surgery.

Critical coronary stenoses may limit the delivery of antegrade cardioplegiato ischemic regions of the heart, particularly when revascularization withthe internal thoracic artery prevents vein graft infusions to the left anteriordescending coronary artery. Retrograde delivery of cardioplegic solution throughthe coronary sinus has been proposed to be a superior method of myocardialprotection ^1–3; however, capillary perfusion may be inadequate. ^4–7

Hypothermia (10° C) may provide additional protection but may preventthe resuscitation of the ischemic myocardium. ⁷ Warm (37° C) blood cardioplegia, delivered either antegradelyor retrogradely, permits earlier recovery of ventricular function, ⁸ but results in greater anaerobicmyocardial metabolism. Interruptions in the delivery of warm blood cardioplegiamay lead to normothermic myocardial ischemia. ⁹ We have recently shown that tepid (29° C) blood cardioplegia,given either antegradely or retrogradely, reduced anaerobic lactate and acidrelease during cardioplegic arrest and preserved ventricular function comparedwith either warm or cold cardioplegia. ¹⁰ However, tepid retrograde cardioplegia resulted in a significantaccumulation of lactate and hydrogen ions, the products of anaerobic metabolism.

An integrated approach to myocardial protection with both antegradeand retrograde delivery has been used to optimize cardioplegic perfusion. ^11–16 We found that alternating retrograde perfusion with intermittentantegrade infusions into the aortic root effectively washed out lactate andacid that accumulated during retrograde delivery. ¹⁴ Retrograde perfusion with simultaneous antegradeinfusions into each completed vein graft resulted in similar protection tothe alternating technique and was technically easier. ¹⁶

We found that increasing normothermic retrograde flow rates from 50to 200 ml/min decreased anaerobic lactate production. ¹⁷ Further increases in flow to 300 or 500 ml/min increasedthe shunt flow without decreasing lactate production. This study was designedto compare delivery of tepid retrograde cardioplegia with simultaneous antegradeinfusions into completed vein grafts at highflow (200 ml/min) versus low flow (100 ml/min).We hypothesized that tepid retrograde cardioplegia alone would result in lessaccumulation of potentially toxic lactate and hydrogen ions than warm retrogradecardioplegia. The addition of antegrade vein graft infusions may wash outany accumulated metabolites, and increasing the flow rate from 100 to 200ml/min may further improve cardioplegic delivery to the ischemic myocardium.

Material and methods

Patient population.
Twenty patients scheduled for isolated coronary artery bypass graftingby one surgeon agreed to participate in a study of alternative cardioplegictechniques. All patients signed a consent form approved by the Human ExperimentationCommittee. One patient in the low flow groupwas excluded intraoperatively because of an inability to insert a retrogradecoronary sinus cannula. The preoperative characteristics of the remaining19 patients are displayed in Table I.

Cardioplegic technique.
Patients were randomly assigned to either high or low flow cardioplegic deliverybefore operation with a computer-generated randomization table. All patientsreceived a tepid (29° C) blood cardioplegic solution that was preparedby mixing four parts of oxygenated blood with one part of a crystalloid solution ¹⁸ and delivered with the Buckbergsystem (Sorin Inc., Irvine, Calif.). Cardiac arrest was achieved with an antegradeinfusion of 500 ml of high-potassium (30 mEq/L) cardioplegic solution givenat a flow rate between 200 and 400 ml/min sufficient to maintain the aorticroot pressure at 70 mm Hg. After this infusion, the aortic root was ventedand retrograde delivery of cardioplegic solution began through an autoinflatablecoronary sinus cannula (Research Medical, Midvale, Utah). Coronary sinus pressureswere monitored continuously by a separate pressure-monitoring line and maintainedat less than 40 mm Hg throughout the procedure. The initial retrograde flowrate in all patients was 100 ml/min. After completion of the distal anastamosisof the vein graft to the right coronary artery, biochemical measurements wereobtained at a retrograde flow rate of 100 ml/min. Retrograde perfusion wasthen modified to include simultaneous antegrade infusions into the completedright coronary artery graft, first at a flow rate of 100 ml/min and then at200 ml/min in all patients. After a 1-minute timed perfusion at each flowrate, simultaneous retrograde and vein graft infusions were continued at theflow rate specified by the randomization table. This protocol discriminatedthe effect of retrograde cardioplegia alone, the addition of a single veingraft at a flow rate of 100 ml/min, and the effect of increasing the flowrate to 200 ml/min. Timed collections of the effluent from the aortic rootwere also measured as indicated in Fig. 1.

View larger version (35K): [in this window] [in a new window]   Fig. 1. Study protocol for comparingflow rates. After antegrade arrest by way of the aortic root, continuous retrogradedelivery was instituted through the coronary sinus at a flow rate of 100 ml/min.Cardioplegic flow was interrupted whenever necessary to visualize the distalanastomosis. After completion of the first distal anastomosis, the cardioplegicsolution was delivered both retrogradely and antegradely into the vein graftat a flow rate of 100 ml/min for 1 minute, then at 200 ml/min for 1 minute.Simultaneous antegrade and retrograde delivery of the cardioplegic solutionwas then given at either low (100 ml/min)or high (200 ml/min) flow for the remainderof the procedure. XCL, Aortic crossclamp; CPB, cardiopulmonary bypass; LITA,left internal thoracic artery.

Arterial and coronary sinus blood samples were assayed to estimatethe myocardial consumption of oxygen and production of lactate or acid. Duringperiods of retrograde perfusion, effluent from the aortic root was used asa source of coronary venous blood. Oxygen content (O₂Con) was calculatedfrom the formula:

O₂Con = 1.39 Hgb x Sao₂ + 0.0031 x Po₂

whereHgb is the hemoglobin concentration, Sao₂ is the oxygen saturation, and Po₂ is the partial pressure of oxygen. Myocardial oxygen extraction (O₂Ex) was calculated as the arterial or cardioplegic oxygen content minusthe coronary effluent oxygen content and myocardial oxygen consumption (MVO₂) determined after correcting for coronary flow (MVO₂ =O₂Ex x flow). Measurements were made at 37° C andthen corrected to the cardioplegic temperature at the time of sampling.

Bloodlactate concentration was determined with the use of a commercially availableassay (Rapid Lactate Stat Pack kit, Calbiochem-Behring, La Jolla, Calif.).Lactate extraction (LEx) was calculated as the difference between arterialand coronary effluent lactate content. Negative lactate extraction is expressedas net lactate release. Lactate consumption or production (MVL) was determinedafter correcting lactate extraction for coronary flow.The concentration of hydrogen ion [H⁺] in blood was determinedby converting the measured pH value to [H⁺] by the formula: [H⁺] = Antilog (–pH). Measurements were made at 37° C and correctedto the myocardial temperature at the time of sampling. Myocardial acid productionwas calculated as the difference in H⁺ concentration between arterialand coronary effluent blood corrected for coronary flow.

Creatine kinase measurement.
An antibody inhibition technique was used to measure the MB isozymeof creatine kinase (CK-MB). Sequential CK-MB measurements were performed at2, 4, 8, 16, 24, and 48 hours after the removal of the aortic crossclamp.Integration of the area under the concentration-time curve for CK-MB withinthe first 48 hours postoperatively allowed calculation of the total CK-MBrelease, expressed as units (IUxhr). We have previously found that thisassessment correlates with infarction as assessed by technetium pyrophosphatescan. ¹⁹

Hemodynamic measurements.
Heart rate, mean arterial pressure, and mean pulmonary artery pressurewere measured preoperatively and postoperatively. Cardiac output was measuredin triplicate via a thermodilution technique by an independent individualwho was unaware of the cardioplegic technique used. Derived hemodynamic indiceswere calculated:

CI = CO/BSA (L/min/m²)

SI = CI/HR (ml/min/m²)

LVSWI = SI x (MAP – PCWP) x 0.0316 (gm·m/m²)

SVRI = (MAP – RAP) x 80/CI (dyne·sec/cm⁵)

where CI = cardiac index, BSA = body surface area, SI =stroke index, LVSWI = left ventricular stroke work index, and SVRI =systemic vascular resistance index.

These hemodynamic variables were measured before initiation of cardiopulmonarybypass and at 2, 4, 8, and 24 hours after removal of the aortic crossclamp.Postoperative preload and afterload were optimized by individuals who wereunaware of the cardioplegic technique used. ²⁰

Statistical analysis.
Statistical analysis was performed using the SAS program (SAS Institute,Cary, N.C.). Categorical variables were analyzed with ² orFisher's exact test as appropriate. Continuous variables were analyzed usinganalysis of variance (ANOVA) or paired t tests as appropriate. A two-way ANOVAwas used to simultaneously evaluate the effect of time and flow rate betweengroups. When the F statistic of the two-wayANOVA was significant, differences between groups were specified by Duncan'smultiple range test. Statistical significance was assumed at p < 0.05.

Results

Table II presents the operative data. Nosignificant differences were found in the number of grafts constructed, theaortic crossclamp time, or the total cardiopulmonary bypass time. All 10 patientsin the high flow group received an initialsaphenous vein graft to the right coronary artery or one of its branches comparedwith eight of nine patients in the low flowgroup. Despite an increased flow rate in the highflow group, the total volume of cardioplegic solution delivered did not differbetween groups (p = 0.749). Similarly, the volume of effluent in theaortic root measured during the last 1-minute timed collection was not differentbetween groups. The volume of effluent in the aortic root did not increasesignificantly when the flow rate was increased to 200 ml/min (low 85 ± 19 ml vs high116 ± 45 ml, p = 0.217). When the volume of cardioplegicsolution delivered was adjusted for the aortic crossclamp time, total cardioplegicdelivery was higher in the high flow group(114 ± 22 ml/min vs low 84 ±18 ml/min, p = 0.005). Similarly, cardioplegic delivery per bypass graftwas also higher in the high flow group (1677 ±365 ml/graft vs low 1264 ± 239 ml/graft, p = 0.01). Ischemictime expressed as the percentage of the crossclamp period during which nocardioplegic solution was given was not different between groups. Minimumcardioplegic temperatures were similar in both groups (low 34° ± 0.5° C vs high35° ± 0.1° C, p = 0.616 by two-way ANOVA).

Metabolic data.
Myocardial oxygen consumption, lactate, and acid production were similarin both groups after antegrade arrest. Table III illustrates myocardial oxygenextraction, lactate, and acid release before aortic crossclamping, after antegradearrest, during the first retrograde dose (at a flow rate of 100 ml/min), andduring reperfusion. No differences were demonstrated betweengroups.

View larger version (29K): [in this window] [in a new window]   Fig. 2. Top panel, Percent change in lactate and acid production and oxygen consumptionafter the addition of antegrade cardioplegic perfusion into the completedright coronary artery graft. Bottom panel,Percent change in lactate and acid production and oxygen consumption achievedby increasing the flow rate from 100 ml/min (low)to 200 ml/min (high). Myocardial oxygen consumptionsignificantly increased as the flow rate increased. Similarly, increasingthe cardioplegic flow rate significantly increased lactate and acid washout.

View larger version (28K): [in this window] [in a new window]   Fig. 3. Panel A, Myocardial lactate release after completion of each distal anastomosis.Washout of accumulated lactate was higher in patients receiving high cardioplegic flow rates after the second distalanastomosis. The difference between high and low flow rates dissipated as additional vein graftsbecame perfused (p = 0.088 by two-wayANOVA). Panel B, Myocardial oxygen consumptionafter completion of each distal anastomosis. Oxygen consumption was higherin patients receiving high cardioplegic flowrates after the first distal anastomosis. This difference dissipated as additionalvein grafts became perfused (p = 0.158by two-way ANOVA). Panel C, Myocardial acidrelease after completion of each distal anastomosis. Washout of accumulatedhydrogen ions was higher in patients receiving highcardioplegic flow rates (p = 0.034 bytwo-way ANOVA) (mean ± standard error of the mean).

View larger version (26K): [in this window] [in a new window]   Fig. 4. Panel A, Cardiac index at baseline (PRE),2, 4, 8, and 24 hours postoperatively. Cardiac index was greater in the high flow group (hollow symbols; p = 0.03 by ANOCOVA). LVEDP, Left ventricular end-diastolic pressure (mm Hg). Panel B, Left ventricular stroke work index (LVSWI)at baseline (PRE), 2, 4, 8, and 24 hours postoperatively.LVSWI was greater in the high flow group (hollow symbols; p =0.05 by ANOCOVA). PCWP, Pulmonary capillarywedge pressure (mm Hg).

Despite apparently adequate blood cardioplegic protection, sensitivemeasures reveal delayed recovery of myocardial metabolism and ventricularfunction. ^7,8 This impairment may be due to inhomogeneous distribution of cardioplegicsolution during either antegrade or retrograde cardioplegia alone. ²¹ An integrated cardioplegic techniqueusing both antegrade and retrograde delivery has been advocated by many authors. ^11–16 However, the optimal flow rate required to improve myocardialperfusion when using integrated cardioplegia is not known. We previously foundthat a flow rate of less than 200 ml/min during normothermic (37° C) retrogradecardioplegia resulted in an accumulation of lactate and acid during the crossclampperiod. ¹⁷ Flow rates in excessof 200 ml/min did not result in further washout of toxic metabolites. However,flow rates of 200 ml/min may be detrimental if they result in high coronarysinus pressures. A coronary sinus pressure of greater than 40 mm Hg has beenreported to result in perivascular hemorrhage and edema, as well as directcoronary sinus injury. ²²

Lowering the temperature from 37° C to 29° C reduced myocardialoxygen consumption by almost 50%. ¹⁰ Therefore a 50% reduction in flow rate from 200 ml/min to 100 ml/minmay not be detrimental at a myocardial temperature of 29° C. This studywas undertaken to determine the optimal flow rate for integrated tepid (29°C) blood cardioplegia and is the first report to investigate flow rates withthis increasingly popular cardioplegic technique.

At 29° C, retrograde flows of 100 ml/min were inadequate to maintainhomogeneous myocardial perfusion. The addition of a single vein graft resultedin increased washout of lactate and acid. Most patients (18 of 19) receivedan initial graft to the right coronary artery or one of its distal branches.Increasing the flow rate from 100 to 200 ml/min resulted in a further washoutof toxic metabolites. We believe that the increased flow rate led to improvedmyocardial perfusion. When perfusion was improved by additional antegradeinfusions into completed vein grafts, the effect of flow rate was attenuated.Thus anaerobic metabolism was stimulated by inadequate myocardial perfusion that was prevented by either increasing theflow rates or by the addition of simultaneous vein graft infusions.

We were able to deliver a flow rate of 200 ml/min in all 10 patientsin the high flow group with a coronary sinuspressure less than 40 mm Hg. We used a single pump head to deliver cardioplegicsolution into the coronary sinus cannula and the vein grafts simultaneously.Possibly, increases in coronary sinus pressure may have resulted in increasedflow down the vein grafts. It is also possible that higher flow rates (inexcess of 250 ml/min) may be better than our high-flow technique. We did notexamine this possibility in our study. We did find, however, that the effluentin the aortic root during a 1-minute timed collection was not different betweengroups. The variability in this measurement likely reflects the variabilityin thebesian shunt flow. Thus increasing flow rates beyond 200 ml/min duringintegrated cardioplegic delivery may increase the shunt fraction as we observedwith retrograde cardioplegia alone. ¹⁷

The improved myocardial perfusion in the high flow group improved earlypostoperative hemodynamics. Fig. 4 illustratesthat at a given preload (left ventricular end-diastolic pressure), cardiacindex and left ventricular stroke work index were higher in the high flow group. No differences were observed betweengroups in clinical outcomes. Our study population consisted of low-risk patientswith excellent collateral circulation and preserved left ventricular function,and clinical differences were not anticipated.

Study limitations.
Coronary venous blood obtained from the aortic root during retrogradedelivery of cardioplegic solution is contaminated by noncoronary collateralblood flow from the pulmonary veins. Contamination is further exacerbatedby simultaneous vein graft perfusions that may deliver oxygenated blood cardioplegicsolution into the aortic effluent. These sources of contamination tend todecrease both lactate and acid concentrations while increasing oxygen tensionsin the aortic effluent. Therefore our measurements of myocardial washout underestimate the true accumulation of lactate and acidin ischemic myocardium. Coronary blood flow during cardioplegic arrest wasassumed to be equivalent to cardioplegic flow rate. Variability in the thebesianshunt fraction at different flow rates also confounds these measurements.

Despite these limitations, we were able to detect subtle differencesin myocardial metabolism during cardioplegic arrest. Our ability to detectdifferences in metabolite washout despite significant contamination suggestsan even larger difference between high- and low-flow groups. Furthermore,the significant improvement in left ventricular function 2 hours after crossclampremoval suggests that improved myocardial protection was achieved at higherflow rates.

Coronary blood flow was not measured during reperfusion. Therefore ourinability to detect metabolic differences during reperfusion may be a resultof differences in coronary blood flow that may have masked true differencesin metabolic activity.

Our technique of "continuous" retrograde delivery of bloodcardioplegic solution required interruption for more than 30% of the crossclampperiod to adequately visualize the distal anastomosis. Maintaining "continuous"flow throughout the crossclamp period may have reduced the accumulation oftoxic metabolites that we observed in this study. However, we believe thatis more prudent to ensure a technically proficient distal anastomosis andcontinue to interrupt cardioplegic delivery whenever necessary. When interruptionsare necessary, a flow rate of 200 ml/min is required to ensure adequate washoutof the accumulated metabolites.

Summary

We conclude from this study that flow rates of 100 ml/min are inadequatewhen using an integrated, tepid blood cardioplegic approach to myocardialprotection. We have previously demonstrated that subtle metabolic and hemodynamicdifferences of the magnitude found in this study correlate with differencesin clinical outcomes in higher risk populations, such as those patients whorequire surgery for unstable angina. ^23,24 Therefore in high-risk patientsflow rates less than 200 ml/min may increase the incidence of postoperativemorbidity and mortality. The possible benefits of increasing flow rates beyond250 ml/min requires further investigation.

We acknowledge the valuable assistance of the nurses in the cardiacoperating room and intensive care unit. In addition, we recognize the participationof the cardiac perfusionists at The Toronto Hospital, without whom these studieswould not be possible. The biochemical expertise of M. K. Mohabeer andL. C. Tumiati is greatly appreciated.

Footnotes

Supported by the Medical Research Council of Canada (Grant MT9829). V.R., is a Pharmaceutical Roundtable Research Fellow of the Heart and Stroke Foundation of Canada. G.C. and M.A.B. are Research Fellows of the Heart and Stroke Foundation of Canada. R.D.W. is a Career Investigator of the Heart and Stroke Foundation of Ontario.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Vivek Rao Gideon Cohen Richard D. Weisel Michael A. Borger Robert J. Cusimano Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rao, V. Articles by Mickle, D. A. Search for Related Content PubMed PubMed Citation Articles by Rao, V. Articles by Mickle, D. A.