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108 JCC, Vol. 40, N o 2, avril 1997 Original Article Article original MYOCARDIAL DISTRIBUTION OF CARDIOPLEGIA ADMINISTERED BY ANTEGRADE AND RETROGRADE ROUTES TO ISCHEMIC MYOCARDIUM Michel Carrier, MD;* Jean Grégoire, MD;† Ahmad Khalil, MD;‡ Pierre Thai, MSc;‡ Jean-Gilles Latour, PhD;‡ B. Charles Solymoss, MD;§ L. Conrad Pelletier, MD* From the *Department of Surgery, †Department of Nuclear Medicine, ‡Department of Laboratory of Medicine and §Department of Experimental Pathology, Montreal Heart Institute, Montreal, Que. Accepted for publication Sept. 25, 1996 Correspondence and reprint requests to: Dr. Michel Carrier, Department of Surgery, Montreal Heart Institute, 5000 Belanger St., Montreal QC H1T 1C8 © 1997 Canadian Medical Association (text and abstract/résumé) OBJECTIVE: To study the distribution of a cardioplegic solution delivered by antegrade and retrograde routes to ischemic myocardium. Retrograde administration has been suggested to improve protection of the ischemic myocardium. However, there are insufficient data on perfusion of ischemic and necrotic zones by the retrograde route. DESIGN: A laboratory study in dogs. METHOD: In 12 dogs, 500 mL of hyperkalemic crystalloid cardioplegia containing 0.5 mCi of thallium- 201 was injected antegradely or retrogradely through the coronary sinus after 3 hours of occlusion and 2 hours of reperfusion of the left anterior descending coronary artery. Myocardial distribution of the cardio- plegic solution was measured by computer planimetry in the normally perfused zone, in the ischemic area and in the necrotic zone. RESULTS: The mean (and standard deviation) area at risk of ischemia (% of the left ventricle) delimited by Evans blue perfusion was smaller in dogs receiving a retrograde injection than in those receiving an ante- grade injection (34% [3%] v. 42% [4%], p = 0.15). The infarct size (% of the area at risk indicated by tri - p henyltetrazolium dye) averaged 25% (11%) and 20% (7%) respectively (p = 0.36). The ratio of thallium- 201 activity in ischemic to normal myocardium averaged 76% (13%) in the retrograde and 89 (12%) in the antegrade groups (p = 0.75). The ratio of thallium activity of infarct to normal myocardium averaged 56% (8%) in the retrograde group and 93% (19%) in the antegrade group (p = 0.18). Large areas of hypoactivity in the left ventricular myocardium were noted on scintigraphic imaging in all dogs that re- ceived retrograde perfusion. CONCLUSIONS: The retrograde injection of cardioplegia through the coronary sinus does not improve the distribution of cardioplegic solution in the acutely ischemic myocardial area nor in the zone of acute infarc- tion in the dog. Because some cells may remain viable in the border zone and into the necrotic area, retro- grade cardioplegia may result in suboptimal protection and incomplete prevention of further damage to the myocardium. OBJECTIF : Étudier la distribution d’une solution cardioplégique injectée par voie antérograde et rétro- grade dans un myocarde ischémique. On a proposé l’administration par voie rétrograde pour mieux pro- téger le myocarde ischémique. Les données sur la perfusion par voie rétrograde de zones ischémiques et nécrosées sont toutefois insuffisantes. CONCEPTION : Étude en laboratoire effectuée sur des chiens. MÉTHODE : On a injecté à 12 chiens, par voie antérograde ou rétrograde, 500 mL de solution cardio- plégique cristalloïde hyperkaliémique contenant 5 mCi de thallium-201 par le sinus coronarien après 3

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Page 1: Original Article Article originalcanjsurg.ca/wp-content/uploads/2014/03/40-2-108.pdf · 14799 April/97 CJS /Page 108 108 JCC, Vol. 40, N o 2, avril 1997 Original Article Article original

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108 JCC, Vol. 40, No 2, avril 1997

Original ArticleArticle original

MYOCARDIAL DISTRIBUTION OF CARDIOPLEGIAADMINISTERED BY ANTEGRADE AND RETROGRADEROUTES TO ISCHEMIC MYOCARDIUM

Michel Carrier, MD;* Jean Grégoire, MD;† Ahmad Khalil, MD;‡ Pierre Thai, MSc;‡ Jean-Gilles Latour, PhD;‡ B. Charles Solymoss, MD;§ L. Conrad Pelletier, MD*

From the *Department of Surgery, †Department of Nuclear Medicine, ‡Department of Laboratory of Medicine and §Department of Experimental Pathology, Montreal HeartInstitute, Montreal, Que.

Accepted for publication Sept. 25, 1996

Correspondence and reprint requests to: Dr. Michel Carrier, Department of Surgery, Montreal Heart Institute, 5000 Belanger St., Montreal QC H1T 1C8

© 1997 Canadian Medical Association (text and abstract/résumé)

OBJECTIVE: To study the distribution of a cardioplegic solution delivered by antegrade and retrograderoutes to ischemic myocardium. Retrograde administration has been suggested to improve protection ofthe ischemic myocardium. However, there are insufficient data on perfusion of ischemic and necrotic zonesby the retrograde route.DESIGN: A laboratory study in dogs.METHOD: In 12 dogs, 500 mL of hyperkalemic crystalloid cardioplegia containing 0.5 mCi of thallium-201 was injected antegradely or retrogradely through the coronary sinus after 3 hours of occlusion and 2hours of reperfusion of the left anterior descending coronary artery. Myocardial distribution of the cardio-plegic solution was measured by computer planimetry in the normally perfused zone, in the ischemic areaand in the necrotic zone.RESULTS: The mean (and standard deviation) area at risk of ischemia (% of the left ventricle) delimited byEvans blue perfusion was smaller in dogs receiving a retrograde injection than in those receiving an ante-grade injection (34% [3%] v. 42% [4%], p = 0.15). The infarct size (% of the area at risk indicated by tri -p henyltetrazolium dye) averaged 25% (11%) and 20% (7%) respectively (p = 0.36). The ratio of thallium-201 activity in ischemic to normal myocardium averaged 76% (13%) in the retrograde and 89 (12%) in theantegrade groups (p = 0.75). The ratio of thallium activity of infarct to normal myocardium averaged56% (8%) in the retrograde group and 93% (19%) in the antegrade group (p = 0.18). Large areas of hypoactivity in the left ventricular myocardium were noted on scintigraphic imaging in all dogs that re-ceived retrograde perfusion.CONCLUSIONS: The retrograde injection of cardioplegia through the coronary sinus does not improve thedistribution of cardioplegic solution in the acutely ischemic myocardial area nor in the zone of acute infarc-tion in the dog. Because some cells may remain viable in the border zone and into the necrotic area, retro-grade cardioplegia may result in suboptimal protection and incomplete prevention of further damage tothe myocardium.

OBJECTIF : Étudier la distribution d’une solution cardioplégique injectée par voie antérograde et rétro-grade dans un myocarde ischémique. On a proposé l’administration par voie rétrograde pour mieux pro-téger le myocarde ischémique. Les données sur la perfusion par voie rétrograde de zones ischémiques etnécrosées sont toutefois insuffisantes.CONCEPTION : Étude en laboratoire effectuée sur des chiens.MÉTHODE : On a injecté à 12 chiens, par voie antérograde ou rétrograde, 500 mL de solution cardio-plégique cristalloïde hyperkaliémique contenant 5 mCi de thallium-201 par le sinus coronarien après 3

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Retrograde administration ofcardioplegic solution throughthe coronary sinus has been

proposed as an essential component ofwarm blood cardioplegia.1,2 It iswidely used in clinical practice withthe hope that oxygen is being deliv-ered continuously and uniformlythroughout the myocardium. How-ever, animal experiments have shownthat the right ventricle and the inter-ventricular septum are less than ade-quately perfused by the retrograderoute.3 In addition, the distribution ofcardioplegic solution administered an-tegradely or retrogradely has not yetbeen well defined in acutely ischemicmyocardium.

The objective of the present studywas to evaluate the myocardial distrib-ution of cardioplegic solution in normal, ischemic and necrotic myo -cardium after antegrade and retro-grade administration. We hypo -thesized that the distribution ofcardioplegia in ischemic and necroticmyocardium will be homogeneouswith the retrograde route and hetero-geneous with the antegrade route;therefore, the retrograde route shouldresult in a better preservation of is-chemic myocardium.

MATERIAL AND METHODS

Myocardial distribution of cardio-plegic solution during antegrade in-jection into the ascending aorta andretrograde injection through the coro-nary sinus was studied in 12 dogs,ranging in weight from 25 to 30 kg.The animals were anesthetized withsodium pentobarbital (30 mg/kg),and ventilated mechanically (HarvardApparatus, South Natick, Mass.). Amedian sternotomy was performed.After systemic injection of 1000 unitsof heparin and perfusion of 100 mg oflidocaine, the left anterior descending(LAD) coronary artery was occludeddistal to the first diagonal branch for3 hours, followed by 2 hours of reper-fusion.

A catheter was placed in the as-cending aorta for the administrationof the cardioplegic solution in the 6dogs of the antegrade group. Trans -atrial cannulation of the coronary si-nus with a coronary sinus catheter(self-inflating 14 French ballooncatheter; Research Medical Inc., Mid-vale, Utah) for retrograde infusion ofcardioplegia was performed on the 6dogs of the retrograde group. Thal-lium-201 (201Tl), 0.5 mCi, was added

to 500 mL of hyperkalemic crystalloidcardioplegia containing 130 mmol ofsodium, 135 mmol of chloride,3 mmol of calcium, 28 mmol of lac-tate, 20 g of mannitol, 0.17 g ofsodium bicarbonate and 34 mmol ofpotassium chloride per litre.The crys-talloid solution was administered atroom temperature (21 °C) in bothgroups.

Retrograde coronary sinus cardio-plegic solution was injected at lowperfusion pressure (20 to 40 mm Hg)after ligation of the azygos vein andthe superior and inferior vena cava,and aortic cross-clamping. The as-cending aorta and the left and rightventricles were vented. Effluent solu-tions from vented catheters were col-lected and analysed. In the antegradegroup, effluent solutions from ventedleft and right atria and from left andright ventricles were collected andanalysed. The antegrade injection wasperformed at high perfusion pressure(50 to 100 mm Hg) in the ascendingaorta. 201Tl activity in the myocardium,and in effluents from the left ventricle,the right ventricle and the aorta wascalculated and expressed as a percent-age of the total dose of injected ra-dioactive tracer.

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heures d’occlusion et 2 heures de reperfusion de l’artère interventriculaire antérieure gauche. On a mesuréla distribution de la solution cardioplégique dans le myocarde par planimétrie informatisée dans la zoneperfusée normalement, dans la zone ischémique et dans la zone nécrosée.RÉSULTATS : La surface moyenne (et l’écart type) à risque d’ischémie (% du ventricule gauche) délimitéepar une perfusion de bleu Evans était moindre chez les chiens qui l’ont reçue par voie rétrograde que chezceux qui l’ont reçue par voie antérograde (34 % [3 %] c. 42 % [4 %], p = 0,15). La taille de l’infarctus (% dela superficie à risque révélée par le colorant au triphényltétrazolium) s’est établie en moyenne à 25 % (11 %)et 20 % (7 %) respectivement (p = 0,36). Le ratio d’activité du thallium-201 dans le myocarde ischémiquepar rapport au myocarde normal s’est établi en moyenne à 76 % (13 %) chez les sujets qui ont reçu l’injec-tion par voie rétrograde et à 89 % (12 %) chez ceux qui l’ont reçue par voie antérograde (p = 0,75). Le ra-tio de l’activité du thallium dans le myocarde atteint d’un infarctus par rapport à celle du myocarde normals’est établi à 56 % (8 %) chez les sujets qui ont reçu l’injection par voie rétrograde et 93 % (19 %) chez ceuxl’ont reçue par voie antérograde (p = 0,18). La scintigraphie a révélé, chez tous les chiens qui ont reçu laperfusion par voie rétrograde, une importante superficie d’hypoactivité dans le myocarde ventriculairegauche.CONCLUSIONS : L’injection d’une solution cardioplégique par voie rétrograde dans le sinus coronarien n’enaméliore pas la distribution dans la zone du myocarde où l’ischémie est aiguë ni dans la zone d’infarctusaigu chez le chien. Comme certaines cellules peuvent demeurer viables dans la zone périphérique et dans lazone nécrosée, une injection de solution cardioplégique par voie rétrograde peut entraîner une protectionsub-optimale et ne pas prévenir tous les autres dommages au myocarde.

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After cardioplegic arrest and com-plete injection of the cardioplegic so-lution, the heart was harvested and theinfarct size quantified.4 The LADcoronary artery at the level of occlu-sion and the aorta above the coronaryostia were cannulated and perfusedwith saline (0.9%) for 5 minutes. Sub-sequently, the aorta was perfused withEvans blue dye (0.5%), and the LADcoronary artery with saline (0.9%) at aconstant pressure (100 mm Hg) for5 minutes. The left heart was thenembedded into polyurethane foamand cut into transverse slices 7 mmthick. The slices were immersed intriphenyltetrazolium chloride (TTC)1.5% in TRIS buffer (2.4%, pH 7.8)for 5 minutes at 37 °C. The normallyperfused zone (Evans blue positive),the area at risk of ischemia (Evans bluenegative) and the infarct zone (Evansblue and TTC negative) were esti-mated by computer planimetry foreach slice. The area at risk of ischemiawas expressed as a percentage of theleft ventricle and the infarct size as apercentage of the area at risk of is-chemia. The 6 central slices of the leftventricle were divided into normal, is-chemic and necrotic regions. Sectionsfrom each region were divided into 3equal subepicardial, mid-wall andsubendocardial portions and wereweighed and counted in a gammacounter (Minaxi 5000; Packard In-strument Co., Inc., La Grange, Ill.).The ratio of 201Tl activity, comparingthe area at risk of ischemia and thenecrotic zone with the normal myo -cardium, was calculated for every ex-periment. Thereafter, the heart sliceswere scanned with a conventional pla-nar gamma camera (256 × 256 × 16bit matrix 106 counts).

Troponin T, a marker of myocardialnecrosis and ischemia, was measuredin peripheral venous blood samplestaken before, and every hour through-out, the experiment in all animals.5

The data are presented as means(and standard errors). Differences be-tween groups were studied by Stu-dent’s t-test, and analysis of variancefor repeated measures was used whenappropriate. A correlation coefficientwas calculated to study the relation-ship between two variables. The levelof statistical significance was estab-lished at 95%. All animals were treatedin accordance with the Guide for theCare and Use of Laboratory Animals.6

RESULTS

Quantitative assessment ofischemic and necrotic myocardium

After ligation of the LAD coronaryartery, the area of myocardium at riskof ischemia averaged 34% (3%) of thetotal left ventricular area in retro-gradely perfused dogs and 42% (4%)in antegradely perfused dogs, a non-significant difference (p = 0.15). Thenecrotic zone averaged 25% (11%) ofthe area at risk of ischemia in the ret-rograde group and 20% (7%) in theantegrade group, again a nonsignifi-cant difference (p = 0.36).

Evaluation of the capillary flowshowed that 79% (5%) and 80% (6%)of total 201Tl activity was recovered inthe myocardium of retrogradely andantegradely perfused hearts respec-tively (p = 0.93). The remaining ra-dioactive tracer was recovered in theaorta, and in the right and left ventric-ular and right atrial effluents.

The release of troponin T duringthe experiment was similar in bothgroups (retrograde 3.1 [1.3] µg/L,antegrade 5.2 [2.3] µg/L, p = 0.5). Astrong correlation was found betweenmaximal level of troponin T and in-farct size (r = 0.91, p = 0.00001). Asignificant negative correlation wasalso found between the maximal levelof troponin T and the normal andresidual areas of the left ventricle after

coronary ligation and reperfusion (r= −0.87, p = 0.0002).

Myocardial distribution of cardioplegic solution

The ratio of 201Tl activity of the areaat risk of ischemia to normal myo -cardium in retrogradely and ante-gradely perfused hearts averaged76% (13%) and 89% (12%) respec-tively, a nonsignificant difference (p =0.75). The ratio of radioactivity ofnecrotic to normal myocardium aver-aged 56% (8%) and 93% (19%) respec-tively, a nonsignificant decrease inretro grade perfusion of necrotic myo - cardial areas (p = 0.18).

The ratio of 201Tl activity of suben-docardial to epicardial area in ischemiczones averaged 139% (19%) in retro-gradely perfused hearts comparedwith 133% (28%) in the antegradegroup, a nonsignificant difference (p =0.86). The ratio of subendocardial toepicardial radioactivity in the necroticarea averaged 121% (25%) in retro-gradely perfused hearts and 83% (10%)in antegradely injected hearts, a non-significant decrease in antegradely per-fused hearts (p = 0.16).

Analysis of scintigraphic images

Analysis of scintigraphic images ofretrogradely perfused hearts showedlarge areas of hypoactivity in the leftventricular free wall corresponding tothe area of myocardial necrosis delin-eated by the TTC method.3 On theother hand, the distribution of 201Tlactivity was more homogeneous in theleft ventricle of antegradely injectedhearts, where no significant zone ofhypoactivity was shown (Fig. 1).

DISCUSSION

Several studies have shown that ret-rograde administration of cardioplegic

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FIG. 1. Example of scintigraphic images (left) and schematic representation (right) of a left ventricle after antegrade (bottom) and retrograde (top) perfu-sion. The myocardium at risk of ischemia represents 41% of the total left ventricular area in antegradely (bottom) and 42% in retrogradely (top) perfusedhearts. The necrotic zones represent 48% of the ischemic area in antegradely (bottom) and 63% in retrogradely (top) perfused hearts. Large areas of hy-poactivity are shown in the infarcted myocardium of retrogradely perfused hearts (top left) and small areas of thallium-201 hypoactivity are shown in theleft ventricle of antegradely perfused hearts (bottom left).

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solution through the coronary sinusprovides excellent clinical results inprotecting myocardial function dur-ing valve and coronary artery bypasssurgery.7,8 The retrograde approachhas been recommended in patientswith complete coronary occlusion,8

particularly when the LAD coronaryartery is occluded,9 and in patientswith myocardial hypertrophy.10

Several experimental studies haveindicated a concern regarding myocar-dial distribution and capillary flowwhen the retrograde route is used forcardioplegic administration.11–14 In a re-cent experiment,3 we showed that 70%to 80% of the total 201Tl activity in-jected retrogradely in the coronary si-nus was recovered in the myocardium,indicating that a high transcapillaryflow resulted from retrograde infusion.However, small areas of the right ven-tricular and septal walls were found tobe nonhomogeneously perfused byretrograde cardioplegic infusion whenthe myocardium was supplied by fullyopen coronary arteries.

Misare and colleagues15 reportedthat the systolic function of ischemicmyocardium remains well preservedafter retrograde, continuous, warmblood cardioplegia, suggesting that inischemic areas, retrograde myocardialperfusion was adequate after a shortperiod of coronary occlusion andmyo cardial reperfusion. In our experi-ments, similar ischemic and necroticareas of the left ventricle were ob-tained in both antegrade and retro-grade groups after ligation of the LADcoronary artery and myocardial reper-fusion. The ratio of 201Tl activity of is-chemic to normal myocardium wassimilar in antegradely and retrogradelyperfused hearts, whereas the ratio ofradioactivity of necrotic to normalmyo cardium was higher with ante-grade than retrograde perfusion, al-though the difference was not statisti-cally significant.

Scintigraphic images of retro-gradely perfused hearts showed largeareas of hypoactivity in the left ventri-cle compared with hearts perfused an-tegradely (Fig. 1). This suggests thatthe radioactive tracer did not accessthe necrotic area when injected by theretrograde route as opposed to the an-tegrade route. This suggestion is inagreement with the lower ratio of 201Tlactivity of necrotic to normal myo -cardium in retrogradely than in ante-gradely perfused hearts, although thedifference was not significant. After in-travenous injection, early myocardialuptake of 201Tl is proportional to re-gional blood flow and myocardial ex-traction.16,17 In animal models, hypoxiaor myocardial stunning does not affectmyocardial uptake of 201Tl.18,19 How-ever, integrity of the cellular mem-brane is necessary for 201Tl to concen-trate in the cell. Necrotic myocardiumdoes not take up 201Tl when injectedafter reperfusion preceded by 3 hoursof coronary occlusion.20 However,early post-reperfusion thallium uptakemay overestimate myocardial viability,possibly because of increased bloodflow.21,22

In our study, even though infarctsize was similar in both groups, 201Tlactivity in the necrotic zone was al-most equal to that of the normal areain the antegrade model (93%), in con-trast to the retrograde model (56%).Possible explanations are that viablemyocardial cells remained in the in-farct area and were still able to con-centrate 201Tl, myocardial perfusionwas increased due to hyperemic bloodflow and, finally, some of the 201Tl mayhave been present in the extracellularcompartment since hearts were har-vested minutes after cardioplegic ar-rest. Whatever the mechanism in-volved, a higher 201Tl uptake in theantegrade model is suggestive of in-creased blood flow or increased myo -cardial viability, or both, compared

with the retrograde group. Whereasboth the antegrade and the retrograderoutes provide hyperperfusion ofsubendocardial muscle irrigated withan open coronary artery, there is un-derperfusion with the antegrade routewhen the artery is occluded.23 In ourstudy, ischemic areas located in thesubendocardium were hyperperfusedin both groups, and necrotic areas inthe subendocardium were hyperper-fused by retrograde injection andslightly underperfused by antegradeinjection. Thus, retrograde and ante-grade injection routes had a similardistribution pattern in the ischemicmyocardial wall. The low ratio of 201Tlactivity in necrotic areas perfused bythe retrograde route suggests a signif-icant maldistribution of the solution,whereas the subendocardium re-mained hyperperfused when com-pared with the subepicardial zone.

Microvascular damage, particularlyto the system of small post-capillaryvenules, could explain the no-reflowphenomenon shown with retrogradeinfusion of the cardioplegic solutionin necrotic areas.24 Although there areconflicting results in regard to the ef-fect of retrograde warm blood cardio-plegia in the setting of acute global is-chemia in animals,25,26 reperfusion ofnecrotic zones and of the viable com-ponent of the border zone throughthe retrograde route could have beensuboptimal.27 Despite the limitationsof an animal model, our data suggestthat both the antegrade and the retro-grade route do not perfuse the is-chemic or necrotic zones normally.

CONCLUSION

Retrograde administration of car-dioplegic solution through the coro-nary sinus did not result in improvedperfusion of acute ischemic myo -cardium in the dog when comparedwith antegrade perfusion.

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