Blood Cardioplegia: Do We Still Need to Dilute? Philippe Menasch6, MD, P h D

Department of Cardiovascular Surgery, H6pital Lariboisi6re, Paris, France

S ince the pioneer ing work of Buckberg [1], it has been a common practice to prepare cold blood cardiople-

gia by mixing four parts of oxygenated blood to one part of cry stalloid solution, and this 4:1 dilution ratio has then been readi ly appl ied to the more recent setting of warm heart surgery [2]. However, when nay colleagues and 1 adopted the latter technique 5 years ago, it soon became apparen t to us [3] and others [4-6] that an alternative, definitely s impler and equally, if not more, effective means of del ivering warm blood cardioplegia was to use pure blood, diverted from the arterial port of the oxygen- ator and only supp lemen ted with arrest ing agents (in practice, potassium which, in our formulation, is mixed with magnesium). We coined the term "mini-cardio- plegia" because these arrest ing agents are concentrated in a small volume of saline solution, which is continu- ously added to the blood cardioplegia circuitry, by means of an electrically driven syringe. Initially, the flow rate of the syringe was de te rmined empirically. Subsequent ly , a nomogram has been deve loped that, based on the target potassium concentration (20 mmol/L for induction of arrest, 10 mmol /L for its maintenance), the pat ient ' s p rebypass serum potass ium level, and the flow rate of the cardioplegia del ivery pump, allows an accurate determi- nation of the flow rate at which the drug pump should be set. This flow is then progressively decreased as long as the heart remains quiescent and is temporar i ly rein- creased whenever there is any resumpt ion of electrome- chanical activity. The mini-cardioplegia technique allows one to opt imize the creation of an aerobic envi ronment through an increase in oxygen supply [7] and to "tailor" the amount of admin is te red potass ium to the pat ient ' s specific needs while it avoids the det r imental conse- quences of volume overload and subsequent hemodi lu- tion, in particular, per iphera l vasodilatation, which is commonly associated with warm systemic perfusion [8]. In addit ion, the system is extremely easy to handle and has a negligible cost due to the l imited number of d isposable suppl ies that it requires (a piece of tubing, a stopcock, and an inexpensive pharmaceut ical p repara- tion).

Since the introduction of warm blood cardioplegia, and in spite of the ongoing controversy regarding the optimal cardioplegic temperature , there has been a trend for "cold" surgeons to warm up blood cardioplegic solutions and for "warm" surgeons to cool theirs a little bit. Thus, in the forthcoming years, a " tep id" t empera ture might emerge as an widely acceptable trade-off. In light of these

Address reprint requests to I)r Menasch(,, Department of Cardiovascular Surgery, l t6pital Lariboisihre, 2. rue Ambroise Par6, 75475 Paris Codex 10, France.

reasonably predic table changes, it seems t imely and appropr ia te to reassess the way blood cardioplegia is diluted. This, in turn, implies a need to address both rheologic and biochemical issues.

Rheologic Issues

The major reason for di lut ing b lood-based cardioplegic solutions is to avoid the increase in viscosity associated with hypothermia [9] with the subsequent ly deleter ious consequences of red blood cell s ludging, that is, occlu- sion of capil laries (the percentage of per fused capil laries decreases by a factor of three when tempera ture is lowered from 37°C to 10°C), and tissue underper fus ion [101. This concern is sound as long as b lood cardioplegia is cooled to 4°C to 10°C. The question is whether such hypothermic levels are really required. Indeed, recent studies have brought convincing evidence that tepid (29°C) blood cardioplegic solutions provided the best myocardial protection, compared with more hypother- mic (9°C) or strictly normothermic (37°C) solutions [11- 13]. These data are consistent with the earl ier f indings that the ul t rastructural ly de te rmined cardioprotect ive effects of 27°C blood cardioplegia were not different from those seen at 4°C [14], whereas, in another study, the functional benefits of 20°C blood cardioplegia were actu- ally decreased by further cooling of the solution to 4°C 1151.

Thus, if blood cardioplegia is given in the 30°C range (in our practice, we simply allow the core t empera tu re to drift to usual ly 32°C to 33°C and give cardioplegia at the same temperature , but a heat exchanger can eventual ly be incorporated in the blood cardioplegia circuitry), in- creased viscosity is no longer a concern because at 32°C the viscosi ty/hematocri t relat ionship is not significantly different from that seen at 37°C, in part icular at clinically relevant shear rates [16]. Indeed, it is mainly at t emper- atures less than 27°C that viscosity sharply increases in response to increasing hematocri t [16] (whereas the ther- mal transit ion of erythrocyte deformabil i ty [greater r igid- ity] is a round 18°C [17]). These assumptions , der ived from in vitro studies, are suppor ted by the clinical find- ings that coronary vascular resistance is not different between patients receiving antegrade warm (37°C) car- dioplegia and those in whom the perfusate is cooled to 29°C [121.

From a practical s tandpoint , reliance on these tepid t empera tures for ensur ing myocardial protect ion implies that it may be no longer necessary to lower the hemato- crit of the blood cardioplegic solution beyond the value a l ready result ing from the dilut ional crystal loid pump prime (which usually averages 25%), at least in the absence of thrombot ic diseases such as polycythemia.

© 1996 by Ihe Society ot Thoracic Surgeons Ann Thorac Surg 1996;62:957 60 ° 0003-49751961515.00 Published by Elsevier Science [no PII S0003-4975(96)00564-4

958 EDITORIAL MENASCHI~ Ann Thorac Surg BLOOD CARDIOPLEGIA 1996;62:957-60

The safety and efficacy of this minimal dilution technique are now validated by our 5-year experience, which en- compasses several hundreds of patients. These results extend those of Bomfim and co-workers [18] who, 15 years ago, reported on the successful use of continuous perfusion of 15°C blood simply enriched with potassium and magnesium (average hematocrit, 22%) in patients undergoing aortic valve replacement. However, for those who wish to move progressively from the standard 4:1 ratio to the use of almost pure blood, new devices are now available that provide great flexibility in the choice of the blood-to-crystalloid mixing ratio. Some degree of dilution can thus be reconciled with avoidance of unnec- essary and potentially harmful volume overload [8].

Biochemical Issues

The second major reason for diluting blood cardioplegia is to supply the myocardium with the various purport- edly cardioprotective additives included in the crystal- loid component of the final mixture. However, the use of a low-dilution delivery technique leads one to question the utility of most of these ingredients.

Arresting Agents Agents that cause electromechanical arrest are, by defi- nition, those whose inclusion is mandatory. Currently, asystole is ubiquitously achieved by potassium. In the future, however, hyperpolarizing compounds (among which potassium-channel openers are currently raising a great deal of interest) might become effective alternative means of inducing cardioplegia because of the lower energy expenditure of hyperpolarized arrest, as com- pared with depolarized arrest [19].

One mechanism whereby potassium-based cardiople- gia is, paradoxically, energy-consuming is the calcium influx associated with membrane depolarization. For this reason, we have supplemented our concentrated potas- sium cardioplegic solution with magnesium (the final formulation consists of 16 mmol/L of potassium chloride and 3 mmol/L of magnesium chloride in a 20-mL am- poule of distilled water). Not only does magnesium contribute to electromechanical arrest, but it also antag- onizes calcium ions at both the sarcolemmal and intra- cellular levels, which largely accounts for its well- established cardioprotective effects [20, 21]. An additional advantage of magnesium is its venodilating effect [22[, which is clinically relevant if cardioplegic solution is to be directly infused into saphenous vein bypass grafts.

Calcium Citrate-phosphate-dextrose is commonly added to blood cardioplegic solutions to reduce plasma levels of ionized calcium with the underlying hope that it will contribute to reduce calcium overload and its well-established tis- sue-damaging effects. This concern, however, is not rel- evant to the use of continuous warm blood cardioplegia because the maintenance of myocardial aerobic metabo- lism should result in sufficiently high energy production to drive the pumps responsible for calcium homeostasis.

In support of this hypothesis, Liu and co-workers [23] have shown, in isolated rat hearts continuously perfused with oxygenated crystalloid cardioplegia, that solutions at 28°C and 37°C did not cause a significant postischemic intracellular calcium overload (in contrast to colder per- fusates). The problem is different if blood cardioplegia is given tepid and in an intermittent fashion because cal- cium overload can then occur during the ischemic inter- vals between cardioplegic infusions. However, the crys- talloid pump prime already results in a dilutional hypocatcemia with resulting levels of ionized calcium that have been shown not to adversely affect postisch- emic myocardial recovery or enzyme leakage provided the cardioplegic solution was supplemented with mag- nesium [24]. Consequently, it is sound to assume that prevention of calcium overload can safely and effectively rely on magnesium rather than on pharmacologic chela- tors like citrate-phosphate-dextrose in view of the previ- ously mentioned ability of magnesium to act as a pow- erful antagonist of calcium ions.

Buffers Buffers, most often tris (hydroxymethyl) aminomethane (THAM), are commonly included in the crystalloid com- ponent of blood-based cardioplegic solutions. When car- dioplegia is given continuously and at normothermic (or tepid) temperatures, the use of exogenous buffers ap- pears unnecessary because one of the objectives of the resulting aerobic environment is precisely to avoid intra- cellular acidosis, the prevention of which should be further enhanced by the wash-out effect of continuous blood perfusion. In this setting, the deliberate creation of an extracellular alkalosis can even become deleterious because of the expected stimulation of the sodium/ proton exchanger, the resulting increase in intracellular sodium level, and an ultimate calcium overload via the sodium/calcium exchanger.

If blood cardioplegia is given tepid, intermittently, or both, the effectiveness of any added buffer becomes primarily determined by its capacity to counteract tissue acidosis over a wide range of temperatures. In this setting, it remains questionable to try to buffer blood. Under these mildly hypothermic conditions (and the same would hold true for colder temperatures), the "good" buffer will be the one that will change its pK with temperature parallel to the changes in neutrality of water [25]. It is not debatable that the buffer that best meets this criterion is the imidazole residue of histidine present in blood. Thus, it is not fortuitous that the crystalloid cardioplegic solution that has a buffering capacity com- parable with that of blood is Bretschneider's solution, which contains a high concentration (195 mmol/L) of histidine [26]. That the addition of THAM does not increase the buffering capacity of blood has been well demonstrated by Neethling and co-workers [27], who failed to show any difference in myocardial pH after 150 minutes of aortic cross-clamping between canine hearts infused with THAM-buffered blood cardioplegia and those receiving unbuffered hyperkalemic blood. Bicar- bonate is expected to be still more useless than THAM

Ann Thorac Surg EDITORIAL MENASCHI~ 959 1996;62:957-60 BLOOD CARDIOPLEGIA

because of its poor buffering capacity at low tempera- tures. This is well apparent from the observation that, at the end of a 4-hour cold cardioplegic arrest, subendocar- dial pH of canine hearts was found to be much more acidotic after the use of bicarbonate-buffered crystalloid cardioplegia (to a pH of 7.80) than after the delivery of blood cardioplegia devoid of any exogenous buffer [28].

Substrates Among substrates, amino acids, in particular aspartate and glutamate, are those whose supply has been the most strongly advocated, primarily because of their pur- ported abil i ty to anaerobical ly genera te adenos ine triphosphate. Whereas this hypothesis is possibly rele- vant to the use of crystalloid cardioplegia, it becomes more questionable when blood is the cardioplegic vehi- cle. Under conditions of cont inuous warm blood perfu- sion, the heart is likely to fuel its oxidative machinery with its preferred metabolic substrates, which are free fatty acids and glucose, not amino acids. Indeed, a recent study using phosphorus 31 nuclear magnetic resonance spectroscopy in blood-perfused pig hearts has failed to demonstrate any increase in high-energy phosphate lev- els after glutamate supplementat ion of the blood car- dioplegic solution [29]. In the setting of cold, intermit tent blood cardioplegic arrest, there has been experimental evidence that energy-depleted hearts might benefit from aspartate and glutamate supplementa t ion , provided these amino acids were normothermically delivered dur- ing cardioplegic induct ion [30l, early reperfusion [31], or both. Reliance on these laboratory findings (in spite of the fact that they are only supported by a limited amount of clinical data [32, 33]) does not preclude the use of the mini-cardioplegia technique because amino acids can easily be concentrated in a small volume of fluid. How'- ever, it should be remembered that the whole concept of exogenous fuel supply remains debatable [34, 35] in that postischemic myocardial s tunning might be more related to abnormal energy utilization rather than to lack of substrate availabili~,.

S u m m a r y

In summary, in the context of warm or tepid blood cardioplegia, the mini-cardioplegia concept has reason- ably wel l -documented advantages over the standard 4:1 dilution ratio, which are of four types: (1) improved oxygen supply because of the combinat ion of a rightward shift of the oxyhemoglobin dissociation curve and a greater n u m b e r of available red blood cells, (2) improved control of blood volume because of the limitation of fluid overload (which greatly contributes to early postoperative extuba- tion), (3) improved practicality because a simple electrically driven pump can substitute for more complex blood/ crystalloid mixing devices, and (4) improved cost-effective- ness because the expenses related to these delivery sys- tems, various biochemical additives, and, eventually, fluid- removing devices like ultrafilters or cell-saving devices are eliminated. Thus, in a period where a positive fea- ture of economic constraints is to force us to reassess our practice patterns, the use of minimally hemodiluted

hyperkalemic blood appears as a sound approach for increasing the simplicity and low cost of cardioplegia delivery without compromising the quality of the protec- tion that it currently provides. Furthermore, this concept of concentrated cardioplegia does not exclude the future inclusion, in a still-limited volume of crystalloid vehicle, of additives that would be of clinical benefit, among which agents favorably interfering with neutrophi l - endothelial cell interactions appear particularly appeal- ing [36].

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35. Asai T, Grossi EA, LeBoutillier M, et al. Resuscitative retro- grade blood cardioplegia. Are amino acids or continuous warm techniques necessary,? J Thorac Cardiovasc Surg 1995; 109:242- 8.

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