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Ann Thorac Surg 1999;68:1995-2001
© 1999 The Society of Thoracic Surgeons

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II. Surgical Myocardial Protection

Intraoperative myocardial protection: current trends and future perspectives

^a Division of Cardiovascular Surgery, The Toronto General Hospital and the University of Toronto, Toronto, Ontario, Canada

Address reprint requests to Dr Weisel, Division of Cardiovascular Surgery, The Toronto General Hospital, EN 14-215, 200 Elizabeth St, Toronto, ON, Canada M5G 2C4
e-mail: rweisel{at}torhosp.toronto.on.ca

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sep 21–24, 1997.

Abstract

Background. The results of contemporary coronary artery bypass graft surgery (CABG) are excellent. However, recently changing trends in the population at risk have necessitated new measures to minimize perioperative morbidity and mortality.

Methods. We reviewed cardioplegic innovations developed, evaluated, and currently employed at the Toronto Hospital. In addition, we conducted an evaluation of novel cardioplegic formulations, with an eye towards future clinical applications.

Results. At the Toronto Hospital, we demonstrated that blood provided better protection than crystalloid cardioplegia. Subsequently, we found that a terminal infusion of warm blood cardioplegia repleted myocardial adenosine triphosphate (ATP) levels and improved postoperative ventricular function. Recently, we reported that tepid (29°C) cardioplegia reduced lactate and acid production during cardioplegic arrest, and improved postoperative ventricular function. Combining antegrade and retrograde cardioplegic delivery reduced lactate production, preserved ATP stores, and improved metabolic recovery after cross-clamp release. Cardioplegic flows of at least 200 mL/min were required to washout detrimental metabolic end-products and improve ventricular function. To further optimize myocardial protection, attempts have been made to harness the beneficial effects of ischemic preconditioning using adenosine. Similarly, insulin cardioplegia has been employed in order to enhance ventricular performance by stimulating early postoperative aerobic metabolism. Finally L-arginine, a nitric oxide donor has been demonstrated to be beneficial in experimental studies and may represent a further option for the enhancement of intraoperative myocardial protection.

Conclusions. Despite continued improvements in cardioplegic techniques, low output syndrome following high-risk CABG remains an ongoing concern. The development of novel additives with various protective properties may provide added protection, allowing for a reduction morbidity and mortality following CABG.

The results of contemporary coronary artery bypass graft surgery (CABG) are exceptional. However, recently changing trends in the population at risk have resulted in increasing numbers of high-risk patients presenting for CABG, with an accompanying rise in postoperative morbidity including low output syndrome (LOS) [1]. In the absence of complications, postoperative LOS may be directly attributable to inadequate intraoperative myocardial protection. Not surprisingly, recent advances in cardiac surgery have centered upon optimization of cardioplegic parameters in the hope of preventing postoperative ventricular dysfunction and improving overall outcome.

The following recounts the evolution of intraoperative myocardial protection at The Toronto Hospital and presents a summary of novel techniques aimed at improving the results of contemporary coronary bypass surgery.

Hypothermic cardioplegia

Early cardioplegic techniques employed cold crystalloid solutions to initiate and maintain intraoperative cardiac arrest. Cold crystalloid cardioplegia, in addition to facilitating adequate visualization of the anastomotic site, provided the presumed advantage of inhibiting myocardial enzymatic activity at a time when perfusion to the heart was suboptimal.

Blood cardioplegia

In the hope of maximizing intraoperative myocardial protection, surgeons at many institutions evaluated oxygenated blood cardioplegia in the early 1980s. A randomized clinical trial of blood versus crystalloid cardioplegia performed by Fremes and colleagues revealed that blood cardioplegia facilitated aerobic myocardial metabolism during the cross-clamp period and reduced anaerobic lactate production [2]. Future studies revealed that blood cardioplegia improved oxygen carrying capacity, enhanced myocardial oxygen consumption and preserved myocardial high-energy phosphate stores [3, 4]. Recent trends at The Toronto Hospital have included a conversion to cardioplegic solutions with increasingly higher concentrations of blood. In 1991, we revised the blood-crystalloid composition of our cardioplegia from 2:1 to 4:1, and have since changed to an 8:1 concentration. More recent approaches include blood-only formulations associated with appropriate electrolyte supplementation.

Substrate enhancement of cardioplegia

Despite such interventions, standard techniques of intermittent cold cardioplegia resulted in myocardial hypothermia, ischemia, and a delay in the recovery of postoperative myocardial metabolism and function [5]. Early studies suggested a depletion of Krebs-cycle intermediates to be partly responsible for this delay. In a trial by Rosenkranz and colleagues, hearts arrested using glutamate-supplemented cardioplegia achieved earlier metabolic recovery [6]. A similar trial at our institution revealed decreased morbidity and mortality in urgent CABG patients undergoing induction with glutamate-aspartate cardioplegia [7].

Antegrade normothermic cardioplegia

Further studies suggested that the delay in metabolic and functional cardiac recovery was secondary to the hypothermic inhibition of myocardial enzymes which would remain inactive for hours following cardioplegic arrest. In 1982, Rosenkranz and coworkers demonstrated that warm induction of cardioplegic arrest improved myocardial metabolic and functional recovery following CABG [8]. Thereafter, Teoh and colleagues from Toronto revealed that a terminal infusion of warm (37°C) blood cardioplegia prior to cross-clamp removal ("hot-shot") facilitated early myocardial metabolic recovery while maintaining electromechanical arrest [9]. Presumably, normothermia enabled the early resumption of temperature-dependent mitochondrial enzymatic function, with a return to aerobic metabolism and adenosine triphosphate (ATP) generation. Moreover, the persistent quiescent state of the heart permitted the use of available ATP for the repair of ischemic cellular injury and the repletion of energy stores rather than the maintenance of unnecessary contractile activity. Thus, between 1986 and 1989, the standard technique of myocardial protection at The Toronto Hospital consisted of intermittent cold-blood cardioplegia with a terminal "hot-shot" infusion [10]. In cases of severe preoperative ischemia, warm induction with substrate enhanced cardioplegia was also utilized.

Warm heart surgery

Although the clinical use of normothermic cardioplegia began as early as 1987, initial reports concerning the use of this method did not surface until 1991 when Lichtenstein and associates described the results of 121 consecutive patients receiving normothermic antegrade blood cardioplegia during CABG [10]. Citing the well-documented deleterious effects of hypothermic cardioplegia [11, 12] including, impairment of mitochondrial energy generation, substrate utilization, and membrane stabilization, Lichtenstein and coworkers [10] suggested that the heart be maintained at a temperature of 37°C throughout the cross-clamp period to enhance perioperative myocardial metabolic function. The metabolic needs of the heart, in turn, would be met using near continuous cardioplegic methods. In comparison to a historical cohort of 133 patients receiving hypothermic antegrade blood cardioplegia, patients in the warm group revealed a decreased incidence of perioperative myocardial infarction and intraaortic balloon pump requirement, despite cardioplegic interruptions approaching 15 minutes in duration. In 1994, Naylor and colleagues from Toronto reported the results of a prospective randomized trial involving nearly 2,000 CABG patients randomized to either normothermic or hypothermic cardioplegic techniques [13]. Although no differences in mortality or myocardial infarction were found between groups, patients in the normothermic group had a significantly lower incidence of postoperative low cardiac output syndrome.

Optimal delivery of antegrade normothermic cardioplegia

To determine the optimal composition and method of delivery of normothermic cardioplegia, we evaluated myocardial metabolism and ventricular function at varying cardioplegic flow rates and hemoglobin concentrations in patients undergoing coronary bypass surgery [14]. Flow rates of 80 mL/min or greater with a blood to crystalloid dilution of 4:1 (or a hemoglobin concentration of 80 g/L) facilitated aerobic metabolism during cardioplegic arrest, and enhanced myocardial performance and diastolic compliance postoperatively. Conversely, flow rates less than 80 mL/min with a blood to crystalloid dilution of 2:1 (or a hemoglobin concentration of 50 g/L) rendered hearts ischemic with the accumulation of an oxygen debt, a stimulation of anaerobic lactate production, and a corresponding impairment in myocardial performance (Fig 1). Thus, effective cardioprotection with normothermic cardioplegia required higher flow rates (80 mL/min or greater), and hemoglobin concentrations of at least 80 g/L.

View larger version (23K): [in this window] [in a new window]   Fig 1. Myocardial oxygen consumption (MVO2) and myocardial lactate consumption (MVL) after cross-clamp release. The MVO2 was higher in the low-flow, low hemoglobin (Hgb) group. Lactate production was not significantly different. (Reprinted with permission from Yau TM, Weisel RD, Mickle DAG, et al. Optimal delivery of blood cardioplegia. Circulation 1991;84(Suppl III):380–8.)

The use of normothermic cardioplegia necessitated the development of novel methods of cardioplegic delivery to enable near-continuous myocardial perfusion. The introduction of coronary sinus perfusion resulted in fewer cardioplegic interruptions, enabled distribution of cardioplegia to regions of myocardium supplied by occluded or stenosed vessels, improved subendocardial cardioplegic delivery, and allowed early perfusion of myocardial regions revascularized using pedicled arterial grafts [15, 16].

Although the concept of retrograde cardioplegia was quite simple, the proper use of this technique demanded sufficient surgical expertise to ensure proper catheter placement and the maintenance of acceptable perfusion pressures (40 mmHg) aimed at preventing perivascular hemorrhage and edema [17]. Moreover, the effectiveness of such a technique was limited by the shunting of blood directly into ventricular cavities via Thebesian channels and arterio-sinusoidal vessels [18]. In fact, our initial echocardiographic studies of sonicated albumin added to retrograde cardioplegia suggested multiple myocardial perfusion defects including, but not limited to the right ventricle and posterior septal regions [19, 20]. Despite such limitations, retrograde perfusion has been used successfully for CABG [21] as well as for valvular and other cardiac procedures [22].

Optimal delivery of retrograde normothermic cardioplegia

To determine the optimal flow rates for retrograde cardioplegia (which would possibly compensate for Thebesian and arterio-sinusoidal shunting) [18], we randomized 57 patients to receive 50, 75, or 100 mL/min of retrograde normothermic blood cardioplegia [23]. We determined that in order to minimize myocardial lactate production, retrograde normothermic cardioplegia required delivery at flows greater than 100 mL/min. Further studies would reveal that retrograde perfusion at 300 mL/min resulted in acceptable coronary sinus pressures nearing 40 mmHg [17]. To determine the effects of such higher flows, we studied 30 patients each of whom were randomly assigned to received flows of 100, 200, and 300 mL/min during cross-clamp. At cardioplegic flow rates of 200 mL/min or greater, lactate production was minimized and coronary venous pH was maintained within physiological limits. Further increases to 300 or 500 mL/min increased the shunt flow without increasing myocardial oxygen consumption or reducing anaerobic lactate production.

Continuous versus intermittent cardioplegia

Continuous delivery of blood cardioplegia at any temperature presents a significant impediment to visibility during construction of distal anastomoses. Thus, at our institution, as in other institutions, normothermic cardioplegia is not administered in a truly continuous fashion, but rather is interrupted to enable visualization. We have noted that the use of normothermic cardioplegia necessitates fewer interruptions when administered via the retrograde route. This finding is likely secondary to the shunting effect of retrograde perfusion [18] which results in less outflow via the coronary arteriotomy. The cost, however, may be relative underperfusion of the myocardium. Although in our hands, interruption of normothermic cardioplegia for up to 8 to 10 minutes has not resulted in detectable abnormalities in sensitive ischemic indices, in order to minimize any possible deleterious effects, we recommend the routine use of a "catch-up" infusion after each interruption [14]. The volume of this "catch-up" infusion is calculated by the perfusionist to compensate precisely for the period of flow cessation, while maintaining the preset average cardioplegic flow rate. This infusion effectively removes harmful metabolites while restoring the normal myocardial extracellular pH and ionic environment.

Antegrade versus retrograde normothermic cardioplegia

In order to determine which cardioplegic method was most protective, a prospective trial was undertaken at our institution whereby 74 patients undergoing isolated elective coronary bypass surgery were randomized to receive either warm antegrade, warm retrograde, or intermittent cold antegrade blood cardioplegia (the latter administered with a terminal "hot-shot" infusion). Three patients suffered postoperative low-output syndrome, all of whom were in the cold group. Postoperative creatine kinase MB isoenzyme release was greatest in patients receiving intermittent cold or retrograde normothermic cardioplegia. The metabolic abnormalities observed after intermittent cold or retrograde normothermic cardioplegia suggested that myocardial energy production was diminished in those groups due to hypothermia and ischemia, respectively. Nonetheless, retrograde normothermic cardioplegia, in addition to improving technical feasibility, has been shown to be effective for procedures including coronary reoperations and valvular surgery despite increased levels of myocardial lactate production [24].

Combination of antegrade and retrograde cardioplegia

To overcome the inherent limitations of both antegrade and retrograde cardioplegic techniques, a combined antegrade and retrograde approach was proposed at our institution in 1994. Among 75 patients undergoing primary isolated coronary bypass surgery, those receiving continuous retrograde along with intermittent antegrade normothermic cardioplegia revealed a reduction in myocardial lactate production, a preservation of ATP and an improvement in functional recovery, suggesting improved perfusion in comparison to antegrade or retrograde techniques alone [20, 24].

Optimal cardioplegic temperature

Due to the detrimental effects of both cold and warm cardioplegia, we investigated the use of tepid (29°C) blood cardioplegia delivered in either an antegrade or retrograde fashion. This was compared to warm (37°C) or cold (9°C) cardioplegic techniques in 72 patients undergoing isolated CABG [25]. Myocardial oxygen consumption and anaerobic lactate release were greatest during warm, intermediate during tepid, and least during cold cardioplegic arrest. Left ventricular stroke work indices were greater after warm antegrade and tepid antegrade cardioplegia in comparison to cold antegrade cardioplegia, and right ventricular stroke work indices were greatest after warm antegrade cardioplegia. Thus, both warm and tepid techniques were viable. However, unlike the situation with warm cardioplegia, tepid antegrade cardioplegia offered additional protection during cardioplegic interruptions. Moreover, by preventing cold-related injury, myocardial functional recovery with tepid techniques was immediate. Similar advantages were documented by Hayashida and colleagues [26] who applied tepid temperatures for combination antegrade and retrograde cardioplegia in 42 patients undergoing elective CABG (Fig 2).

View larger version (17K): [in this window] [in a new window]   Fig 2. Relation between left ventricular stroke work index (LVSWI) and pulmonary capillary wedge pressure (PCWP) before cardiopulmonary bypass (PRE), as well as 1 hour (1 HR) and 4 hours (4 HRS) after cardiopulmonary bypass is depicted. Tepid perfusion resulted in greater LVSWI versus cold or warm at 1 hour following cardiopulmonary bypass, and versus cold at 4 hours following cardiopulmonary bypass despite similar filling pressures (PCWP). (Reprinted with permission of the Society of Thoracic Surgeons, from Hayashida N, Weisel RD, Shirai T, et al. Tepid antegrade and retrograde cardioplegia. Ann Thorac Surg 1995;59:723–9.)

After determining that tepid temperatures improved protection during cardioplegic arrest, we used tepid cardioplegia to evaluate two different techniques of combination antegrade–retrograde cardioplegia. Sixty patients undergoing isolated CABG were randomized to receive near continuous tepid retrograde cardioplegia in combination with either intermittent antegrade cardioplegia via the aortic root (alternate technique) or antegrade cardioplegia delivered concurrently through each completed vein graft (simultaneous technique) [27]. Myocardial lactate extraction following cross-clamp release was found to be greater in the simultaneous group compared to the alternate group (Fig 3). Postoperative ventricular function, however, was shown to be improved in the alternate group (Fig 4). Although both techniques of cardioplegic delivery permitted rapid postoperative recovery of myocardial metabolism and function, simultaneous delivery was simple to apply and did not require aortic root de-airing between antegrade infusions.

View larger version (27K): [in this window] [in a new window]   Fig 3. Myocardial metabolism during reperfusion: myocardial oxygen extraction, lactate extraction, and acid release before aortic cross-clamping, immediately, 5, and 10 minutes after cross-clamp (XCL) removal, and 5 and 10 minutes after discontinuation of cardiopulmonary bypass (CPB). Lactate extraction recovered more quickly in the simultaneous group than in the alternate group (p = 0.03 by ANOVA), and lactate extraction was greater 10 minutes on CPB and 10 minutes after CPB. No differences in oxygen extraction or acid release were detected between groups. (Reprinted with permission from Shirai T, Rao V, Weisel RD, et al. Antegrade and retrograde cardioplegia: alternate or simultaneous? J Thorac Cardiovasc Surg 1996;112:787–96.)

View larger version (22K): [in this window] [in a new window]   Fig 4. Postoperative cardiac function. The relation between left ventricular stroke work index or cardiac index and pulmonary capillary wedge pressure (PCWP) is depicted. Left ventricular stroke work index decreased in both groups postoperatively (time p < 0.0001). The decrease was greater in the simultaneous group than the alternate group (p = 0.04 by analysis of covariance). Stroke work index was lower in the simultaneous group 4 hours after the operation at a higher wedge pressure. Cardiac index increased (time p = 0.017) similarly in both groups after the operation. (Reprinted with permission from Shirai T, Rao V, Weisel RD, et al. Antegrade and retrograde cardioplegia: alternate or simultaneous? J Thorac Cardiovasc Surg 1996;112:787–96.)

Optimal flow rates for integrated myocardial protection

To determine the optimal flow rate for simultaneous tepid cardioplegia we performed a prospective randomized trial where 20 patients undergoing elective CABG were randomized to receive either high (200 mL/min) or low (100 mL/min) flow cardioplegic delivery [28]. Tepid retrograde cardioplegia resulted in an accumulation of lactate and hydrogen ions during construction of the first two bypass grafts. The addition of antegrade vein graft infusions at a flow rate of 100 mL/min resulted in a washout of these accumulated metabolites. A flow rate of 200 mL/min further improved the washout of metabolic end-products.

Future perspectives in myocardial protection

To date, strategies aimed at minimizing the risks associated with coronary bypass surgery have almost exclusively involved manipulation of ischemic and reperfusion conditions. As a result, low-risk patients presenting for coronary bypass surgery face extremely low risks for morbidity and mortality. Unfortunately, despite such advances, current cardioplegic techniques have proven suboptimal in high-risk patients. Thus, future directions in cardioplegic management will likely involve the use of cardioplegic additives to further improve protective effects.

Myocardial preconditioning
Ischemic preconditioning is by far the most powerful endogenously mediated form of myocardial protection known and may account for the heart’s inherent ability to tolerate brief episodes of cardioplegic interruption during CABG [29]. Adenosine, believed to be a mediator of ischemic preconditioning, may enable pharmacologic preconditioning without the need for an ischemic stimulus [30]. Indeed, recent studies have suggested a possible role for adenosine in clinical preconditioning. Lee and colleagues administered intravenous adenosine to patients undergoing elective CABG immediately prior to the initiation of cardiopulmonary bypass [31]. Patients receiving adenosine pretreatment revealed improved cardiac indices and a reduction in postoperative creatine kinase MB isoenzyme release in comparison to non-randomized controls. Pilot studies from our institution have shown evidence of metabolic benefit with adenosine precross-clamp and cardioplegic treatments [32]. Patients treated with both high and low adenosine doses demonstrated a preservation of myocardial ATP stores in comparison to controls where ATP levels fell by 15% following cardioplegic arrest.

Insulin cardioplegia
Persistent lactate production following aortic cross-clamp release suggests a delay in the recovery of aerobic metabolism and has been shown to predict postoperative ventricular dysfunction [33]. By stimulating the rate limiting enzyme pyruvate dehydrogenase (PDH), insulin may facilitate the conversion from anaerobic to aerobic metabolism thus improving the results of CABG. We performed a preliminary prospective, double-blind trial where 48 patients undergoing isolated CABG were randomized to receive simultaneous antegrade and retrograde tepid blood cardioplegia enhanced with either insulin (10 IU/L) or placebo [34]. Although cardioplegic arrest induced anaerobic lactate release in both groups, following cross-clamp removal, patients in the insulin group immediately converted to aerobic lactate extraction compared to persistent lactate release in the placebo group. Moreover, left ventricular stroke work index at similar filling pressures 2 hours postoperatively was significantly elevated in the insulin group (Fig 5). We are currently undertaking a multicenter prospective randomized trial designed to determine the benefits of insulin cardioplegia in patients undergoing urgent CABG.

View larger version (22K): [in this window] [in a new window]   Fig 5. (Upper Panel) Myocardial lactate flux during and after cardioplegic arrest. Patients who received insulin enhanced cardioplegia displayed lactate extraction immediately after cross-clamp removal compared to persistent lactate release in the placebo group. (Lower Panel) Left ventricular function at similar filling pressures was better preserved in the insulin cardioplegia group after 2 hours of reperfusion. (LVEDP = left ventricular end diastolic pressure.)

Conclusions

Current techniques of intraoperative myocardial protection are constantly evolving. Despite long-held beliefs, traditional methods of cardioplegia are being abandoned in favor of less conventional modalities. To date, changes in cardioplegic composition, temperature, and delivery have been successful in optimizing intraoperative myocardial protection. As such, stable patients presenting for elective coronary bypass surgery face a relatively low risk of perioperative morbidity and mortality. Since the results of contemporary coronary bypass surgery in low-risk patients are excellent, such patients likely have little to gain from additional intraoperative protective measures. Thus, if any future benefit of cardioplegic supplementation is to be found, it will likely be observed in high-risk patients with poor ventricular function, for whom current protective techniques are inadequate.

Acknowledgments

Gideon Cohen, Michael A. Borger, and Vivek Rao are Fellows of the Heart and Stroke Foundation of Canada. Richard D. Weisel is a Career Investigator of the Heart and Stroke Foundation of Canada.

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