Gérard Bloch

Hypothermia During Cardiopulmonary Bypass Delays but Does Not Prevent Neutrophil– Endothelial Cell Adhesion A Clinical Study

BACKGROUND An accurate evaluation of warm heart surgery cannot be limited to the assessment of the myocardial effects of warm blood cardioplegia but should also address the effects of systemic normothermia on the inflammatory response to cardiopulmonary bypass. A major component of this response is the endothelial adhesion of neutrophils, because it is linked to the release of cytotoxic compounds. This study was designed (1) to characterize the bypass-induced changes in the expression of neutrophil adhesion molecules (L-selectin and beta 2-integrins) and (2) to assess the influence of bypass temperature on these changes. METHODS AND RESULTS Twenty case-matched patients undergoing open-heart procedures were divided into two equal groups according to the core temperature during cardiopulmonary bypass: warm (33.4 +/- 0.3 degrees C) or cold (27.1 +/- 0.4 degrees C, P < .0001 versus warm). Arterial blood samples were collected before, during, and 30 minutes after bypass and processed for the expression of L-selectin and beta 2-integrins (CD11a, CD11b, and CD11c) with flow cytometry. Warm bypass was associated with an early and sustained upregulation of CD11b. In contrast, hypothermia resulted in a strikingly less pronounced CD11b upregulation during bypass. However, CD11b expression sharply increased thereafter so that 30 minutes after bypass, it was no longer significantly different between the two groups. Changes in CD11c expression grossly paralleled those described for CD11b. Neither CD11a nor L-selectin changed significantly from baseline values in either group. CONCLUSIONS Clinical cardiopulmonary bypass is associated with a marked upregulation of the neutrophil CD11b and CD11c integrins. Hypothermia delays but does not prevent the increased expression of these adhesion molecules, which could consequently represent logical targets for interventions designed to blunt the neutrophil-mediated component of bypass-induced inflammatory tissue damage.

Preconditioning with potassium channel openers: ☆ ☆☆ ★ ★★ ♢: A new concept for enhancing cardioplegic protection?

Ischemic preconditioning defines an adaptive endogenous mechanism in which a brief episode of reversible ischemia renders the heart more resistant to a subsequent period of sustained ischemia. Because the cardioprotective effects of ischemic preconditioning might be mediated by an activation of adenosine triphosphate-sensitive potassium channels, this study was designed to assess whether these effects could be duplicated by the preischemic administration of a potassium channel opener. Fifty isolated isovolumic buffer-perfused rat hearts underwent 45 minutes of normothermic potassium arrest followed by 1 hour of reperfusion. They were divided into five equal groups that differed with regard to the preconditioning regimen: Group 1 hearts were left untreated and served a controls; in group 2, preconditioning was achieved with 5 minutes of total global ischemia followed by 5 minutes of buffer reperfusion before cardioplegic arrest; in group 3, the preconditioning stimulus consisted of a 5-minute infusion of the potassium channel opener nicorandil (10 mumol/L) followed by 5 minutes of drug-free buffer perfusion before arrest; group 4 hearts underwent a similar protocol except that the infusion of nicorandil was preceded by that of the potassium channel blocker glibenclamide (10 mumol/L); group 5 hearts were ischemically preconditioned like those of group 2 except that the no-flow preconditioning period was also preceded by a 5-minute infusion of glibenclamide (50 mumol/L). The results demonstrate that ischemic preconditioning significantly improved contractility and reduced contracture during reperfusion, as compared with results in control hearts. These protective effects were duplicated by pretreatment with nicorandil but were abolished when the drug was antagonized by a prior infusion of glibenclamide. Likewise, the glibenclamide-induced blockade of potassium channels largely blunted the beneficial effects of ischemic preconditioning. These data suggest that opening of adenosine triphosphate-sensitive potassium channels substantially contributes to preconditioning-induced cardiac protection in a surgically relevant model of global ischemia and, consequently, that the use of potassium channel openers like nicorandil could be an effective means of enhancing cardioplegic protection.

Retrograde warm blood cardioplegia preserves hypertrophied myocardium: A clinical study☆

The ability of retrograde warm blood cardioplegia to preserve hypertrophied myocardium remains controversial. This two-part study was undertaken to address this question in patients subjected to aortic valve replacement for calcified aortic valve stenosis complicated with echocardiographically defined left ventricular hypertrophy. Part 1 was designed to assess the intraoperative patterns of myocardial oxidative metabolism in 20 patients in whom the severity of left ventricular hypertrophy was reflected by a mean (+/- standard error of the mean) myocardial mass index of 213 +/- 15 g/m2. After antegrade arrest, warm blood cardioplegia was continuously given through the coronary sinus at a flow rate of 200 +/- 5 mL/min. The use of a low-dilution cardioplegia delivery technique enabled us to keep hematocrit at 25.6% +/- 0.9% and the core temperature was allowed to drift to 32.7 +/- 0.2 degrees C. At the end of the arrest period, blood samples were simultaneously taken from inflow (coronary sinus catheter) and outflow (left coronary ostium) cardioplegia and assayed for blood gases, oxygen content and saturation and lactate. Part II was designed to compare the clinical outcomes of these 20 warm patients with those of 20 case-matched patients in whom a conventional hypothermic myocardial protection technique was used. The results of part I show that after an average arrest period of 72 +/- 4 minutes, the residual oxygen demand was still high as reflected by a percent oxygen extraction of 34.8% +/- 4.1%. This demand, however, was adequately met by the supply, as demonstrated by (1) the absence of transmyocardial acid production, (2) a negligible release (outflow minus inflow) of lactate (0.28 +/- 0.1 mmol/L), and (3) a high residual oxygen saturation (65.7% +/- 3.8%) in outflow cardioplegia. The results of part II show that the clinical outcomes of warm patients were overall good and not different from those of the cold group. We conclude that retrograde warm blood cardioplegia can adequately preserve hypertrophied myocardium by keeping its metabolism predominantly aerobic during aortic cross-clamping provided that measures are taken to optimize the determinants of the oxygen demand/supply ratio throughout. These measures include avoidance of left ventricular distention, immediate ablation of any recurring activity during arrest, maintenance of high retrograde flow rates, limitation of hemodilution, and uninterrupted mode of cardioplegia delivery.

Simplified method for delivering normothermic blood cardioplegia

We describe a simple technique for optimizing oxygen delivery during normothermic continuous blood cardioplegia. It involves the use of a minimal volume of cardioplegic agents, the infusion rate of which is adjusted so as to keep the heart arrested. The resulting enhancement of oxygen supply is marshalled from the maintenance of hematocrit values in the range of 0.25.

Normothermic cardioplegia: Is aortic cross-clamping still synonymous with myocardial ischemia?

The enthusiastic clinical reports on normothermic blood cardioplegia contrast with the paucity of data on the myocardial metabolic effects of this technique. The present study was therefore designed to assess whether normothermic blood cardioplegia really provides an aerobic environment during aortic cross-clamping. Thirty-one patients undergoing coronary (16 patients), valve (13 patients), and transplantation (2 patients) procedures were given continuous normothermic blood cardioplegia through the coronary sinus. Myocardial metabolism was assessed either immediately before aortic unclamping (16 patients) by collecting blood simultaneously from the cardioplegia infusion line and the aortic effluent or during reperfusion (15 patients) by collecting blood simultaneously from the radial artery and the coronary sinus. All samples were assayed for markers of anaerobiosis (blood gases, lactates), leukocyte activation (elastase), and lipid peroxidation (malondialdehyde, vitamin E). At the end of arrest, oxygen extraction was low, whereas the production of lactates was small, thereby suggesting the efficacy of normothermic blood cardioplegia in maintaining a predominantly aerobic metabolism. This was confirmed by postarrest data, as oxygen extraction measured immediately after cross-clamp removal was unchanged from prearrest values, whereas lactate metabolism yielded transient and limited production followed by prompt recovery of normal extraction patterns. There was no release of elastase from the myocardium, which suggests adequate protection of the coronary endothelium from ischemic injury and the related increase in leukocyte activation. Likewise, postarrest coronary sinus concentrations of malondialdehyde and vitamin E were identical to the respective arterial concentrations, thereby ruling out the occurrence of intramyocardial lipid peroxidation at the time of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Pretreatment with captopril improves myocardial recovery after cardioplegic arrest.

Summary: Among the interventions designed to limit postischemic oxidative injury, those that enhance the myocardial content of thiol groups are attractive because thiols are powerful antioxidants. Indeed, part of the protection afforded by the angiotensin-converting enzyme (ACE) inhibitor captopril in regional myocardial ischemia is attributed to its thiol group. This study assesses the effects of captopril in a surgically relevant model of global ischemic arrest. Thirty rats were implanted subcutaneously (s.c.) with osmotic pumps that allowed continuous delivery of captopril (total dose 75 mg), enalapril (a nonthiol-containing ACE inhibitor, total dose 7.5 mg) or saline in 48 h. Drug concentrations were equipotent in their effect on angiotensin I (ANGI) pressor response. Hearts were then excised, perfused under isovolumic conditions, and subjected to 90-min cardioplegic arrest at 30°C followed by 1-h reperfusion. Pre- and postischemic coronary flows were significantly higher to a similar extent in the two drug-pretreated groups than in controls. However, captopril-pretreated hearts had the best recovery of contractility (dP/dtmax: 3,590 ± 74 versus 2915 ± 64 mm Hg s−1 in the enalapril group, p < 0.001), and diastolic pressures (13.7 ± 0.9 mm Hg vs. 20.0 ± 1.6 mm Hg in the enalapril group, p < 0.05). We conclude that pretreatment with ACE inhibitors improves myocardial recovery after cardioplegic arrest and that captopril is more effective than enalapril. The additional protection afforded by captopril was not flow mediated, suggesting that the cardioprotective effects of this drug not only involve an ACE inhibition-dependent coronary vasodilation but could be related to a thiol-dependent limitation of oxidative injury.