Canine Model Of Cardiopulmonary Bypass Research Articles

Levosimendan Reduces Lung Injury in a Canine Model of Cardiopulmonary Bypass.

Background and ObjectivesTo explore the lung-protective effect of levosimendan (LS) during cardiopulmonary bypass in a canine model by determining the wet/dry weight (W/D) ratio of lung tissue, malonaldehyde (MDA) and superoxide dismutase (SOD) concentrations, and performing a histological evaluation.Materials and MethodsThirty-two canines were divided randomly into four groups and underwent a routine aortic cross-clamping cardiopulmonary bypass procedure for 1 h, followed by recovery for 2 h. Animals were handled as follows: group C (means control group), no special treatment after aortic cross clamping; group P (means pulmonary artery perfusion group), pulmonary artery perfusion with cold oxygenated blood after aortic cross clamping; group LSIV (means intravenous injection of LS group), intravenous injection of LS (65 µg/kg) before thoracotomy, and the rest of the procedure was identical to the control group; group LPS (means pulmonary perfusion with LS group), pulmonary perfusion with cold oxygenated blood combined with LS (65 µg/kg) after aortic cross clamping. Lung tissues were removed and subjected to evaluation of pathological alterations, W/D ratio and MDA and SOD concentrations.ResultsIn group C, the W/D ratio and MDA concentration were higher, while the SOD concentrations were lower (p<0.05). Compared with groups P and LSIV, the MDA concentration was lower in group LPS, while that of SOD was higher (p<0.05); Light and electron microscopy indicated that LS intervention reduced impairment of lung tissues.ConclusionOur findings suggest that LS plays an important role in protecting lung tissues.

Receptor for Advanced Glycation End Products Involved in Lung Ischemia Reperfusion Injury in Cardiopulmonary Bypass Attenuated by Controlled Oxygen Reperfusion in a Canine Model

Controlled oxygen reperfusion could protect the lung against ischemia-reperfusion injury in cardiopulmonary bypass (CPB) by downregulating high mobility group box 1 (HMGB1), a high affinity receptor of HMGB1. This study investigated the effect of controlled oxygen reperfusion on receptor for advanced glycation end products (RAGE) expression and its downstream effects on lung ischemia-reperfusion injury. Fourteen canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest followed by 90 minutes of reperfusion. Animals were randomized to receive 80% FiO2 during the entire procedure (control group) or to a test group receiving a controlled oxygen reperfusion protocol. Pathologic changes in lung tissues, RAGE expression, serum interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated. The lung pathologic scores after 25 and 90 minutes of reperfusion were significantly lower in the test group compared with the control group (p < 0.001). RAGE expression, TNF-α, and IL-6 were downregulated by controlled oxygen treatment (p < 0.001). RAGE might be involved in the lung ischemia-reperfusion injury in canine model of CPB, which was downregulated by controlled oxygen reperfusion.

Controlled oxygen reperfusion protects the lung against early ischemia-reperfusion injury in cardiopulmonary bypasses by downregulating high mobility group box 1

ABSTRACTRestricting oxygen delivery during the reperfusion phase of cardiopulmonary bypass (CPB) protects the heart, but effects on lung ischemia reperfusion (IR) in CPB are unknown. We examined whether extracellular high mobility group box 1 (HMGB1) mediated inflammation during early lung IR injury in CPB. Fourteen healthy canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest, followed by 90 minutes reperfusion. Following surgery, the animals were randomized into control (n = 7) or test (n = 7) groups. Control animals received a constant level of 80% FiO2 during the entire procedure, and the test group received a gradual increase in FiO2 during the first 25 minutes of reperfusion. In the test group, the FiO2 was initiated at 40% and increased by 10% every 5 minutes, to 80%. Histology, lung injury variables, HMGB1 expression, and inflammatory responses were assessed at baseline (T1) and at 25 minutes (T2) and 90 minutes (T3) after starting reperfusion. Treatment with controlled oxygen significantly suppressed lung pathologies, lung injury variables, and inflammatory responses (all P < .001). After lung IR injury, HMGB1 mRNA and protein expressions were significantly decreased in the controlled oxygen group (all P < .001). Controlled oxygen reperfusion is protective in the early stages of lung IR injury in a canine CPB model, and this protection is linked to HMGB1 downregulation.

Cardioprotective effects of hydrogen sulfide

The gaseous mediator hydrogen sulfide (H 2S) is synthesized mainly by cystathionine γ-lyase in the heart and plays a role in the regulation of cardiovascular homeostasis. Here we first overview the state of the art in the literature on the cardioprotective effects of H 2S in various models of cardiac injury. Subsequently, we present original data showing the beneficial effects of parenteral administration of a donor of H 2S on myocardial and endothelial function during reperfusion in a canine experimental model of cardiopulmonary bypass. Overview of the literature demonstrates that various formulations of H 2S exert cardioprotective effects in cultured cells, isolated hearts and various rodent and large animal models of regional or global myocardial ischemia and heart failure. In addition, the production of H 2S plays a role in myocardial pre- and post-conditioning responses. The pathways implicated in the cardioprotective action of H 2S are multiple and involve K ATP channels, regulation of mitochondrial respiration, and regulation of cytoprotective genes such as Nrf-2. In the experimental part of the current article, we demonstrate the cardioprotective effects of H 2S in a canine model of cardiopulmonary bypass surgery. Anesthetized dogs were subjected hypothermic cardiopulmonary bypass with 60 min of hypothermic cardiac arrest in the presence of either saline (control, n = 8), or H 2S infusion (1 mg/kg/h for 2 h). Left ventricular hemodynamic variables (via combined pressure—volume-conductance catheter) as well as coronary blood flow, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside were measured at baseline and after 60 min of reperfusion. Ex vivo vascular function and high-energy phosphate contents were also measured. H 2S led to a significantly better recovery of preload recruitable stroke work ( p < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the H 2S group ( p < 0.05). While the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the H 2S-treated group ( p < 0.05) both in vivo and ex vivo. Furthermore, high-energy phosphate contents were better preserved in the H 2S group. Additionally, the cytoprotective effects of H 2S were confirmed also using in vitro cell culture experiments in H9c2 cardiac myocytes exposed to hypoxia and reoxygenation or to the cytotoxic oxidant hydrogen peroxide. Thus, therapeutic administration of H 2S exerts cardioprotective effects in a variety of experimental models, including a significant improvement of the recovery of myocardial and endothelial function in a canine model of cardiopulmonary bypass with hypothermic cardiac arrest.

Effect of recombinant aprotinin on postoperative blood loss and coronary vascular function in a canine model of cardiopulmonary bypass

Aprotinin is a widely used serine protease inhibitor during cardiopulmonary bypass to reduce blood loss and preserve platelet function. However, the bovine-derived aprotinin can induce hypersensitivity reaction with fatal complications. Furthermore, vascular effects of aprotinin are not completely elucidated. The current study is designed to investigate the effects of recently developed recombinant aprotinin on blood loss and coronary vascular function in a clinically relevant canine model of cardiopulmonary bypass without aortic cross-clamping and cardioplegia. Twenty-four dogs underwent cardiopulmonary bypass without aortic cross-clamping and cardioplegia. Dogs were divided into three groups in a blinded fashion: control animals (n=8) received placebo, aprotinin treatment groups received bovine (n=8) or recombinant aprotinin (n=8) according to the Hammersmith method. The doses of bovine and recombinant aprotinin were the same. Coagulation parameters and blood loss were measured regularly at different time points. Endothelium-dependent and -independent vasorelaxation were investigated in isolated left anterior descendent coronary arterial rings by using acetylcholine and bradykinin or sodium nitroprusside and adenosine, respectively. Postoperative blood loss was significantly reduced in the aprotinin-treated groups in comparison to control and there was no significant difference between the two aprotinin-treated groups. Endothelium-dependent relaxation of coronary arteries to acetylcholine and bradykinin was unaffected in the aprotinin treatment groups. Both types of aprotinin significantly increased vasorelaxation to adenosine when compared with controls, but did not affect that to sodium nitroprusside. The effectiveness of recombinant aprotinin on blood loss was equivalent to bovine-derived aprotinin. Neither types of aprotinin impaired endothelium-dependent relaxation in a canine model of cardiopulmonary bypass.

Infusion of sodium sulfide improves myocardial and endothelial function in a canine model of cardiopulmonary bypass

Hydrogen sulfide is produced endogenously by a variety of enzymes involved in cysteine metabolism. Clinical data indicate that endogenous levels of hydrogen sulfide are diminished in various forms of cardiovascular diseases. The aim of the current study was to investigate the effects of hydrogen sulfide supplementation on cardiac function during reperfusion in a clinically relevant experimental model of cardiopulmonary bypass. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or the sodium sulfide infusion (1 mg/kg/hour, n = 6). Biventricular hemodynamic variables were measured by combined pressure–volume–conductance catheters. Coronary and pulmonary blood flow, vasodilator responses to acetylcholine and sodiumnitroprusside and pulmonary function were also determined. Administration of sodium sulfide led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 minutes of reperfusion. Coronary blood flow was also significantly higher in the sodium sulfide-treated group (P < 0.05). Sodium sulfide treatment improved coronary blood flow, and preserved the acetylcholine-induced increases in coronary and pulmonary blood (P < 0.05). Myocardial ATP levels were markedly improved in the sulfide-treated group. Thus, supplementation of sulfide improves the recovery of myocardial and endothelial function and energetic status after hypothermic cardiac arrest during cardiopulmonary bypass. These beneficial effects occurred without any detectable adverse hemodynamic or cardiovascular effects of sulfide at the dose used in the current study.

Effect of INS50589, a Reversible ADP-Receptor Antagonist, on Platelet Function and Blood Loss in a Canine Model of Cardiopulmonary Bypass.

Open-heart surgery performed with cardiopulmonary extracorporeal bypass (CPB) of anticoagulated blood often is complicated by excessive postoperative hemorrhage due to an acquired platelet function defect and thrombocytopenia inherent to the procedure. One strategy for reducing excessive blood loss is to protect the platelets pharmacologically from activation and damage during the surgical procedure and the CPB, but most inhibitors of platelet activation used in this way would exacerbate bleeding because of the duration of their effect. INS50589 is a competitive and selective P2Y12 receptor antagonist in development by Inspire Pharmaceuticals Inc. Previous studies in normal dogs indicate that 20μM ADP induced ex vivo whole blood platelet aggregation is completely inhibited by the administration of INS50589 and that the effect is quickly reversed upon discontinuation of the administration. This drug is now being tested for efficacy and safety in a canine model of CPB established at East Carolina University. Subjects in the range of 20–30 kg are prepared by sternotomy for extracorporeal recirculation of blood after systemic heparinization. CPB occurs for ninety minutes, followed by weaning from the pump and maintenance for a four hour postoperative period. INS50589 was administered by continuous infusion at a rate of 17 mg/kg/min at initiation of sternotomy and throughout CPB until weaned. Special testing in all subjects includes ex vivo whole blood aggregometry with two doses of ADP, thromboelastography with the TEG® ADP Mapping kit, bleeding times using a 23 gauge puncture of the exposed jugular vein, and measurements of blood loss from the surgical fields. In the placebo treated group, there was a significant loss of platelet response to ADP during CPB that remained in the post-op period at approx 50% of initial values; in contrast, the drug-treated subjects show post-op recovery of ADP response to within 90% of initial values (p<0.01). The vessel bleeding time (VBT) within both groups was greatly prolonged during CPB. Preliminary analysis suggests that in the post-operative period the VBT returned to baseline values after the infusion was discontinued; however, the return was faster in the INS50589 -treated animals when compared with the placebo group. The volume of post-operative blood loss was variable but appears to be less in the drug-treatment group versus placebo controls. When adjusted on the basis of red cell mass in the shed blood per body weight the difference was significant (4.78±1.99e10 vs. 10.1±2.91e10 red blood cells/kg), p <0.05. Other preliminary findings in the treatment group included a lesser CPB-related decrease in platelet count, a higher average hematocrit, higher post-op fibrinogen concentration, and a more stable post-op course. These preliminary findings suggest that INS50589 should be effective in protecting platelet function and reducing blood loss in human patients undergoing open-heart surgery.

Role of poly(ADP-ribose) polymerase activation in the pathogenesis of cardiopulmonary dysfunction in a canine model of cardiopulmonary bypass.

To investigate the effects of PARP inhibition on cardiac and pulmonary function during reperfusion in a clinically relevant experimental model of cardiopulmonary bypass. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or the potent PARP-inhibitor PJ34 (5 mg/kg; n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow, vasodilator responses to acetylcholine and sodium-nitroprusside and pulmonary function were also determined. The cardiac and pulmonary activation of PARP was detected by poly(ADP-ribose) immunohistochemistry. Administration of PJ34 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the PJ34 treated group (P < 0.05) PJ34 treatment preserved the acetylcholine-induced increases in coronary and pulmonary blood (P < 0.05) Pulmonary function in terms of alveolar arterial oxygen difference was better maintained in the PJ34 treated animals (P < 0.05). Immunohistochemical staining revealed PARP activation after cardiopulmonary bypass in both the heart and lung, which was prevented by PJ34. PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and protects against the development of remote pulmonary injury during cardiopulmonary bypass.

Poly-ADP-ribose syhthase inhibition reduces mesenteric injury after cardiopulmonary bypass

Objectives: Mesenteric dysfunction is a rare but severe complication after cardiac surgery, which may be related to free radical production and subsequent activation of poly-ADP-ribose synthase (PARS). We investigated the effects of PARS-inhibition on intestinal injury in a canine model of cardiopulmonary bypass (CPB).

Poly-ADP-Ribose Polymerase Inhibition Reduces Mesenteric Injury after Cardiopulmonary Bypass

We investigated the effects of PARS inhibition on intestinal injury in a canine model of cardiopulmonary bypass (CPB). Twelve dogs underwent 90 minutes of hypothermic CPB. 6 dogs received 5 mg/kg PJ34, a selective PARP inhibitor during CPB, 6 vehicle-treated animals served as controls. Mesenteric blood flow (MBF) and mesenteric vascular resistance (MVR) were measured before and 60 minutes after weaning from CPB. Endothelium-dependent vasorelaxation to acetylcholine (ACH) and endothelium-independent vasorelaxation to sodium-nitroprusside (SNP) were expressed as percent change of MVR. In addition, mesenteric creatine kinase (CK) and lactate release were determined. Baseline hemodynamics, MBF, response to ACH (- 41 +/- 3 vs. - 55 +/- 6 %) and SNP (- 60 +/- 2 vs. - 56 +/- 4 %) did not differ significantly between the groups. The response to ACH decreased significantly in the control group while it remained unchanged in the PJ34 group (- 29 +/- 5 vs. - 46 +/- 9 %, p < 0.05). The response to SNP did not change. Mesenteric CK release (325 +/- 99 vs. 16 +/- 10 U/l, p < 0.05) and lactate production (0.96 +/- 0.17 vs. 0.4 +/- 0.2 mmol/l, p < 0.05) were significantly lower in the PJ34 group. PARP inhibition prevents CPB-induced mesenteric endothelial dysfunction and tissue damage.

Increased matrix metalloproteinase activity after canine cardiopulmonary bypass is suppressed by a nitric oxide scavenger

Objectives: We tested whether nitric oxide scavenging with a ruthenium-based compound (AMD6221) would improve hemodynamics and alter nitric oxide synthase and matrix metalloproteinase activities in a canine model of cardiopulmonary bypass. Methods: Dogs were randomized to either cardiopulmonary bypass (n = 12) or control (n = 12) groups. They were further randomized to receive a continuous infusion of AMD6221 or placebo. Cardiopulmonary bypass was maintained for 90 minutes, and then, 4 hours later, dogs were killed. Cardiac, lung, and brain sections were snap frozen in liquid nitrogen for determination of nitric oxide synthase, matrix metalloproteinase 2, and matrix metalloproteinase 9 activities. Results: After cardiopulmonary bypass, 3 of 6 placebo-treated (cardiopulmonary bypass-placebo) and 0 of 6 AMD6221-treated (cardiopulmonary bypass-6221) animals required phenylephrine infusion to maintain a predetermined blood pressure (P <.05). Total fluid administration was lower in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (983 ± 134 vs 1617 ± 254 mL, respectively; P <.005). After cardiopulmonary bypass, matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in the lung, left ventricle, and left atrium were decreased in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (P <.05). Ca2+-independent nitric oxide synthase activity and matrix metalloproteinase 2 activity in the brain were also lower (P <.05) in the cardiopulmonary bypass-SCV group. Finally, neutrophil expression of CD18, an adhesion complex, was lower at 4 hours after cardiopulmonary bypass in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (38 ± 27 vs 81 ± 11; P <.05). Conclusions: We found that (1) infusion of an nitric oxide scavenger, AMD6221, was associated with improved predefined hemodynamics; (2) cardiopulmonary bypass increased activities of Ca2+-independent nitric oxide synthase and matrix metalloproteinases in multiple organs; and (3) AMD6221 could ameliorate the increased generation of nitric oxide and increased matrix metalloproteinase activities.J Thorac Cardiovasc Surg 2003;125:661-8

Myocardial protection using diadenosine tetraphosphate with pharmacological preconditioning

Background. We have reported a similar cardioprotective effect and mechanism of diadenosine tetraphosphate (AP4A) and ischemic preconditioning in rat hearts. In this study, the applicability of AP4A administration to cardiac surgery was tested by using a canine cardiopulmonary bypass model. Methods. Hearts underwent 60 minutes of cardioplegic arrest (34°C) by a single dose of cardioplegia. Cardioplegia contained either AP4A (40 μmol/L; n = 6) or saline (n = 6). Beagles were weaned from cardiopulmonary bypass 30 minutes after reperfusion, and left ventricular function was evaluated after another 30 minutes by using the cardiac loop analysis system. Results. Administration of AP4A significantly improved the postischemic recovery of cardiac function and reduced the leakage of serum creatine kinase compared with saline. Systemic vascular resistance, mean aortic blood pressure, and the electrocardiographic indices were not significantly altered by AP4A administration. Conclusions. Administration of AP4A was cardioprotective without apparent adverse effects. Because the cardioprotective mechanism may be similar to that of ischemic preconditioning, the addition of AP4A into cardioplegia may be a novel safe method for clinical application of preconditioning cardioprotection.

438 Efficacy of aprotinin with various anticoagulatns in a canine model of cardiopulmonary bypass

438 Efficacy of aprotinin with various anticoagulatns in a canine model of cardiopulmonary bypass

The effects of normothermic and hypothermic cardiopulmonary bypass on defibrillation energy requirements and transmyocardial impedance: Implications for implantable cardioverter-defibrillator implantation

The influence of normothermic and hypothermic cardiopulmonary bypass on defibrillation energy requirements and transcardiac impedance is not well characterized. However, this relationship is of clinical importance during automatic defibrillator implantation done with concomitant cardiac surgery, and there is anecdotal information that criteria for successful implantation are harder to achieve after such operations. We studied the effect of controlled hypothermia on defibrillation energy requirements and transcardiac impedance in a canine model of cardiopulmonary bypass in which 26 animals underwent right atrial and femoral arterial cannulation, as well as continuous hemodynamic and intramyocardial temperature monitoring. The defibrillation energy requirements were evaluated at 60-minute intervals with an epicardial patch system, and transcardiac impedance was measured before and after the multiple inductions and terminations of ventricular fibrillation. In group 1 ( n = 10) defibrillation energy requirements were evaluated immediately after initiation of cardiopulmonary bypass at 37° C (T 0 ), after gradual cooling to 28° C (T 1 ), and after rewarming to 37° C (T 2 ). Group 2 ( n = 16) comprised time controls that were identically instrumented and studied, but maintained at 37° C throughout. Percent successful defibrillation was plotted against delivered energy, and the raw data fit by logistic regression. The energy at which 50% of shocks were successful (E 50 ) was 3.23 ± 0.89 joules at T 0 , 5.12 ± 1.85 joules at T 1 , and 4.42 ± 1.22 joules at T 2 in group 1; this was not significantly different from the corresponding group 2 E 50 values, which were 3.11 ± 1.39 joules, 4.95 ± 2.47 joules, and 5.59 ± 3.18 joules, respectively. Both groups demonstrated a significant increase in E 50 during the first hour of cardiopulmonary bypass (mean increase from T 0 to T 1 was 1.89 joules in group 1 and 1.84 joules in group 2, p < 0.05). Transmyocardial impedance fell progressively during the group 2 experiments from 73.6 ± 12.9 Ω at the beginning of the T 0 shock series to 61.4 ± 8.9 Ω at the end of the T 2 shock series. A similar reduction in transmyocardial impedance was observed during the course of all the group 1 experiments; however, at the beginning of the T 1 shock series impedance was significantly elevated to 77.4 ± 12.3 Ω ( p < 0.05 compared with group 2 and with end T 0 in group 1). There was no relationship between defibrillation energy requirements and transcardiac impedance; there was also no correlation between either of these parameters and intramyocardial extracellular pH or left ventricular end-diastolic pressure. We conclude that defibrillation energy requirements significantly and persistently increase during the first hour of cardiopulmonary bypass and the effect is temperature independent Systemic hypothermia significantly and reversibly elevates transmyocardial impedance but multiple shocks reduce this effect at 28° C as they do at 37° C. (J T HORAC C ARDIOVASC S URG 1995;109:981-8)

Application of Combinatorial Libraries and Protein Engineering to the Discovery of Novel Anti-Thrombotic Drugs

Combinatorial libraries and protein engineering represent two new powerful tools in drug discovery and development. The application of a combinatorial ssDNA library to thrombin led to the discovery of a sequence-specific nucleotide-based thrombin inhibitor (thrombin aptamer). The thrombin aptamer has a novel tertiary structure revealed by NMR and shows potent rapid anticoagulation with a short half-life in vivo. It has been used successfully to replace heparin in a canine cardiopulmonary bypass model. Functional mapping of the surface residues of thrombin led to the generation of a modified thrombin with markedly diminished procoagulant properties while retaining its ability to activate protein C. This engineered thrombin functions as a protein C activator and demonstrates potent anticoagulation in vivo without prolongation of the bleeding time.

Calcium paradox in an in vivo model of multidose cardioplegia and moderate hypothermia: Prevention with diltiazem or trace calcium levels

The production and prevention of calcium paradox injury in myocardium was studied in a canine model of cardiopulmonary bypass with multidose, moderately hypothermic, crystalloid cardioplegic solution. During 4 1/2 hours of global ischemia, three groups of six dogs each received one of three histidine-buffered cardioplegic solutions (500 ml initially and 250 ml every 30 minutes) at 27 degrees C. Group 1 cardioplegic solution was calcium free, group 2 solution contained a trace amount of calcium chloride (70 mumols /L), and group 3 cardioplegic solution was calcium free but contained diltiazem (150 micrograms/kg body weight). Left ventricular function measured as percent control of developed pressure revealed significantly greater (p less than 0.05) recovery in groups 2 and 3. Triphenyltetrazolium chloride staining showed 35% +/- 9% (mean +/- standard error) of heart mass necrosis in group 1 versus 0% and 0.5% +/- 0.4% in groups 2 and 3, respectively (p less than 0.001). Electron microscopy revealed ultrastructural changes characteristic of calcium paradox injury in group 1 myocardium. Calcium paradox injury was produced in an in vivo model of global myocardial ischemia and multidose cardioplegia despite moderate hypothermia and non-coronary collateral flow. The addition of either trace levels of calcium or diltiazem to the cardioplegic solution was effective in preventing this injury.

Asanguineous Reperfusion in a Canine Model of Cardiopulmonary Bypass and Controlled Postischemic Work

This study was designed to test the hypothesis that asanguineous reperfusion with a standard crystalloid cardioplegic solution results in improved myocardial salvage after a period of global ischemia. Four groups of 6 dogs each were placed on cardiopulmonary bypass. Control group A (work only) performed two hours of controlled work by contracting against a saline-filled left intraventricular balloon. Control group B (ischemia only) underwent 45 minutes of global normothermic ischemia before simple blood reperfusion while supported on bypass. Groups C and D were subjected to ischemia and reperfusion as in group B, followed by controlled work stress as in group A. Group D, however, received 500 mL of St. Thomas' Hospital solution immediately before blood reperfusion. Morphological analysis showed no significant injury in groups A and B, whereas group C had 11.4% +/- 2.4% necrosis of heart mass versus 2.5% +/- 1.1% in group D (p less than 0.001). Biochemical data from left ventricular biopsies showed no significant differences between groups B, C, and D. Functional analyses showed deterioration of diastolic compliance in group C (p less than 0.05), although a significant difference in systolic functional indexes could not be detected. Myocardial protection and salvage was improved by initial reperfusion with an asanguineous cardioplegic solution versus reperfusion with blood alone.