Custodiol-N, the novel cardioplegic solution reduces ischemia/reperfusion injury after cardiopulmonary bypass.

BACKGROUNDS: On the basis of Custodiol preservation and cardioplegic solution a novel cardioplegic solution was developed to improve the postischemic cardiac and endothelial function. In this study, we investigated whether its reduced cytotoxicity and its ability to reduce reactive oxygen species generation during hypoxic condition have beneficial effects in a clinically relevant canine model of CPB. METHODS: 12 dogs underwent cardiopulmonary bypass with 60 minutes of hypothermic cardiac arrest. Dogs were divided into 2 groups: Custodiol (n = 6) and Custodiol-N (n = 6) (addition of L-arginin, N-α-acetyl-L-histidine and iron-chelators: deferoxamine and LK-614). Left ventricular hemodynamic variables were measured by a combined pressure-volume conductance catheter at baseline and after 60 minutes of reperfusion. Coronary blood flow, myocardial ATP content, plasma nitrate/nitrite and plasma myeloperoxidase levels were also determined. RESULTS: The use of Custodiol-N cardioplegic solution improved coronary blood flow (58 ± 7 ml/min vs. 26 ± 3 ml/min) and effectively prevented cardiac dysfunction after cardiac arrest. In addition, the myocardial ATP content (12,8 ± 1,0 µmol/g dry weight vs. 9,5 ± 1,5 µmol/g dry weight) and plasma nitrite (1,1 ± 0,3 ng/ml vs. 0,5 ± 0,2 ng/ml) were significantly higher after application of the new cardioplegic solution. Furthermore, plasma myeloperoxidase level (3,4 ± 0,4 ng/ml vs. 4,3 ± 2,2 ng/ml) significantly decreased in Custodiol-N group. CONCLUSIONS: The new HTK cardioplegic solution (Custodiol-N) improved myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest. The observed protective effects imply that the Custodiol-N could be the next generation cardioplegic solution in the protection against ischemia-reperfusion injury in cardiac surgery.

[Myocardial protection of cardioplegic solution with Salvia miltiorrhizae in extracorporeal circulation of coronary artery bypass graft].

OBJECTIVE: To observe the myocardial protection of cardioplegic solution with Salvia miltiorrhizae (SM) in extracorporeal circulation of coronary artery bypass graft (CABG) and to investigate the mechanisms of SM. METHODS: 30 patients who received CABG under extracorporeal circulation were randomly assigned to two groups, the observation group (15 cases) and the control group (15 cases). Patients in the observation group received the cardioplegic solution with SM and those in the control group received the cardioplegic solution without SM. The indices such as serum SOD activities, MDA contents, LDH, CK-MB, cTnl levels, the rate of heart reskip, activated coagulation time (ACT), the time of assisted respiration, and the days of in-hospital after operation were observed in the two groups pre-operation, post-operation, 6 h and 24 h post-operation, respectively. RESULTS: When compared with the control group, MDA contents, LDH, CK-MB, cTnl levels were lower, SOD activities (all P<0.05) and heart re-skip rate (P>0.05) higher in the observation group. There was no statistical significance in the time of assisted respiration, the days of in-hospital, or ACT in the two groups (P>0.05). CONCLUSIONS: The application of cardioplegic solution with SM in extracorporeal circulation of CABG showed obvious myocardial protection. It had better effects than the cardioplegic solution with no SM.

Glucose-insulin-potassium therapy in adult patients undergoing cardiac surgery: a meta-analysis.

Glucose-insulin-potassium (GIK) has long been used as adjuvant treatment for patients with serious cardiovascular disease. Although many studies have reported their results based on GIK therapy in the setting of heart surgery, the outcomes remain controversial and inconclusive. The aim of this meta-analysis of randomized controlled trials (RCTs) was to determine the clinical effects of GIK in adult cardiac surgery patients. Electronic databases and manual bibliographical searches were conducted. A meta-analysis of all RCTs comparing GIK with control in heart surgery was performed. Data for all-causes mortality (within 2 months after surgery), perioperative myocardial infarction, postoperative inotropic support, atrial fibrillation, cardiac index, durations of intensive unit care stay and total hospital stay were extracted, and we summarized the combined results of the data of the RCTs as relative risk (RR), with 95% confidence intervals (CIs). A total of 33 RCTs including 2113 patients were assessed in this study. GIK infusion was associated with significantly fewer perioperative myocardial infarctions (RR = 0.63, 95% CI 0.42-0.95), less inotropic support requirement (RR = 0.66, 95% CI 0.45-0.96), better postoperative cardiac index (weighted mean difference (WMD) = 0.43, 95% CI 0.31-0.55), and reduced length of stay in the intensive care unit (WMD = -7.96, 95% CI -13.36 to -2.55). Further analysis showed that diabetic patients were benefited from GIK with glycemic control, but not GIK infusion without glucose control. GIK significantly reduced myocardial injury and improved hemodynamic performance in patients undergoing cardiac surgery. Glycemic control with GIK might be required for cardiac surgery patients with diabetes.

Comparison of glucose-insulin-potassium and insulin-glucose as adjunctive therapy in acute myocardial infarction: a contemporary meta-analysis of randomised controlled trials.

BACKGROUND: There is conflicting evidence regarding two different insulin regimens for acute myocardial infarction (AMI), one focusing on delivering insulin ('insulin focus', glucose-insulin-potassium (GIK)) and one focusing on tight glycaemic control ('glycaemia focus', insulin-glucose). A longstanding controversy has focused on which strategy provides the greatest reduction in mortality. The aim of this study was to perform a meta-analysis of randomised controlled trials (RCTs) comparing GIK or insulin-glucose therapy versus standard therapy for AMI in the reperfusion era. METHODS: A MEDLINE/EMBASE/CENTRAL search was conducted of RCTs evaluating GIK or insulin-glucose as adjunctive therapy for AMI. The primary endpoint was all-cause mortality. The data were analysed with a random effect model. RESULTS: A total of 11 studies (including 23 864 patients) were identified, eight evaluating insulin focus with GIK and three evaluating glycaemia focus with insulin-glucose. Overall, insulin focus with GIK was not associated with a statistically significant effect on mortality (RR 1.07, 95% CI 0.89 to 1.29, p=0.487). Before the use of reperfusion, GIK also had no clear impact on mortality (RR 0.92, 95% CI 0.70 to 1.20, p=0.522). Pooled data from the three studies evaluating glycaemia focus showed that insulin-glucose did not reduce mortality in the absence of glycaemia control in patients with AMI with diabetes (RR 1.07, 95% CI 0.85 to 1.36, p=0.547). CONCLUSIONS: Current evidence suggests that GIK with insulin does not reduce mortality in patients with AMI. However, studies of glycaemia are inconclusive and it remains possible that glycaemic control is beneficial.

[Effect of high dose glucose-insulin-potassium infusion in patients with acute ST-segment elevation myocardial infarction: analysis of 7510 patients in China as part of CREATE-ECLA study].

OBJECTIVE: To investigate the effect of high-dose glucose-insulin-potassium (GIK) infusion on the outcomes of ST-elevation myocardial infarction (STEMI) in China. METHODS: As part of the international multicentre CREATE-ECLA study, 7510 patients with STEMI, aged (62 +/- 12), presenting their symptoms within 12 hours of onset who were hospitalized in 274 centers throughout China from July 2001 through July 2004 were randomized to receive GIK intravenous infusion for 24 hours plus routine treatment (3739) or control group (n=3771) receiving routine treatment alone. The patients were flowed up in the out-patient department 30 days after the randomization to assess the rates of mortality, cardiac arrest, cardiogenic shock and re-infarction. RESULTS: The median time from symptom onset to randomization was 5.8 hours. The mortality of the control group was 10.4%, not significantly different from that of the GIK group (11.2%, hazard ratio = 1.05, 95% CI: 0.916-1.207, P = 0.476). There rates of cardiac arrest, cardiogenic shock, and re-infarction of the GIK group were 0.8%, 6.8%, and 2.0% respectively, all not significantly different from those of the control group (1.0%, 6.4%, and 1.9% respectively, all P > 0.05). At the Day 7 the heart failure rate of the GIK group was 19.7%, not significantly different from that of the control group (18.3%, P = 0.102). The symptomatic hypotension rate of the GIK group was 3.7%, significantly higher than that of the control group (1.2%, P < 0.01). The phlebitis rate of the GIK group was 2.2%, significantly higher than that f the control group (0.1%, P < 0.01). The net increased fluid volume of the control group wasl3 584 ml. more than that of the GIK group (1036 ml). CONCLUSIONS: High dose GIK infusion has neutral effect on mortality, cardiac arrest or cardiogenic shock in patients with acute STEMI in China.

Calcium-supplemented University of Wisconsin solution in long-term myocardial preservation.

The purpose of this study was to assess the effects of the addition of calcium to University of Wisconsin solution in long-term myocardial perfusion. In a heterotopic heart transplantation model, performed in pigs, the donor heart was preserved for 24 hours by means of continuous perfusion in this solution, without (24hUW group) or with calcium, 2.4 mmol/L (24hUW+Ca). During this period, the oxygenation and pH of the solution were measured, as were the calcium and lactate concentrations and enzyme release. After two hours of reperfusion, samples were collected from both ventricles for the morphological study. In the control group, there were no signs that reperfusion had triggered the calcium paradox. The addition of this cation to the preservation solution improved the intercellular junction integrity but, at the same time, favored intracellular calcium overload. This is manifested by increased enzyme release during preservation (LDH: 242+/-95 vs 140+/-25; CK: 668+/-371 vs 299+/-83 (U/L). p<0.01 in both cases) and signs of ventricular contracture: hardness and stiffness were significantly more prominent than in the group without calcium supplementation. Moreover, in comparison with the control group, the structural morphology of 24hUW+Ca is characterized by the more prominent and extensive presence of contraction bands and disorganized actin structure. Thus, under the experimental conditions employed in this study, we consider the addition of calcium to Wisconsin solution to be unadvisable.

Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction.

CONTEXT: The clinical benefit of glucose-insulin-potassium (GIK) infusion in patients with ST-segment elevation myocardial infarction (STEMI) is unclear. While some smaller trials suggest benefit, in the CREATE-ECLA trial, GIK infusion had no effect on 30-day mortality in 20,201 patients. OBJECTIVES: To determine the association between GIK infusion therapy and 30-day and 6-month outcomes in patients with STEMI. DESIGN, SETTING, AND PARTICIPANTS: Primary analysis of the OASIS-6 GIK randomized controlled trial of 2748 patients with acute STEMI; prespecified analyses of the combined trial data from the OASIS-6 GIK and CREATE-ECLA GIK trial populations of 22,943 patients with acute STEMI; subgroup analysis on the timing of initiation of GIK infusion therapy and outcomes; and post hoc analyses exploring whether GIK infusion may cause early harm by increasing glucose and potassium levels and net fluid gain. INTERVENTION: High-dose GIK solution consisting of 25% glucose, 50 U/L of regular insulin, and 80 mEq/L of potassium infused at 1.5 mL/kg per hour for 24 hours. MAIN OUTCOME MEASURES: Mortality rates at 30 days and 6 months in the OASIS-6 GIK trial and rates of death, heart failure, and the composite of death or heart failure at 3 and 30 days in the combined OASIS-6 GIK and CREATE-ECLA GIK trial populations. RESULTS: At 6 months, 148 (10.8%) GIK infusion patients and 143 (10.4%) control patients died in the OASIS-6 trial (hazard ratio [HR], 1.04; 95% CI, 0.83-1.31; P = .72); 153 (11.1%) GIK patients and 185 (13.5%) control patients had heart failure (HR, 0.83; 95% CI, 0.67-1.02; P = .08); and 240 (17.5%) GIK patients and 264 (19.2%) control patients had a composite of death or heart failure (HR, 0.91; 95% CI, 0.76-1.08; P = .27). In the prespecified analyses of the combined trial data, there were 712 deaths (6.2%) in the GIK group and 632 deaths (5.5%) in the control group at 3 days (HR, 1.13; 95% CI, 1.02-1.26; P = .03). This difference disappeared by 30 days, with 1108 deaths (9.7%) in the GIK group and 1068 (9.3%) in the control group (HR, 1.04; 95% CI, 0.96-1.13; P = .33). GIK therapy increased levels of glucose, potassium, and net fluid gain postinfusion, all 3 of which predicted death after adjusting for multiple confounders. Adjusting for glucose, potassium, and net fluid gain eliminated the apparent increase in mortality at 3 days observed with GIK infusion, suggesting a direct association with these factors. Administration of GIK infusion within 4 hours of symptom onset yielded no benefit compared with later initiation. CONCLUSIONS: Infusion of GIK provided no benefit and may cause early harm following STEMI. Avoidance of infusion-related hyperglycemia, hyperkalemia, and net fluid gain may be advisable in future studies of metabolic modulation in patients with STEMI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00064428.

Age- and gender-related differences in ischemia/reperfusion injury and cardioprotection: effects of diazoxide.

BACKGROUND: Recent studies have demonstrated that aging is associated with reduced tolerance to ischemia and that the aged (not senescent) female heart has greater susceptibility to ischemia as compared with the aged male heart. Previously, we have shown that ischemia can be modulated with cardioplegia in the male heart; however, efficacy in the female heart was unknown. METHODS: In this study, male and female mature (15 to 20 weeks) aged (>32 months) rabbit hearts (n = 134) were subjected to Langendorff perfusion. Control hearts were perfused for 180 minutes. Global ischemia hearts received 30 minutes of equilibrium, 30 minutes of global ischemia, and 120 minutes of reperfusion. Cardioplegia +/- diazoxide was infused separately, 5 minutes before global ischemia. RESULTS: Global ischemia significantly decreased postischemic functional recovery and significantly increased infarct size in the mature and aged male and female heart (p < 0.05 versus control). The effects of global ischemia were significantly exacerbated (p < 0.05) in the aged heart as compared with the mature heart. Cardioplegia +/- diazoxide significantly increased postischemic functional recovery and significantly decreased infarct size in mature male and female hearts, but these effects were significantly decreased in the aged heart (p < 0.05) and in the aged female as compared with the aged male heart. CONCLUSIONS: Postischemic functional recovery and infarct size are affected by age but not by gender. The cardioprotection afforded by cardioplegia is affected by age and gender with a strong age-by-gender interaction for end-diastolic pressure and infarct size. Our results indicate that currently optimized cardioplegia protocols effective in the male heart are not as efficacious in the aged female heart.

Sudden cardiac death: directing the scope of resuscitation towards the heart and brain.

BACKGROUND: The fundamental goal of cardiopulmonary resuscitation (CPR) is recovery of the heart and the brain. This is best achieved by (1) immediate CPR for coronary and cerebral perfusion, (2) correction of the cause of cardiac arrest, and (3) controlled cardioplegic cardiac reperfusion. Failure of such an integrated therapy may cause permanent brain damage despite cardiac resuscitation. METHODS: This strategy was applied at four centers to 34 sudden cardiac death patients (a) after acute myocardial infarction (n = 20), (b) "intraoperatively" following successful discontinuation of cardiopulmonary bypass (n = 4), and (c) "postoperatively" in the surgical ICU (n = 10). In each witnessed arrest the patient failed to respond to conventional CPR with ACLS interventions, including defibrillation. The cardiac arrest interval was 72 +/- 43 min (20-150 min). Compression and drugs maintained a BP > 60 mmHg to avoid cerebral hypoperfusion. Operating room (OR) transfer was delayed until the blood pressure was monitored. In four patients femoral bypass maintained perfusion while an angiographic diagnosis was made. RESULTS: Management principles included no repeat defibrillation attempts after 10 min of unsuccessful CPR, catheter-monitored peak BP > 60 mmHg during diagnosis and transit to the operating room, left ventricular venting during cardiopulmonary bypass and 20 min global and graft substrate enriched blood cardioplegic reperfusion. Survival was 79.4% with two neurological complications (5.8%). CONCLUSIONS: Recovery without adverse neurological outcomes is possible in a large number of cardiac arrest victims following prolonged manual CPR. Therapy is directed toward maintaining a monitored peak BP above 60 mmHg, determining the nature of the cardiac cause, and correcting it with controlled reperfusion to preserve function.

Glucose-insulin and potassium infusions in septic shock.

Glucose-insulin and potassium (GIK) infusions are beneficial in treating ischemic myocardial depression. Myocardial depression is also an important feature in septic shock. We describe two cases of pressor-resistant hypodynamic septic shock that responded to high-dose GIK infusions. In each case, hemodynamic profiles improved sufficiently to allow withdrawal of vasopressor agents. Further assessment of GIK in patients with hypodynamic septic shock is necessary to confirm efficacy and prognostic significance.

High-dose glucose-insulin-potassium treatment reduces myocardial apoptosis in patients with acute myocardial infarction.

BACKGROUND: Several clinical trials have suggested that a metabolic cocktail of glucose-insulin-potassium (GIK) decreases mortality rates in patients with acute myocardial infarction (AMI). It has also been reported that Fas-mediated apoptosis plays an important role in ischaemic/reperfusion injury in the rat model. This study was designed to evaluate the interaction of ischaemic/reperfusion and reperfusion therapy coadministered with high-dose GIK treatment on soluble Fas/APO-1 (sFas) and Fas ligand (sFasL) plasma concentration in patients with AMI. MATERIALS AND METHODS: Seventy-four patients presenting with AMI who underwent reperfusion therapy were randomized into a GIK group (n = 35) receiving high-dose GIK for 24 h or a vehicle group (n = 39). Thirty-four control subjects were also enrolled in the present study. Strepavidin-biotin ELISA was used to determine the soluble sFas and sFasL plasma concentration at baseline, 24 h (h), 3 day (d), 7 d and 14 d. RESULTS: Soluble Fas and sFas-L serum concentrations ([sFas] and [sFas-L]) of patients with AMI were significantly elevated at baseline as compared with normal controls (NCs; P < 0.01 vs. NC). The sFas in the GIK and vehicle groups markedly decreased 24 h after the GIK infusion (10.7-->5.9 ng mL(-1) and 9.7-->6.5 ng mL(-1); P < 0.01 vs. baseline) and then increased during the 3-7-d period (5.9-->12.1 ng mL(-1) and 6.5-->11.1 ng mL(-1); P < 0.01 vs. 24 h). The GIK group demonstrated reduced sFas (12.1-->5.9 ng mL(-1)) at 14 d (P < 0.01 vs. 7 d), with no concomitant changes in the vehicle group. The sFas-L in the GIK and vehicle groups was not significant different during the 14-d period. CONCLUSIONS: These results indicate that the sFas and sFasL in patients with AMI increased significantly compared with NC. Owing to the cardioprotective effects reported here and by others, a high-dose GIK infusion co-administered with the timely re-establishment of nutritive perfusion should be strongly considered as a treatment of choice for AMI. Additionally, sFas may be a valuable marker of the physiological response to ischaemic/reperfusion injury and reperfusion associated with high-dose GIK treatment.

Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial.

CONTEXT: Glucose-insulin-potassium (GIK) infusion is a widely applicable, low-cost therapy that has been postulated to improve mortality in patients with acute ST-segment elevation myocardial infarction (STEMI). Given the potential global importance of GIK infusion, a large, adequately powered randomized trial is required to determine the effect of GIK on mortality in patients with STEMI. OBJECTIVE: To determine the effect of high-dose GIK infusion on mortality in patients with STEMI. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial conducted in 470 centers worldwide among 20,201 patients with STEMI who presented within 12 hours of symptom onset. The mean age of patients was 58.6 years, and evidence-based therapies were commonly used. INTERVENTION: Patients were randomly assigned to receive GIK intravenous infusion for 24 hours plus usual care (n = 10,091) or to receive usual care alone (controls; n = 10,110). MAIN OUTCOME MEASURES: Mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days after randomization. RESULTS: At 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients (10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95-1.13; P = .45). There were no significant differences in the rates of cardiac arrest (1.5% [151/10 107] in control and 1.4% [139/10,088] in GIK infusion; HR, 0.93; 95% CI, 0.74-1.17; P = .51), cardiogenic shock (6.3% [640/10 107] vs 6.6% [667/10 088]; HR, 1.05; 95% CI, 0.94-1.17; P = .38), or reinfarction (2.4% [246/10,107] vs 2.3% [236/10,088]; HR, 0.98; 95% CI, 0.82-1.17; P = .81). The rates of heart failure at 7 days after randomization were also similar between the groups (16.9% [1711/10,107] vs 17.1% [1721/10,088]; HR, 1.01; 95% CI, 0.95-1.08; P = .72). The lack of benefit of GIK infusion on mortality was consistent in prespecified subgroups, including in those with and without diabetes, in those presenting with and without heart failure, in those presenting early and later after symptom onset, and in those receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous coronary intervention). CONCLUSION: In this large, international randomized trial, high-dose GIK infusion had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI.

Efficiency of L-arginine enriched cardioplegia and non-cardioplegic reperfusion in ischemic hearts.

OBJECTIVE: Endothelial dysfunction with decreased nitric oxide (NO) levels has been implicated on reperfusion injury. Although L-arginine has been shown to diminish reperfusion injury in in vitro studies, clinical studies were very limited. METHODS: Forty patients with acute myocardial ischemia undergoing CABG were randomized to a study and a control group. L-Arginine was added to cardioplegia solutions in study group. A non-cardioplegic warm blood solution with 8 mmol/l L-arginine infused for controlled reperfusion. Control patients received same protocol without L-arginine. Myocardial O2, lactate, nitrite and malondialdehyde extractions were measured in addition to calculation of CK-MB/CPK ratio and hemodynamic data. RESULTS: While there was no mortality in study group, one patient in control group died. Overall and nitrite (P=0.01) and lactate extractions (P=0.04) was higher in study and control groups, respectively. Myocardial O2 uptake was higher and malondialdehyde extraction was lower in study group. CK-MB/CPK ratio at postoperative sixth hour was also significantly lower in study group. Ninety percent of the study group had spontaneous return of the sinus rhythm, while 80% of the control patients required defibrillation (P<0.0001). In addition to significantly better hemodynamics, perioperative myocardial infarction incidence was lower (P=0.037), the length of intensive care unit (P=0.009) and hospital (0.014) stays were shorter in study group. CONCLUSIONS: Use of L-arginine for protection of acutely ischemic myocardium appears to be a safe technique. L-Arginine supplementation increased NO levels and attenuated free O2 radical mediated myocardial injury. Controlled reperfusion with l-arginine enriched non-cardioplegic blood could be a new therapeutic entity to diminish ischemia/reperfusion injury.

Minimally-diluted blood cardioplegia supplemented with potassium and magnesium for combination of 'initial, continuous and intermittent bolus' administration.

BACKGROUND: The present study was designed to examine the hypothesis that minimally-diluted blood cardioplegia (BCP) supplemented with potassium and magnesium provides superior myocardial protection in comparison with the standard-diluted BCP for a combination of 'initial, continuous, and intermittent bolus' BCP administration. METHODS AND RESULTS: Seventy patients undergoing elective coronary revascularization between 1997 and 2001 (M : F =55:15, mean age 67.6+/-7.5 years) were randomly divided into 2 groups: Group C (n=35) was given the standard 4:1-diluted blood-crystalloid BCP, and Group M (n=35) was given minimally-diluted BCP supplemented with potassium-chloride and magnesium-sulfate. The BCP temperature was maintained at 30 degrees C. Cardioplegic arrest was induced with 2 min of initial antegrade BCP infusion, followed by continuous retrograde BCP infusion. Intermittent antegrade BCP was infused every 30 min for 2 min. The time required for achieving cardioplegic arrest was significantly shorter in Group M (47.5+/-16.3 vs 62.5+/-17.6 s, p<0.0001). The number of patients showing spontaneous heart beat recovery after reperfusion was significantly larger in Group M (28 vs 15, p=0.0029), and the number of patients suffering from atrial fibrillation during the postoperative period was significantly smaller in Group M (n=3 vs 11, p=0.034). Both the postoperative maximum dopamine dose (3.57+/-2.46 vs 5.44+/-2.23 microg/kg per min, p=0.0014) and peak creatine kinase-MB (19.5+/-8.5 vs 25.8+/-11.9 IU/L, p=0.0128) were significantly less in Group M. The number of patients showing paradoxical movement of the ventricular septum in the early postoperative echocardiography was significantly smaller in Group M (9 vs 24, p=0.0007). CONCLUSIONS: These results suggest that 'initial, continuous and intermittent bolus' administration of minimally-diluted BCP supplemented with potassium and magnesium is a reliable and effective technique for intraoperative myocardial protection.

Comparison of hyperkalemic cardioplegia with altered [CaCl2] and [MgCl2] on [Ca2+]i transients and function after warm global ischemia in isolated hearts.

AIM: [MgCl(2)] and [CaCl(2)] may modify the cardioprotective effects of hyperkalemic cardioplegia (CP). We changed [MgCl(2)] and [CaCl(2)] in a CP solution to examine their effects on [Ca(2+)]i transients and cardiac function before and after global normothermic ischemia. METHODS: After stabilization and loading of indo 1-AM in Kreb's solution (KR), each heart was perfused with either KR or 1 of 4 CP solutions before 37 degrees C, 30 min ischemia followed by reperfusion with KR. The KR solution contained, in mM, 4.5 KCl, 2.4 MgCl(2) and 2.5 CaCl(2); the CP solutions had in addition to 18 KCl: CP 1 (control CP): 2.4 MgCl(2), 2.5 CaCl(2); CP 2: 7.2 MgCl(2), 2.5 CaCl(2); CP 3, 7.2 MgCl(2), 1.25 CaCl(2); CP 4: 2.4 MgCl(2), 1.25 CaCl(2). RESULTS: In the KR group [Ca(2+)]i markedly increased on early reperfusion while functional return (LVP, dLVP/dt((max and min))) was much reduced; each CP group led to reduced [Ca(2+)]i loading and improved function. The rates of cytosolic Ca(2+) fluxes (d[Ca(2+)]/dt(max) and d[Ca(2+)]/dt(min)) increased significantly compared to baseline in the KR group, but were mostly suppressed in the CP groups, and d[Ca(2+)]/dt(min) was lower after CP 4 compared to CP 1 on reperfusion. At 60 min reperfusion, LVP area to [Ca(2+)] area and cardiac efficiency to phasic [Ca(2+)] relationships were shifted after KR, but not after CP 1-4. With similar functional recovery, [Ca(2+)] transient and [Ca(2+)] area were significantly lower after CP 4 than after CP 1. CONCLUSION: Increasing [MgCl(2)] (CP 2 and 3) did not improve cardiac function or reduce Ca(2+) transients on reperfusion better than the other CP groups, but reducing [CaCl(2)] (CP 3 and 4) was more effective in reducing [Ca(2+)] transients on reperfusion after global ischemia.

Therapy with insulin in cardiac surgery: controversies and possible solutions.

Insulin has been used in the treatment of patients undergoing cardiac surgery or suffering from acute myocardial infarction. Most of these investigations have demonstrated that the metabolic cocktail consisting of glucose-insulin-potassium (GIK) improves recovery of function and outcome after cardiac surgery and substantially reduces mortality of patients with acute myocardial infarction. There is also evidence suggesting that insulin is not effective under these conditions, as demonstrated in a recent large randomized trial in cardiac surgery. It is therefore not surprising that insulin or GIK is not used routinely in clinical practice. Many hypotheses have been advanced to explain the effects of insulin and GIK but none of them has enjoyed convincing support. In cardiac surgery the many different application protocols described make it difficult to compare the results. The application of GIK after cardiac surgery may be complicated by severe disturbances in glucose or potassium homeostasis. In this article we review the literature in this field, addressing the areas of controversy. We discuss the different mechanisms suggested and we propose potential solutions. We conclude that a multifactorial mechanism is likely to explain the effects of insulin or GIK after ischemia and we propose that in a practical sense the application of high-dose insulin during reperfusion, utilizing a newly described, direct nonmetabolic effect, is a convincing concept. We will further demonstrate our clinical experience in establishing a protocol for putting this concept into clinical practice.

Dose dependency of L-arginine in neonatal myocardial protection: the nitric oxide paradox.

OBJECTIVES: Recent experimental studies have suggested that enriching cardioplegic solution with L-arginine improves myocardial protection by increasing nitric oxide production. Nitric oxide, however, also generates the toxic oxygen-derived free radical peroxynitrite; thus these beneficial effects may be dose dependent, especially in vulnerable (stressed) hearts. METHODS: Fifteen neonatal piglets underwent 60 minutes of ventilator hypoxia (inspired oxygen fraction 8%-10%) followed by 20 minutes of normothermic ischemia on cardiopulmonary bypass (stress). They were then protected for 70 minutes with multiple doses of blood cardioplegic solution. In 5 (group 1), the cardioplegic solution contained no L-arginine, in 5 (group 2), it was enriched with a 4 mmol/L concentration of L-arginine, and in 5 (group 3), a 10 mmol/L concentration of L-arginine. Myocardial function was assessed by means of pressure volume loops and expressed as a percentage of control, and coronary vascular resistance and conjugated diene production were measured during infusions of cardioplegic solution. RESULTS: Compared with the protection afforded by blood cardioplegic solution without L-arginine (group 1), the addition of a 4 mmol/L concentration of L-arginine (group 2) significantly improved myocardial protection, resulting in complete return of systolic function (end-systolic elastance 38% vs 100%; P <.001 vs 4 mmol/L L-arginine) and preload recruitable stroke work (40% vs 100%; P <. 001 vs 4 mmol/L L-arginine); minimal increase in diastolic stiffness (239% vs 158%; P <.001 vs 4 mmol/L L-arginine); and lower coronary vascular resistance, conjugated diene production, and myeloperoxidase activity (P <.001 vs 4 mmol/L L-arginine in each case). Conversely, supplementing the cardioplegic solution with a 10 mmol/L dose of L-arginine (group 3) negated these beneficial effects, resulting in depressed systolic function (end-systolic elastance 41% +/- 2%; P <.001 vs 4 mmol/L L-arginine) and preload recruitable stroke work (40% +/- 2%; P <.001 vs 4 mmol/L L-arginine); increased diastolic stiffness (246% +/- 7%; P <.001 vs 4 mmol/L L-arginine); and higher conjugated diene production, myeloperoxidase activity, and coronary vascular resistance (P <.001 vs 4 mmol/L L-arginine in each case). CONCLUSIONS: Enriching cardioplegic solution with a 4 mmol/L concentration of L-arginine significantly improves myocardial protection by reducing oxygen-derived free radical formation by white blood cells, thus preserving vascular and myocardial function. However, these beneficial effects are dose dependent because 10 mmol/L concentrations of L-arginine increase oxygen-derived free radical production, resulting in vascular and myocardial dysfunction.

Metabolic intervention for the ischemic and post-ischemic heart.

There is increasing evidence that the availability of different metabolic substrates can influence post-ischemic functional recovery of the heart and the damage incurred during episodes of myocardial ischemia. Here we present the rationale for metabolic interventions, describe their mechanisms of action and suggest potential clinical applications. In cardiac surgery, basic research, studies of human myocardial metabolism after cardiac operations, and available experience with metabolic interventions provide a rationale for metabolic support with glutamate and/or high-dose glucose-insulin-potassium (GIK) in postoperative cardiac failure. In the treatment of acute myocardial infarction GIK deserves serious evaluation as recent randomized studies in diabetics with myocardial infarction and in patients undergoing reperfusion strategies demonstrate significant reductions in mortality. However, before large scale prospective randomized studies are undertaken, further studies of myocardial metabolism in acute myocardial infarction and the impact of different GIK regimes may be advisable in order to determine appropriate doses. A brief overview of metabolic modulation with pharmacological measures is given as it eventually may prove that we have to await the introduction of pharmacological agents which enhance full glucose oxidation at the expense of free fatty acids to create the commercial interest necessary to achieve widespread use of metabolic therapies.

Can L-arginine improve myocardial protection during cardioplegic arrest? Results of a phase I pilot study.

BACKGROUND: L-arginine appears to improve myocardial protection during cardioplegic arrest in animal models. METHODS: To study the clinical effect and safety of L-arginine in humans, a phase I pilot study was performed with 50 patients who underwent coronary artery bypass grafting. We randomly assigned half to a treatment group, which received 1 g of L-arginine administered during the first 30 minutes of cardioplegic arrest induced by either warm or cold blood cardioplegia, and half to a control group, which did not receive L-arginine supplementation. RESULTS: Age, sex, and preoperative clinical status were similar in both groups. Seventeen patients of each group were administered intermittent warm antegrade blood cardioplegia, whereas the solution needed to be cooled to obtain complete standstill of the remaining eight hearts in each group. An internal thoracic artery graft to the left anterior descending coronary artery was performed in all patients. There was no death and no myocardial infarction in the treatment group, but there were one death and two infarctions in the control group. The amount of serial release of troponin I during the first 72 hours after the operation was similar between the L-arginine group and the control group (p > 0.05). Peak serum troponin levels averaged 4.9 +/- 1.0 microg/L in the arginine group and 3.9 +/- 1.0 microg/L in the control group (p > 0.05). A multivariate analysis of variance showed no effect of L-arginine (p > 0.05) but a significant effect of the temperature of the cardioplegic solution on the release of troponin I (p < 0.05). Serum troponin I levels averaged 2.2 +/- 0.4 microg/L, 4.5 +/- 0.4 microg/L, and 6.9 +/- 0.4 microg/L in the patients with cold cardioplegia and 1.4 +/- 0.3 microg/L, 2.4 +/- 0.3 microg/L, and 3.3 +/- 0.3 microg/L in the patients with warm cardioplegia 1, 2, and 6 hours, respectively, postoperatively. CONCLUSIONS: The administration of 1 g of L-arginine during the first 30 minutes of blood cardioplegic arrest did not result in a decrease in the postoperative release of cardiac enzyme; however, cold cardioplegic arrest significantly increased the release of cardiac troponin I postoperatively. There was no significant side effect related to the addition of L-arginine to the cardioplegic solution.