Uwe Mehlhorn

Risk stratification in heart surgery: comparison of six score systems

OBJECTIVE Risk scores have become an important tool in patient assessment, as age, severity of heart disease, and comorbidity in patients undergoing heart surgery have considerably increased. Various risk scores have been developed to predict mortality after heart surgery. However, there are significant differences between scores with regard to score design and the initial patient population on which score development was based. It was the purpose of our study to compare six commonly used risk scores with regard to their validity in our patient population. METHODS Between September 1, 1998 and February 28, 1999, all adult patients undergoing heart surgery with cardiopulmonary bypass in our institution were preoperatively scored using the initial Parsonnet, Cleveland Clinic, French, Euro, Pons, and Ontario Province Risk (OPR) scores. Postoperatively, we registered 30-day mortality, use of mechanical assist devices, renal failure requiring hemodialysis or hemofiltration, stroke, myocardial infarction, and duration of ventilation and intensive care stay. Score validity was assessed by calculating the area under the ROC curve. Odds ratios were calculated to investigate the predictive relevance of risk factors. RESULTS Follow-up was able to be completed in 504 prospectively scored patients. Receiver operating characteristics (ROC) curve analysis for mortality showed the best predictive value for the Euro score. Predictive values for morbidity were considerably lower than predictive values for mortality in all of the investigated score systems. For most risk factors, odds ratios for mortality were substantially different from ratios for morbidity. CONCLUSIONS Among the investigated scores, the Euro score yielded the highest predictive value in our patient population. For most risk factors, predictive values for morbidity were substantially different from predictive values for mortality. Therefore, development of specific morbidity risk scores may improve prediction of outcome and hospital cost. Due to the heterogeneity of morbidity events, future score systems may have to generate separate predictions for mortality and major morbidity events.

Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria.

OBJECTIVES To elucidate the structural basis for the electrophysiologic remodeling induced by chronic atrial fibrillation (AF), we investigated connexin40 and connexin43 (Cx40 and Cx43) expression and distribution in atria of patients with and without chronic AF and in an animal model of AF with additional electrophysiologic investigation of anisotropy (ratio of longitudinal and transverse velocities). BACKGROUND Atrial fibrillation is a common arrhythmia that has a tendency to become persistent. Since gap junctions provide the syncytial properties of the atrium, changes in expression and distribution of intercellular connections may accompany the chronification of AF. METHODS Atrial tissues isolated from 12 patients in normal sinus rhythm at the time of cardiac surgery and from 12 patients with chronic AF were processed for immunohistology and immunoblotting for the detection of the gap junction proteins. The functional study of the cardiac tissue anisotropy was performed in rat atria in which AF was induced by 24 h of rapid pacing (10 Hz). RESULTS Immunoblotting revealed that AF did not induce any significant change in Cx43 content in human atria. In contrast, a 2.7-fold increase in expression of Cx40 was observed in AF. Immunohistologic analysis indicated that AF resulted in an increase in the immunostaining of both connexins at the lateral membrane of human atrial cells. A similar spatial redistribution of the Cx43 signal was seen in isolated rat atria with experimentally-induced AF. In addition, AF in rat atria resulted in decreased anisotropy with slightly enhanced transverse conduction velocity. CONCLUSIONS This experimental study showed that AF is accompanied by spatial remodeling of gap junctions that might induce changes in the biophysical properties of the tissue.

Basic Fibroblast Growth Factor Controls Migration in Human Mesenchymal Stem Cells

Little is known about the migration of mesenchymal stem cells (MSCs). Some therapeutic approaches had demonstrated that MSCs were able to regenerate injured tissues when applied from different sites of application. This implies that MSCs are not only able to migrate but also that the direction of migration is controlled. Factors that are involved in the control of the migration of MSCs are widely unknown. The migratory ability of isolated MSCs was tested in different conditions. The migratory capability was examined using Boyden chamber assay in the presence or absence of basic fibroblast growth factor (bFGF), erythropoietin, interleukin‐6, stromal cell‐derived factor‐β, and vascular endothelial growth factor. bFGF in particular was able to increase the migratory activity of MSCs through activation of the Akt/protein kinase B (PKB) pathway. The results were supported by analyzing the orientation of the cytoskeleton. In the presence of a bFGF gradient, the actin filaments developed a parallelized pattern that was strongly related to the gradient. Surprisingly, the influence of bFGF was not only an attraction but also routing of MSCs. The bFGF gradient experiment showed that low concentrations of bFGF lead to an attraction of the cells, whereas higher concentrations resulted in repulsion. This ambivalent effect of bFGF provides the possibility to a purposeful routing of MSCs.

Cardiac surgery in patients with end-stage renal disease: 10-year experience

BACKGROUND End-stage renal disease is known to be an important risk factor complex for cardiac operations performed with cardiopulmonary bypass. METHODS To investigate the influence of preoperative status on perioperative mortality and morbidity, we retrospectively analyzed data from 65 patients (20 women and 45 men with a mean age of 58.8+/-10.0 years [+/-standard deviation]) with end-stage renal disease who were on dialysis and who underwent a cardiac surgical procedure between 1988 and 1998. RESULTS Fifty-one percent of the patients had isolated coronary artery bypass grafting, 35% had replacement or reconstruction of one valve or two valves, and 14% underwent combined coronary artery bypass grafting and valve replacement. The perioperative mortality rate was 13.8% with 78% (7 of 9) of deaths occurring in patients having a valve procedure. Six of the 9 patients who died had compromised left ventricular function preoperatively, and all 9 were in New York Heart Association class III or IV. Mean preoperative duration of dialysis was longer (80+/-70 months) in the 9 patients who died compared with that in the surviving 56 patients (45+/-49 months) (p = 0.05). We found dyspnea at rest, duration of dialysis of 60 months or more, combined procedures (coronary artery bypass grafting and valve operation), and New York Heart Association class IV to be associated with a higher relative risk for perioperative death. Neither angina pectoris nor isolated coronary artery bypass grafting was associated with increased relative risk for perioperative death. However, after a cardiac operation, mortality in patients with end-stage renal disease was substantially higher than in those with normal renal function. CONCLUSIONS These data are comparable with those in the literature and possibly suggest that both indications and referral for surgical intervention have been delayed in patients who have end-stage renal disease combined with coronary artery disease, valve disease, or both. The delay may contribute to the relatively high perioperative mortality.

Large-dose hydroxyethyl starch 130/0.4 does not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with hydroxyethyl starch 200/0.5 at recommended doses.

Background Hydroxyethyl starch (HES) 130/0.4 may impair blood coagulation less than other HES solutions and, thus, may be used at larger doses without increasing the risk of postoperative bleeding. This study tested the hypothesis that volume replacement with 6% HES 130/0.4 at a dose of up to 50 ml/kg does not increase blood loss and transfusion requirements in elective coronary artery bypass surgery compared with 6% HES 200/0.5 at a dose of up to 33 ml/kg. Methods One hundred twenty adult patients scheduled for elective coronary artery bypass surgery were randomized to receive up to 50 ml/kg of 6% HES 130/0.4 or up to 33 ml/kg of 6% HES 200/0.5 for volume replacement during surgery and until 24 h thereafter. Volume requirements in excess of the respective maximum dose of HES were treated with gelatin. Colloid use was at the discretion of the attending physicians and not dictated by protocol. The primary outcome variable was chest tube drainage volume during the first 24 h after surgery. Results The data from 117 patients (HES 130/0.4, 59 patients; HES 200/0.5, 58 patients) who completed the study according to protocol were analyzed. The median volumes of HES administered were 49 and 33 ml/kg in the HES 130/0.4 and HES 200/0.5 groups, respectively (P < 0.001). Consequently, patients in the HES 130/0.4 group required less gelatin in addition to HES than those in the HES 200/0.5 group (medians: 7 ml/kg vs. 20 ml/kg, P < 0.001). The combined volumes of HES and gelatin were similar for both groups (P = 0.21). The 24-h chest tube drainage (medians: 660 ml vs. 705 ml, P = 0.60) did not differ significantly between the groups, nor did transfusion outcome. Conclusion Six percent HES 130/0.4 at a median dose of 49 ml/kg did not increase blood loss and transfusion requirements in coronary artery bypass surgery compared with 6% HES 200/0.5 at a median dose of 33 ml/kg.

Myocardial fluid balance

Fluid accumulation in the cardiac interstitium or myocardial edema is a common manifestation of many clinical states. Specifically, cardiac surgery includes various interventions and pathophysiological conditions that cause or worsen myocardial edema including cardiopulmonary bypass and cardioplegic arrest. Myocardial edema should be a concern for clinicians as it has been demonstrated to produce cardiac dysfunction. This article will briefly discuss the factors governing myocardial fluid balance and review the evidence of myocardial edema in various pathological conditions. In particular, myocardial microvascular, interstitial, and lymphatic interactions relevant to the field of cardiac surgery will be emphasized.

Impact of cardiopulmonary bypass management on postcardiac surgery renal function.

Objective: Cardiac surgery on cardiopulmonary bypass (CPB) is associated with postoperative renal dysfunction and up to 4% of patients with normal preoperative renal function develop acute renal failure (ARF) requiring dialysis. According to recent investigations, CPB management is not evidence-based and, thus, current clinical CPB practice may favor renal dysfunction. The purpose of our study was to investigate if postcardiac surgery renal dysfunction is influenced by CPB management. Methods: We selected three groups of patients with normal preoperative renal function who had been subjected to cardiac surgical procedures on CPB: 44 patients with postoperative ARF requiring hemofiltration/dialysis (ARF group), 51 patients with postoperative renal dysfunction not requiring hemofiltration/dialysis (serum creatinine increase > 0.5 mg/dl within 48 h postsurgery: CREAgroup), and 48 patients with normal postoperative renal function (Control group). The patients’ on-line CPB records were analyzed for CPB duration, CPB perfusion pressure, CPB flow, and periods on CPB at a perfusion pressure < 60 mmHg. On-CPB diuretic and vasoconstrictor medication was recorded. Results: Patient demographics were similar for the three groups. In the ARF group, CPB duration was longer (166± 77 [standard deviation, SD] min) compared to CREA (115± 41 min; p < 0.001) and to Control groups (107± 40 min; p < 0.001), and mean CPB flow was lower (2.35± 0.36 l/min/m2) compared to CREA (2.61± 0.35 l/min/m2; p=0.0015) and to Control groups (2.51± 0.33 l/min/m2; p = 0.09). Mean arterial pressure on CPB (ARF: 61± 10; CREA: 60± 7; Control: 63± 9 mmHg; p = 0.19) as well as furosemide and norepinephrine medication on CPB were similar for the groups. Compared to Control (46± 26 min), CPB duration at arterial pressures < 60 mmHg was longer in ARF (78± 60 min; p = 0.034) and in CREA (62± 36 min; p=0.048). Conclusions: Our data suggest that current clinical CPB management impacts postoperative renal function. We found that patients with normal preoperative renal function who developed postoperative ARF had longer CPB duration, lower CPB perfusion flow, and longer periods on CPB at pressures < 60 mmHg compared to patients with no post CPB ARF. However, our data do not allow us to separate these CPB-related factors from the potential influence of perioperative low cardiac output syndrome as a cause for postoperative ARF. Thus, future clinical studies are required to elucidate CPB-induced ARF and to optimize CPB management for ARF prevention.

Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium

The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly β1‐selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). The rank order of β1‐selectivity as judged by competition experiments to 3H‐CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l−1, Kiβ2) or ICI 118.551 (50 nmol l−1, Kiβ1) were NEB(Kiβ2/Kiβ1: 40.7)>BIS(15.6)>MET(4.23)>CAR(0.73)>BUC(0.49). The rank order of the negative inotropic potency of the β‐adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 μmol l−1)‐stimulated force (IC50) was: MET (0.6 μmol l−1)>CAR (4.1 μmol l−1)>NEB (7.0 μmol l−1). NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic activity (ISA) as determined by measurements of force development in forskolin (0.3 μmol l−1) pre‐treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 μmol l−1)‐stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl‐5′‐yl imidodiphosphate (Gpp(NH)p). Although all studied β‐adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the β1‐selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with β‐adrenoceptor antagonists.

N-acetylcysteine prevents reactive oxygen species–mediated myocardial stress in patients undergoing cardiac surgery: results of a randomized, double-blind, placebo-controlled clinical trial

OBJECTIVE Reactive oxygen species have been shown to contribute to myocardial stress in patients undergoing cardiac surgery, as demonstrated by myocardial 8-iso-prostaglandin-F(2)alpha and nitrotyrosine formation. We hypothesized that the reactive oxygen species scavenger N-acetylcysteine attenuates reactive oxygen species-mediated myocardial stress in patients undergoing cardiac surgery. METHODS Forty patients undergoing coronary artery surgery (mean age +/- SD, 66 +/- 9 years; 9 women and 31 men) were randomized to receive either N-acetylcysteine (100 mg/kg into cardiopulmonary bypass prime followed by infusion at 20 mg.kg(-1).h(-1), n = 20) or placebo (n = 20). Patients and clinical staff were blinded to group assignment. Transmural left ventricular biopsy specimens collected before and at the end of cardiopulmonary bypass were subjected to immunocytochemical staining against 8-iso-prostaglandin-F(2)alpha (primary measure) as an indicator for reactive oxygen species-mediated lipid peroxidation and nitrotyrosine (coprimary measure) as a marker for peroxynitrite-mediated tissue injury. Cardiomyocyte staining was quantitatively determined by using densitometry (in gray units). Global left ventricular function was measured on the basis of fractional area of contraction by using transesophageal echocardiography. RESULTS Patient characteristics in both groups were comparable. The change in left ventricular cardiomyocyte staining (end of cardiopulmonary bypass--before cardiopulmonary bypass) differed significantly between groups for both primary measures: 8-iso-prostaglandin-F(2)alpha, -1.8 +/- 7.5 gray units (mean +/- SD, N-acetylcysteine group) versus 5.0 +/- 4.1 gray units (placebo group; 95% confidence interval, 2.6-11.0, P =.003); nitrotyrosine, -6.4 +/- 10.0 gray units (N-acetylcysteine group) versus 9.2 +/- 8.4 gray units (placebo group; 95% confidence interval, 9.4-21.7, P <.001). Hemodynamics and clinical outcomes were comparable in both groups. CONCLUSIONS Reactive oxygen species scavenging with N-acetylcysteine attenuates myocardial oxidative stress in the hearts of patients subjected to cardiopulmonary bypass and cardioplegic arrest.

Normothermic Continuous Antegrade Blood Cardioplegia Does Not Prevent Myocardial Edema and Cardiac Dysfunction

BACKGROUND Normothermic continuous blood cardioplegia (BC) has been proposed to completely protect the myocardium during cardiac surgery. However, previous work from our laboratory suggests that BC could cause myocardial edema that produces cardiac dysfunction. The purpose of this present study was to evaluate the impact of BC on myocardial fluid balance and left ventricular function. METHODS AND RESULTS In 11 dogs, myocardial water content (MWC) was determined by microgravimetry. Myocardial lymph flow rate was measured after cannulation of the major prenodal cardiac lymphatic. Preload recruitable stroke work (PRSW) was calculated by sonomicrometry and micromanometry. The dogs were placed on normothermic cardiopulmonary bypass (CPB), and BC was delivered at either 80 to 90 mm Hg (BChigh; n = 6) or 40 to 50 mm Hg (BClow; n = 5) for 1 hour. Coronary sinus lactate and oxygen saturation monitoring demonstrated ischemia avoidance. BC was associated with substantial myocardial lymph flow rate decrease (P < .05) and myocardial edema development in both groups. MWC increased from 76.0 +/- 1.9% to 79.2 +/- 1.7% (P < .05) after 10 minutes of BChigh and from 75.9 +/- 0.6% to 78.9 +/- 1.4% (P < .05) after 30 minutes of BClow. PRSW decreased to 63 +/- 19% (BChigh) and 69 +/- 15% of control (BClow) at 30 minutes after CPB (P < .05). Myocardial lymph flow rate increases of threefold to fourfold that of control (P < .05) resulted in significant myocardial edema reduction associated with PRSW improvement to 71 +/- 17% (BChigh) and to 78 +/- 11% (BClow) at 2 hours after CPB. CONCLUSIONS We conclude that BC is associated with compromised cardiac function despite ischemia avoidance. This cardiac dysfunction is due to myocardial edema caused by the combination of increased myocardial microvascular fluid filtration and decreased myocardial lymph flow rate during BC.