Henk te Velthuis

Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial

BACKGROUND Elderly patients and those with poor ventricular function have increased morbidity and mortality rates when undergoing surgery. We aimed to ascertain whether an oral immune-enhancing nutritional supplement could improve preoperative host defence, and subsequently lower postoperative infections and organ dysfunction in patients undergoing elective cardiac surgery who are at high risk of infection. METHODS In this prospective, randomised, double-blind, placebo-controlled study, we randomly assigned 50 patients who were scheduled to undergo coronary artery bypass to receive either an oral immune-enhancing nutritional supplement containing L-arginine, omega3 polyunsaturated fatty acids, and yeast RNA (n=25), or a control (n=25) for a minimum of 5 days. Patients were included if they were aged 70 years or older, or had an ejection fraction of less than 0.4, or were scheduled to undergo mitral valve replacement. The main outcome was preoperative host defence (delayed-type hypersensitivity response to recall antigens, expression of HLA-DR epitopes on monocytes, and concentration of interleukin 6 in plasma). Analysis was per protocol. FINDINGS Five patients (two in the treatment group) were excluded because they did not take the minimum dose. Preoperative expression of HLA-DR epitopes on monocytes was significantly higher in patients given the study treatment (109% [95% CI 92-128]) than those given the control (69% [58-82]) compared with baseline (100%) (p=0.02, repeated measures ANOVA). However, concentration of interleukin 6 was significantly lower in the treatment group (0.90 pg/L [0.69-1.18]) than in the control group (1.94 pg/L [1.45-2.59]) (p=0.032, repeated measures ANOVA). Additionally, delayed-type hypersensitivity response to recall antigens improved preoperatively and remained better until hospital discharge. INTERPRETATION Intake of an oral immune-enhancing nutritional supplement for a minimum of 5 days before surgery can improve outlook in high-risk patients who are undergoing elective cardiac surgery.

Reduced complement activation and improved postoperative performance after cardiopulmonary bypass with heparin-coated circuits

A randomized controlled trial that involved 30 patients undergoing elective coronary artery bypass grafting was done to determine the effect of heparin-coated circuits and full heparinization on complement activation, neutrophil-mediated inflammatory response, and postoperative clinical recovery. Peak concentrations of terminal complement complex were 38% lower (p = 0.004) in 15 patients treated with heparin-coated circuits (median 775 micrograms/L, interquartile range 600 to 996) compared with those in 15 patients treated with uncoated circuits (median 1249 micrograms/L, interquartile range 988 to 1443). Although no significant intergroup differences in concentrations of polymorphonuclear neutrophil elastase were found, a positive correlation (rs = 0.74, p < 0.0007) was calculated between peak concentrations of terminal complement complex and polymorphonuclear neutrophil elastase. Differences in patient recovery were analyzed with use of a score composed of fluid balance, postoperative intubation time, and the difference between rectal temperature and skin temperature. The score was significantly lower in patients treated with heparin-coated circuits (p = 0.03), whereas its components showed no intergroup significance. We conclude that the use of heparin-coated circuits with full systemic heparinization results in improved biocompatibility, as assessed by complement activation, and leads to an improved postoperative recovery of the patient.

Heparin coating of extracorporeal circuits inhibits contact activation during cardiac operations

OBJECTIVE Heparin coating reduces complement activation on the surface of extracorporeal circuits. In this study we investigated its effect on activation of the contact system in 30 patients undergoing coronary artery bypass grafting with the use of a heparin-coated (Duraflo II, Baxter Healthcare Corp., Edwards Division, Santa Ana, Calif.; n = 15) or an uncoated extracorporeal circuit (n = 15). METHODS Plasma markers that reflect activation of contact (kallikrein-C1-inhibitor complexes), coagulation (prothrombin fragments F1 + 2), or fibrinolytic (plasmin-alpha 2-antiplasmin complexes) systems were determined before and during the operation. The generation of kallikrein-C1-inhibitor complexes was reduced by 62% (p = 0.06) after the onset of cardiopulmonary bypass and by 43% (p = 0.026) after the cessation of bypass in the group in which a heparin-coated circuit was used compared with the group in which the circuit was uncoated. Generation was reduced by 58% (p = 0.06) when the ratio of kallikrein-C1-inhibitor to prekallikrein after onset of bypass was considered. We detected significant increases in F1 + 2 levels in both groups and increases in plasmin-alpha 2-antiplasmin complexes in the heparin-coated group at cessation of bypass, but no intergroup differences were observed. Thus use of heparin-coated extracorporeal circuits during cardiac operations reduces formation of kallikrein-C1-inhibitor complexes when compared with use of uncoated circuits. The heparin coating is not accompanied by similar reductions in coagulation or fibrinolysis, suggesting that thrombin and plasmin formation during cardiopulmonary bypass occurs mainly independently of the contact system activation.

Myocardial performance in elderly patients after cardiopulmonary bypass is suppressed by tumor necrosis factor

The aim of this study was to determine whether elderly patients (aged > or = 65 years, n = 20) in comparison with younger patients (aged < or = 55 years, n = 23) demonstrate a different biochemical and hemodynamic response to coronary artery bypass operations. In the elderly group, we calculated a smaller body surface area (p < 0.01) than that in the younger group, and more female patients were included in this group (p < 0.05). During cardiopulmonary bypass, the elderly had higher endotoxin plasma concentrations (p < 0.01) than the younger patients, and significantly more circulating tumor necrosis factor-alpha was found after operation (p < 0.04). In the intensive care unit, the elderly patients had a significantly higher pulmonary capillary wedge pressure (p < 0.001), a higher mean pulmonary artery pressure (p < 0.01), and a lower calculated left ventricular stroke work index (p < 0.05). Multivariate analysis for the postoperative outcome showed that the intergroup differences in tumor necrosis factor-alpha, mean pulmonary artery pressure, and pulmonary capillary wedge pressure could be explained mainly by the difference in age between the groups and that the calculated left ventricular stroke work index difference could be explained by the difference in circulating tumor necrosis factor-alpha levels. Thus in elderly patients higher circulating endotoxin and tumor necrosis factor-alpha concentrations were detected than in younger patients, which clinically resulted in a suppressed myocardial performance.

Inflammatory response to cardiopulmonary bypass using roller or centrifugal pumps

BACKGROUND The inflammatory response in 29 patients undergoing coronary artery bypass grafting using either roller or centrifugal (CFP) pumps was evaluated in a prospective study. METHODS Patients were randomized in roller pump (n = 15) and CFP (n = 14) groups. Terminal complement complex activation (SC5b-9) and neutrophil activation (elastase) were assessed during the operation. Cytokine production (tumor necrosis factor-alpha, interleukin-6, interleukin-8) and circulating adhesion molecules (soluble endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1) were assessed after the operation. RESULTS Release of SC5b-9 after stopping cardiopulmonary bypass and after protamine administration was higher in the CFP group (p = 0.01 and p = 0.004). Elastase level was higher after stopping cardiopulmonary bypass using CFP (p = 0.006). Multivariate analysis confirmed differences between roller pump and CFP groups in complement and neutrophil activation. After the operation, a significant production of cytokines was detected similarly in both groups, with peak values observed within the range of 4 to 6 hours after starting cardiopulmonary bypass. However, interleukin-8 levels were higher using CFP 2 hours after starting cardiopulmonary bypass (p = 0.02). Plasma levels of adhesion molecules were similar in both groups within the investigation period. CONCLUSIONS During the operation, CFP caused greater complement and neutrophil activation. After the operation, the inflammatory response was similar using either roller pump or CFP.

Reduction in prime volume attenuates the hyperdynamic response after cardiopulmonary bypass

BACKGROUND A hyperdynamic response to cardiopulmonary bypass is characteristically observed in the post-operative course. To determine the effect of prime volume on the hemodynamic response, a database study was performed on patients who underwent elective coronary artery bypass grafting with an extracorporeal circuit with either a large prime volume (2,350-mL prime, n = 20) or a small prime volume (1,400-mL prime, n = 20). METHODS Measurements were carried out at fixed time points before and after cardiopulmonary bypass (until 18 hours postoperatively) and include hematocrit, colloid oncotic pressure, fluid balance, and hemodynamic profile (mean of three measurements). RESULTS The lower colloid oncotic pressure in the large prime group (16.2 +/- 0.6 mm Hg versus 19.1 +/- 1.1 mm Hg, p = 0.0002) was associated with a highly positive fluid balance (5.5 +/- 0.9 L versus 2.8 +/- 0.7 L, p = 0.0001). With the on-bypass hematocrit aimed at 22% to 23%, autologous blood was predonated by 16 patients in the small prime group but by none in the large prime group. Reinfusion of autologous blood resulted in a reduction in blood bank requirements (p = 0.03). Mean arterial pressure was 83 +/- 4 mm Hg for small prime versus 76 +/- 4 mm Hg for large prime (p = 0.01). Cardiac index was 2.9 +/- 0.2 L.min-1.m-2 for small prime versus 3.8 +/- 0.3 L.min-1.m-2 for large prime (p = 0.0001). Pulmonary vascular resistance index was 281 +/- 40 dyne.s.cm5.m-2 for small prime versus 188 +/- 22 dyne.s.cm5.m-2 for large prime (p = 0.0009). Oxygen delivery was 42 +/- 5 mL.min-1.m-2 for small prime versus 51 +/- 3 mL.min-1.m-2 for large prime (p = 0.004). Vasoactive medication was not different among groups. CONCLUSIONS Reduction in prime volume attenuates the hyperdynamic response after cardiopulmonary bypass. Furthermore, an important reduction in blood bank products can be obtained with small prime volumes.

Heparin coating with aprotinin reduces blood activation during coronary artery operations.

BACKGROUND This study was performed to evaluate whether the combination of heparin-coated extracorporeal circuits (ECC) and aprotinin treatment reduce blood activation during coronary artery operations. METHODS Sixty patients were prospectively divided into two groups (heparin-coated ECC and uncoated ECC groups), which were comparable in terms of age, sex, left ventricular function, preoperative aspirin use and consequent intraoperative aprotinin use, number of grafts, duration of aortic cross-clamping, and duration of cardiopulmonary bypass. Blood activation was assessed at different times during cardiopulmonary bypass by determination of complement activation (C3 and C4 activation products C3b/c and C4b/c and terminal complement complex), leukocyte activation (elastase), coagulation (scission peptide fibrinopeptide 1 + 2), and fibrinolysis (D-dimers). RESULTS Univariate analysis showed that heparin-coated ECC, under conditions of standard heparinization, did not reduce perioperative blood loss and need for transfusion. Heparin coating, however, reduced maximum values of C3b/c (446 +/- 212 nmol/L versus 632 +/- 264 nmol/L with uncoated ECC; p = 0.0037) and maximum C4b/c values (92 +/- 48 nmol/L versus 172 +/- 148 nmol/L with uncoated ECC; p = 0.0069). Levels of terminal complement complex, elastase, fibrinopeptide 1 + 2, and D-dimers were not significantly modified by the use of heparin-coated ECC. Multivariate analysis showed that the intergroup differences in maximum C3b/c and C4b/c values were more pronounced in women in part with high baseline values of C3b/c. We also found that aprotinin contributed to the reduction of maximum values of fibrinopeptide 1 + 2 and D-dimers, whereas heparin coating had no significant influence on these parameters. CONCLUSIONS We found no evidence of combined properties of heparin-coated ECC and aprotinin in reducing complement activation, coagulation, and fibrinolysis. We therefore recommend use of both together to achieve maximal reduction of blood activation during cardiopulmonary bypass for coronary artery operations.

Circulating endothelin in cardiac operations: influence of blood pressure and endotoxin

BACKGROUND Endothelin is involved in the control of cardiovascular and renal functions and acts as a neuromodulator. METHODS In a prospective study among 15 male patients who underwent coronary artery bypass grafting, we investigated the release pattern and possible stimuli of circulating endothelin. RESULTS We detected a steep increase in endothelin concentrations after the onset of cardiopulmonary bypass (CPB), and a second minor increase during CPB. The steep increase in endothelin concentrations correlated with the change in arterial pressures at the onset of CPB (r = -0.57; p < 0.03). The slow increase in endothelin concentrations during CPB, however, correlated with mean endotoxin levels during and after CPB (r = 0.60; p < 0.02). CONCLUSIONS The change in arterial pressure at the onset of CPB seems to induce a steep and fast increase in circulating endothelin level, which is probably mediated through the baroreceptors. The slow increase in endothelin level during CPB is associated with increased circulating endotoxin concentration. It may be that either endothelin-mediated vasoconstriction induces endotoxin transmigration from the intestine or endotoxin stimulates secretion from endothelial cells.

Inflammatory response to cardiopulmonary bypass using two different types of heparin-coated extracorporeal circuits

Previous reports have highlighted the disparity in biocompatibility of two differently engineered heparin coatings during the cardiopulmonary bypass (CPB) procedure. The aim of this prospective study was to evaluate the impact of the difference in haemocompatibility provided by either the Duraflo II equipment or the Carmeda equipment in the terminal inflammatory response observed after coronary artery surgery. Thirty patients were randomly allocated to two groups to be operated on using either Duraflo II equipment (group I) or Carmeda equipment (group 2) for extracorporeal circulation (ECC). Initial inflammatory response was assessed by terminal complement complex activation (SC5b-9). The late inflammatory response observed in the postoperative period was assessed by measuring cytokine production (tumour factor necrosis (TNFα), interleukin IL-6, interleukin IL-8) and circulating concentrations of adhesion molecules (ELAM-1, ICAM-1). The release of SC5b-9 after CPB and after protamine administration was lower in group 2 than in group 1 (p = 0.0002 and p = 0.006, respectively). A significant production of cytokines was detected in both groups with peak values observed within the time range of 4-6 h after the start of CPB. However, no difference was observed between the groups except for the IL-8 level in group 2, which was lower 2 h after the start of CPB (p = 0.01). Plasma levels of adhesion molecules were similar in both groups within the investigation period. Although the Carmeda equipment was more effective in reducing complement activation, the late inflammatory response was similar using either the Duraflo II or Carmeda equipment for extracorporeal circulation as reflected by the changes of cytokine and circulating adhesion molecule levels.

Glycine does not add to the beneficial effects of perioperative oral immune-enhancing nutrition supplements in high-risk cardiac surgery patients

BACKGROUND Elderly patients and patients with a poor cardiac function have increased morbidity rates when undergoing cardiac surgery. The aim of this study was to determine whether addition of glycine to a standard preoperative oral immune-enhancing nutrition supplement (OIENS) improves outcome. Glycine-enriched OIENS was compared with 2 formulas: standard OIENS and control. METHODS In this double-blind, 3-armed study, patients scheduled to undergo cardiac surgery with the use of extracorporeal circulation received either the glycine-enriched OIENS (OIENS + glyc, n = 24), standard OIENS (OIENS, n = 25), or control formula (Control, n = 25) for minimally 5 preoperative days. Patients were included if they were aged 70 years or older, had a compromised left ventricular function, or were planned for mitral valve surgery. Main outcome measures were postoperative infectious morbidity, organ function, and postoperative recovery. RESULTS Infectious morbidity was significantly lower in both treatment groups compared with the control group (p = .02). An infection was diagnosed in 5 and 4 patients in the OIENS + glyc and OIENS groups, respectively, and in 12 control patients. Less supportive therapy was necessary to stabilize circulation in both treatment groups compared with the control group. Median length of hospital stay was 7.0, 6.5, and 8.0 days in the OIENS + glyc, OIENS, and control groups, respectively. Inflammatory responses, as measured by systemic levels of proinflammatory cytokines and surface markers on polymorphonuclear cells, were comparable for all groups. CONCLUSIONS Preoperative OIENS reduces postoperative infectious morbidity and results in a more stable circulation; the addition of glycine does not result in any beneficial effect over standard OIENS.