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New therapeutic alternatives, such as innovative medical devices, are frequently the only treatment options left for patients when other efficient medical modalities are lacking or insufficient. Development of novel devices, which are safe and effective, requires understanding of complex premarket and postmarket provisions, including characteristics of clinical trials. Speeding up patient access to new technologies may imply the need to make choices in terms of extent and robustness of clinical evaluation without losing the patient safety perspective. In such situations, some challenges can readily arise due to existing methodological solutions and aspects of current legislation in the field. In this context, some challenges, occurring at various stages of the device lifecycle, will be presented in order to observe the changes and hopefully to contribute to better knowledge and improvements in the area.

Background Previously, nitric oxide has been shown to possess antimicrobial effects. In this study, we aim to test the effect of glyceryl trinitrate (GTN) on Staphylococcus aureus growth during simulated extracorporeal circulation (SECC) and also to examine the effect of S. aureus, alone and in combination with GTN, on activation markers of the innate immune system during SECC. Methods In an in vitro system of SECC, we measured GTN-induced changes in markers of leukocyte activation in whole blood caused by S. aureus infestation, as well as the effect of GTN on S. aureus growth. Results GTN had no effect on S. aureus growth after 240 minutes SECC. Staphylococcus aureus reduced the expression of granulocyte Fc gamma-receptor CD32 but stimulated the expression of monocyte CD32. Staphylococcus aureus stimulated expression of some leukocyte adhesion key proteins, activation marker CD66b, lipopolysaccharide-receptor CD14, and C3b-receptor CD35. Staphylococcus aureus and GTN addition induced significant increases in monocyte CD63 (lysosomal granule protein) levels. Conclusion GTN does not affect S. aureus growth during SECC and has no effect on SECC-induced leukocyte activation.

Objectives. During extracorporeal circulation (ECC), a mechanical pump and an oxygenator replace the functions of the heart and lungs. The aim of this study is to test the effect of the nitric oxide donor glyceryl-tri-nitrate on activation markers of the innate immune system during simulated ECC. Design. Whole blood concentrations of selected leukocyte adhesion molecules, complement system components and myeloperoxidase (MPO) were measured in an in vitro system of simulated ECC. Results. Simulated ECC stimulated the expression of monocyte LPS-receptor CD14 and C3b-receptor CD35. Glyceryl-tri-nitrate significantly reduced the expression of leukocyte Fcγ receptor CD32 over time, compared to control. Simulated ECC increased the concentrations of MPO, terminal complement complex, and complement component C3a. Addition of glyceryl-tri-nitrate did not significantly affect these changes. Conclusions. Simulated ECC induces the increased expression of some leukocyte markers. Glyceryl-tri-nitrate addition significantly reduces the expression of some leukocyte activation markers.

Background: Several factors contribute to postoperative bacterial infections in cardiac surgery. Long operation times and the use of extracorporeal circulation increase the risk of infection. Nitric oxide has been shown to possess a broad spectrum antimicrobial effect. Methods: In this study, we investigated the effect of nitric oxide on S. aureus growth in whole blood during simulated extracorporeal circulation. Results: S. aureus growth increased 6.2-fold after 180 min SECC in the presence of nitric oxide. Leukocyte counts remained unchanged without any differences between the groups. We observed a steady increase in markers of oxidative stress and activity of the innate immune system. Myeloperoxidase levels increased 8-fold, and C3a and terminal complement complex by 2-fold after 180 min. Conclusion: S. aureus growth is not due to the effect of nitric oxide on the innate immune system but from its effect on the bacteria itself. It has been shown that nitric oxide stimulates the expression of inducible lactate dehydrogenase, specific to S. aureus, which improves its resistance to oxidative stress, and may give S. aureus a survival advantage resulting in increased growth.

BACKGROUND:

Endothelial cell (EC) dysfunction contributes to hypertension and mechanisms of atherosclerosis. Agents that improve EC function may provide vascular protection, especially in patients with multiple risk factors. In this study, we examined the effects of beta(1)-selective antagonists, nebivolol and metoprolol, on vascular and renal EC function in spontaneously hypertensive (SH) rats with diabetes.

METHODS:

Male SH rats were treated with streptozotocin (STZ) to induce type 2 diabetes, followed by treatment with nebivolol or metoprolol at 2 mg/kg/day (vs. vehicle). After 4 weeks, aortic and glomerular ECs were isolated, stimulated with calcium ionophore (CaI), and assayed for nitric oxide (NO), and peroxynitrite (ONOO(-)) release using amperometric approaches.

RESULTS:

Glucose and mean blood pressure (BP) levels were significantly elevated in diabetic SH rats. In aortic ECs isolated from diabetic SH rats, NO production decreased by 20% whereas ONOO(-) increased by 16%, an effect linked to NAD(P)H oxidase and endothelial NO synthase (eNOS) uncoupling. Nebivolol treatment reduced glucose and BP levels and restored aortic EC function in diabetic SH rats, as indicated by a 30% increase and 23% decrease in NO and ONOO(-) levels, respectively. The NO/ONOO(-) ratio increased by more than twofold with nebivolol treatment in aortic and glomerular ECs. Despite similar reductions in glucose and mean BP levels, metoprolol had a smaller effect on the NO/ONOO(-) ratio in glomerular ECs but no effect in aortic ECs.

CONCLUSIONS:

Vascular and renal NO was significantly reduced in diabetic hypertensive rats and correlated with metabolic changes. Nebivolol reversed these effects in a manner consistent with enhanced endothelial function.

Background: Surgical wound infection (SWI) of the leg after saphenous vein harvesting is an important complication of coronary artery bypass graft (CABG) procedures. SWIs may restrict mobility in the postoperative period and increase costs of postoperative hospitalisation and antibiotic treatment. Methods: A total of 356 patients were followed. Surgical risk factors were evaluated for SWI following saphenous vein harvesting, and the effectiveness of an occlusive glycerinated hydrogel dressing in reducing postoperative SWIs was assessed. In addition, the ability of postoperative clinical wound assessment to predict SWI following CABG 30 and 60 days after operation was investigated. Results: The most important risk factor for SWI after saphenous vein harvesting was the use of a monofilament suture for skin closure (glycomer 4-0 Biosyn® Tyco Healthcare, Stockholm, Sweden) (p > 0.001). The hydrogel dressing did not prevent the development of SWIs. The clinical wound assessment showed that wound gap was associated with leg infection, but other signs were poor predictors of SWI. Conclusion: The choice of suture and suturing technique is important to prevent SWI following saphenous vein harvesting. More precise definitions of wound signs are necessary if they are to be used as predictors of SWI.

Elevated blood glucose following coronary artery bypass graft (CABG) is associated with an increased risk of surgical wound infection (SWI). It is unclear whether hyperglycaemia, the diabetic state, the longstanding vascular effects of diabetes, or the systematic inflammatory response confers the increased vulnerability to SWI. This study was designed to examine the significance of postoperative blood glucose control as a risk factor for SWI after vein graft harvesting on the leg and sternotomy. Patients with and without diabetes had a CABG within 60 days to be eligible. The present study was part of a larger protocol investigating SWI following CABG in a total of 374 patients. Potential risk factors, duration of diabetes, pre-operative glycated haemoglobin (HbA_1c) and presence of long-term complications were recorded. All patient records were reviewed retrospectively to record 10% glucose infusions during the operation, and blood glucose concentrations and insulin therapy on postoperative days 0, 1 and 2. Patients were contacted by telephone 30 and 60 days after surgery and interviewed in accordance with a questionnaire about symptoms and signs of wound infection. In the present study, it was not possible to separate the effect of diabetes as a risk factor for SWI from that of hyperglycaemia. However, in the subgroup of patients without a pre-operative diagnosis of diabetes, increased blood glucose concentrations during postoperative days 0, 1 and 2 was associated with an increased risk of mediastinitis.

Surgical wound infections (SWIs) after coronary artery by-pass graft (CABG) within 30 and 60 days of operation were registered. Already known risk factors and possible risk factors for wound infection were studied. SWIs of sternal and/or leg wounds have been reported to occur in 2–20% of patients after CABG. Deep sternal infection, mediastinitis, occurs after 0.5–5% of CABG procedures. The duration and methods of follow-up, as well as definitions of SWI, vary in different studies. Previously known and possible new risk factors were registered for 374 patients. Patients were contacted by telephone 30 and 60 days after surgery and interviewed in accordance with a questionnaire about symptoms and signs of wound infections. Our definition of SWI was based on the Centers for Disease Control and Prevention (CDC) definition. SWIs were diagnosed in 114 of 374 (30.5%) of the patients. In total SWI were diagnosed in 120 surgical-site incisions. Almost all SWIs of the sternum (93.3%) were diagnosed within 30 days of surgery. Most of the SWIs of the leg (73%) were diagnosed within 30 days of surgery and 27% were diagnosed within 31 to 60 days of surgery. Being female was the most important risk factor for SWI of the leg. Low preoperative haemoglobin concentrations were the most important risk factor for superficial SWI on the sternum. Patients with mediastinitis had higher BMI and had more often received erythrocyte transfusions on postoperative day two or later than those without infections.

BACKGROUND: The technique of harvesting the saphenous vein for coronary artery bypass grafting influences the fate of vein grafts. The patency rate of a novel "no-touch" technique in which the vein is harvested with a pedicle of surrounding tissue and not distended was compared with two other techniques.

METHODS: One hundred fifty-six patients who underwent coronary artery bypass grafting were randomized to three saphenous vein harvesting groups: group C (conventional)--the vein was stripped, distended, and stored in saline; group I (intermediate)--the vein was stripped, local application of papaverine was used instead of distention, and the vessel was then stored in heparinized blood; and group NT (no-touch)--the vein was harvested with surrounding tissue, not distended, and stored in heparinized blood. Surgical and clinical factors that might influence graft occlusion were recorded. One hundred twenty-seven vein grafts in group C, 116 in group I, and 124 in group NT, as well as 118 left internal mammary artery grafts, were angiographically assessed at 18 months mean follow-up time.

RESULTS: The vein graft patency was 88.9% in group C, 86.2% in group I, and 95.4% in group NT. There was a statistically significant difference between the patency of the single-vein grafts in NT and the other two groups (p = 0.025). The higher the flow, the better the patency irrespective of the technique used. A higher attrition rate was found in vein segments taken from the knee area in group I. Poor vein quality affected patency in all groups. Forty-seven of all 51 sequential grafts (92.2%) were patent. The patency of left internal mammary artery grafts was 108 of 118 (91.5%).

CONCLUSIONS: We conclude that preservation of the surrounding tissue of the saphenous vein using this no-touch technique abolishes venospasm intraoperatively and plays an important role in maintaining vein graft function and patency.