Bektas Atasever

START Trial: a pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease.

Background—Granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently shown to increase collateral flow index in patients with coronary artery disease. Experimental models showed beneficial effects of GM-CSF on collateral artery growth in the peripheral circulation. Thus, in the present study, we evaluated the effects of GM-CSF in patients with peripheral artery disease. Methods and Results—A double-blinded, randomized, placebo-controlled study was performed in 40 patients with moderate or severe intermittent claudication. Patients were treated with placebo or subcutaneously applied GM-CSF (10 &mgr;g/kg) for a period of 14 days (total of 7 injections). GM-CSF treatment led to a strong increase in total white blood cell count and C-reactive protein. Monocyte fraction initially increased but thereafter decreased significantly as compared with baseline. Both the placebo group and the treatment group showed a significant increase in walking distance at day 14 (placebo: 127±67 versus 184±87 meters, P=0.03, GM-CSF: 126±66 versus 189±141 meters, P=0.04) and at day 90. Change in walking time, the primary end point of the study, was not different between groups. No change in ankle-brachial index was found on GM-CSF treatment at day 14 or at day 90. Laser Doppler flowmetry measurements showed a significant decrease in microcirculatory flow reserve in the control group (P=0.03) and no change in the GM-CSF group. Conclusions—The present study does not support the use of GM-CSF for treatment of patients with moderate or severe intermittent claudication. Issues that need to be addressed are dosing, the selection of patients, and potential differences between GM-CSF effects in the coronary and the peripheral circulation.

Pulsatile flow during cardiopulmonary bypass preserves postoperative microcirculatory perfusion irrespective of systemic hemodynamics

The onset of nonpulsatile cardiopulmonary bypass is known to deteriorate microcirculatory perfusion, but it has never been investigated whether this may be prevented by restoration of pulsatility during extracorporeal circulation. We therefore investigated the distinct effects of nonpulsatile and pulsatile flow on microcirculatory perfusion during on-pump cardiac surgery. Patients undergoing coronary artery bypass graft surgery were randomized into a nonpulsatile (n = 17) or pulsatile (n = 16) cardiopulmonary bypass group. Sublingual mucosal microvascular perfusion was measured at distinct perioperative time intervals using sidestream dark field imaging, and quantified as the level of perfused small vessel density and microvascular flow index (vessel diameter < 20 μm). Microcirculation measurements were paralleled by hemodynamic and free hemoglobin analyses. The pulse wave during pulsatile bypass estimated 58 ± 17% of the baseline blood pressure waveform. The observed reduction in perfused vessel density during aorta cross-clamping was only restored in the pulsatile flow group and increased from 15.5 ± 2.4 to 20.3 ± 3.7 mm/mm(2) upon intensive care admission (P < 0.01). The median postoperative microvascular flow index was higher in the pulsatile group [2.6 (2.5-2.9)] than in the nonpulsatile group [2.1 (1.7-2.5); P = 0.001]. Pulsatile flow was not associated with augmentation of free hemoglobin production and was paralleled by improved oxygen consumption from 70 ± 14 to 82 ± 16 ml·min(-1)·m(-2) (P = 0.01) at the end of aortic cross-clamping. In conclusion, pulsatile cardiopulmonary bypass preserves microcirculatory perfusion throughout the early postoperative period, irrespective of systemic hemodynamics. This observation is paralleled by an increase in oxygen consumption during pulsatile flow, which may hint toward decreased microcirculatory heterogeneity during extracorporeal circulation and preservation of microcirculatory perfusion throughout the perioperative period.

Distinct alterations in sublingual microcirculatory blood flow and hemoglobin oxygenation in on-pump and off-pump coronary artery bypass graft surgery

OBJECTIVEnThe authors hypothesized that cardiopulmonary bypass (CPB) (on-pump) is associated with more severe changes in the microcirculatory blood flow and tissue oxygenation as compared with off-pump coronary artery bypass surgery.nnnDESIGNnAn observational study.nnnSETTINGnA university hospital and teaching hospital.nnnPARTICIPANTSnPatients undergoing on-pump (n = 24) or off-pump (n = 24) cardiac surgery.nnnINTERVENTIONSnMicrocirculatory measurements were performed before CPB and 10 minutes after the switch to CPB or before and during cardiac luxation in off-pump patients.nnnMEASUREMENTS AND MAIN RESULTSnSublingual microcirculatory perfusion was investigated using side-stream dark field imaging, and sublingual microcirculatory oxygenation was measured using reflectance spectrophotometry. Conversion to CPB resulted in an increase in cardiac output from 4.0 ± 0.2 to 4.8 ± 0.3 L/min (p < 0.01) and a 40% reduction in arterial hemoglobin concentration. Cardiopulmonary bypass was associated with an increase in venular blood velocity from 349 ± 201 μm/s to 563 ± 227 μm/s (p < 0.05), a reduction in functional capillary density of 43%, and an increase in hemoglobin oxygenation of the red blood cells in the remaining filled capillaries from 47.2% ± 6.1% to 59.7% ± 5.2% (p < 0.001). The decrease in cardiac output during cardiac luxation from 4.5 ± 1.7 to 1.8 ± 0.8 L/min (p < 0.01) without hemoglobin changes was associated with a complete halt of capillary blood flow and a reduction in maximum capillary blood velocity from 895 ± 209 to 396 ± 178 μm/s (p < 0.01). The functional capillary density remained unchanged, whereas the hemoglobin oxygenation declined from 64.2% ± 9.1% to 48.6% ± 8.7% (p < 0.01).nnnCONCLUSIONSnOn-pump and off-pump cardiac surgery are associated with distinct alterations in sublingual microcirculatory perfusion and hemoglobin oxygenation. Although on-pump surgery results in a fall out of capillaries resulting in decreased oxygen extraction, off-pump surgery results in a cessation of flow during luxation resulting in decreased convection of oxygen transport.

Red blood cell transfusion compared with gelatin solution and no infusion after cardiac surgery: effect on microvascular perfusion, vascular density, hemoglobin, and oxygen saturation.

BACKGROUND: After cardiac surgery, red blood cell (RBC) transfusion may improve systemic hemodynamics and thereby microvascular blood flow and O2 delivery (DO2).

Cardiac displacement during off-pump coronary artery bypass grafting surgery: effect on sublingual microcirculation and cerebral oxygenation

Cardiac displacement during off-pump coronary artery bypass (OPCAB) surgery causes a fall in cardiac output. Here, we investigate how this drop in systemic perfusion is transferred to the oxygenation of sublingual and cerebral tissue. Sublingual microcirculatory perfusion or microcirculatory hemoglobin oxygen saturation (μHbSO(2)) measurements were performed using sidestream dark-field imaging and reflectance spectrophotometry, respectively (both n = 12). The cerebral tissue oxygenation index was measured by near-infrared spectrophotometry (n = 12). Cardiac output was calculated by pulse contour analysis of arterial pressure. Cardiac displacement reduced the cardiac output from 4.3 ± 0.8 to 1.2 ± 0.3 l/min (P < 0.05), paralleled by a decrease in μHbSO(2) from 64.2 ± 9.1 to 48.6 ± 8.7% (P < 0.01). Cardiac displacement did not change functional capillary density, while red blood cell velocity decreased from 895 ± 209 to 396 ± 178 μm/s (P<0.01). Cerebral tissue oxygenation index decreased from 69.5 ± 4.0 to 57.4 ± 8.5% (P<0.01) during cardiac displacement. After repositioning of the heart, all the values returned to baseline. Our data suggest that systemic hemodynamic alterations during cardiac displacement in OPCAB surgery reduce sublingual and cerebral tissue oxygenation. These findings are particularly important for patients at risk for the consequences of cerebral ischemia.

Design of the START-trial: STimulation of ARTeriogenesis using subcutaneous application of GM-CSF as a new treatment for peripheral vascular disease. A randomized, double-blind, placebo-controlled trial

Peripheral arterial disease (PAD) affects a large percentage of the elderly population. Standard invasive treatment, apart from risk factor modulation, consists of bypass surgery or percutaneous transluminal angioplasty. However, symptomatic recurrence rates are high for both procedures and a substantial part of the patient population with PAD is not a candidate for invasive revascularization due to complexity of the lesion and/or co-morbidity. Therapeutic arteriogenesis has been proposed as an alternative treatment option. The present paper describes the design of the START-trial. This trial aims to determine the potential of the proarteriogenic substance granulocyte/macrophage colony stimulating factor (GM-CSF) to increase maximal walking distance in patients with intermittent claudication. A double-blinded, randomized, placebo-controlled study will be performed in 40 patients with peripheral obstructive arterial disease Rutherford grade I, category 2 or 3, that are candidates for bypass surgery or percutaneous transluminal angioplasty. Based on pharmacokinetic and toxicologic studies, a dose of 10 mg/kg will be used. Patients will be treated for a period of 14 days on each consecutive day, with the last injection applied on day 12. The primary endpoint will be the change in walking distance from day 0 to day 14 as assessed by an exercise treadmill test. Secondary endpoints will be the ankle-brachial index at rest and after exercise, the pain-free walking distance and cutaneous microcirculatory alterations as assessed by laser Doppler fluxmetry. Iliac flow reserve and conductance will be measured by magnetic resonance imaging.