Evidence for inflammatory responses of the lungs during coronary artery bypass grafting with cardiopulmonary bypass.

OBJECTIVE: The occurrence of a systemic inflammatory reaction during cardiac surgery with cardiopulmonary bypass (CPB) has been well established, and the heart itself has been shown to release inflammatory mediators after ischemia. The hypothesis of the present study was that the lungs are also a site of inflammatory responses during early reperfusion. METHODS: In 20 consecutive patients undergoing coronary artery bypass grafting, blood was simultaneously drawn from the right atrium (RA) and the pulmonary vein (PV) before CPB and at 1 min, 10 min, and 20 min of reperfusion. The levels of interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha were determined, as well as the adhesion molecules CD41 and CD62 on platelets and CD11b and CD41 on leukocytes. As a measure of the pulmonary release, ratios of PV and RA levels were calculated. RESULTS: Before CPB, the concentrations of cytokines tended to be lower in the PV compared with the RA. At 1 min of reperfusion, no significant concentration increases were found in the PV. At 10 min of reperfusion, the PV/RA ratio (mean +/- SEM) for IL-6 was 2.06 +/- 0.37 and 1.24 +/- 0.15 for IL-8 (p = 0.02 and p = 0.04, respectively, compared with the pre-CPB ratios of 0.89 +/- 0.4 and 0.99 +/- 0.2). At 20 min of reperfusion, PV/RA ratios for IL-6 (1.95 +/- 0.37) and IL-10 (0.99 +/- 0.4) were higher than before CPB (0.89 +/- 0.04, p = 0.05 and 0.85 +/- 0.06, p = 0.03, respectively). Adhesion molecule counts on platelets and polymorphonuclear neutrophils (PMNs) tended to be higher in the PV than in the RA before CPB. At 1 min of reperfusion, the PV/RA ratio of CD41 on monocytes (0.89 +/- 0.04) and of CD41 on PMNs (1.05 +/- 0.05) was less than before CPB (1.24 +/- 0.08, p = 0.0002 and 1.55 +/- 0.14, p = 0.0002). At 10 min and 20 min of reperfusion, similar changes were found. CONCLUSIONS: The observed changes indicate an inflammatory response of the lungs. Proinflammatory cytokines are increased in pulmonary venous blood. At the same time, activated blood cells are retained in the pulmonary circulation. This may contribute to pulmonary dysfunction almost routinely observed after CPB.

The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass.

The effect of preoperative anticoagulant therapy on intraoperative heparin response in patients undergoing cardiac operations was examined in a prospective study. The study included 45 patients with different preoperative anticoagulant treatments: 10 patients received treatment with phenprocoumon (a warfarin analogue) (group M), 12 patients received treatment with intravenous heparin (group Hiv), and 13 patients received treatment with subcutaneous heparin (group Hsc). The control group consisted of 10 patients who did not receive anticoagulant therapy before operation (group C). Preoperative antithrombin III activity was highest in group M (85% +/- 6%) and lowest in group Hiv (70% +/- 15%, p less than 0.05). The activated clotting time, determined 10 minutes after bolus injection of 250 IU (group M) or 375 IU heparin (all other groups), was 529 +/- 109 seconds in group C, greater than 1000 seconds in group M, 483 +/- 99 seconds in group Hsc, and 406 +/- 63 seconds in group Hiv (p less than 0.05). Heparin consumption during cardiopulmonary bypass varied between 4.6 +/- 1.4 IU/kg.min (group Hiv) and 2.6 +/- 0.9 IU/kg.min (group M) (p less than 0.05). Despite this increased heparin consumption, the patients who had received heparin before operation demonstrated increased activation of coagulation at the end of cardiopulmonary bypass (thrombin-antithrombin III complex, 19 +/- 4.1 ng/ml in group M and 61 +/- 7 ng/ml in group Hsc, p less than 0.05; cross-linked fibrin fragments, 257 +/- 92 ng/ml in group M and 875 +/- 152 ng/ml in group Hiv, p less than 0.05). Increased platelet activation was also found in patients with preoperative heparin therapy (beta-thromboglobulin at the end of cardiopulmonary bypass was 585 +/- 88 ng/ml in group M versus 1341 +/- 190 ng/ml in group Hsc, p less than 0.05). Drainage from the chest tube 24 hours after operation was 815 +/- 305 ml in group C, 644 +/- 238 ml in group M, 1133 +/- 503 ml in group Hsc, and 950 +/- 505 ml in group Hiv (p less than 0.05 for group M versus group Hsc). This study suggests that patients who receive heparin therapy before operation face a high risk of insufficient anticoagulation during cardiopulmonary bypass if standard heparin doses are used. Therefore, for patients who receive preoperative heparin therapy, a larger (500 IU/kg) initial bolus of heparin is recommended before cardiopulmonary bypass. On the other hand, patients who undergo preoperative treatment with phenprocoumon receive sufficient anticoagulative effect with a heparin bolus of 250 IU/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

Reduction of blood utilization during myocardial revascularization.

The efficacy of four different blood conservation techniques in decreasing the homologous blood requirement in cardiac operations was studied prospectively in 100 patients undergoing myocardial revascularization. The patients were randomly assigned to four groups of 25 each as follows: group I, retransfusion of oxygenator blood after termination of extracorporeal circulation; group II, processing of oxygenator content by means of a cell separator; group III, predonation of autologous blood and isovolumetric substitution of hydroxyethyl starch (10 ml/kg bodyweight) after the induction of anesthesia in addition to the use of a cell separator; and group IV, predonation and the use of a cell separator plus postoperative retransfusion of shed mediastinal blood. To form homologous groups, we accepted only male patients without impairment of left ventricular function for the study. In addition, patients with internal mammary artery grafts and a duration of extracorporeal circulation less than 45 minutes or more than 90 minutes were excluded. The bank blood requirement during hospitalization was 2132 +/- 824 ml in group I, 1371 +/- 928 ml in group II, 833 +/- 599 ml in group III, and 408 +/- 559 ml in group IV. The use of blood conservation techniques resulted in reductions of homologous blood requirements of 34%, 60%, and 80%, respectively, in groups II to IV as compared with the requirement in group I. There were no complications related to autologous blood transfusion. We conclude that the use of blood conservation techniques can considerably reduce the homologous blood requirement in cardiac operations and therefore decrease transfusion-related risks.

Cardiac surgery with deep hypothermic circulatory arrest produces less systemic inflammatory response than low-flow cardiopulmonary bypass in newborns.

OBJECTIVE: We sought to compare low-flow cardiopulmonary bypass with deep hypothermic circulatory arrest in respect to the influence on the systemic inflammatory response. METHODS: Twenty-three infants weighing less than 10 kg and scheduled for repair of congenital malformations were enrolled in a randomized, controlled study. Eleven patients underwent cardiac surgery with deep hypothermic circulatory arrest (the DHCA group). Low-flow cardiopulmonary bypass was used in another 12 patients (the LF group). Interleukin 6 and 8 and anaphylatoxin C3a levels were measured 6 times perioperatively. Also, perioperative weight gain and a radiologic soft-tissue index were compared. RESULTS: All patients had an uneventful clinical course. Duration of deep hypothermic circulatory arrest was 40 +/- 4 minutes; the bypass time was significantly shorter in the DHCA group (85 +/- 8 vs 130 +/- 19 minutes). However, the duration of the operation was similar in both groups (245 +/- 30 vs 246 +/- 30 minutes). During cardiopulmonary bypass (rewarming), the concentration of C3a (3751 +/- 388 vs 5761 +/- 1688 ng/mL, mean +/- SEM) was significantly lower in the DHCA group than in the LF group. The interleukin 8 level was significantly lower, and the interleukin 6 level had a tendency to be lower in the DHCA group compared with levels in the LF group. There was less weight gain on the first postoperative day in the DHCA group (65 +/- 61 vs 408 +/- 118 g). The soft-tissue index suggested reduced edema formation in the DHCA group. CONCLUSION: Deep hypothermic circulatory arrest produces less systemic inflammatory response than low-flow cardiopulmonary bypass. In addition, there is an indication of less fluid accumulation postoperatively.

Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations.

The effect of high-dose aprotinin treatment on hemostatic activation during cardiopulmonary bypass in pediatric patients having cardiac operations was investigated. Sixty patients weighing less than 10 kg undergoing cardiac operations for different types of congenital heart diseases were studied: 20 patients were treated with aprotinin 2 x 15,000 KIU/kg, 20 patients with 2 x 30,000 KIU/kg, and 20 patients without aprotinin treatment served as the control group. Different split products of fibrinogen and/or fibrin and the fibrinolytic activity on fibrin plates were measured to assess fibrinolytic activation. F1/F2 prothrombin fragments, thrombin-antithrombin III-complex, and fibrin monomers were measured to estimate thrombin activation. There was a significant dose-dependent reduction in fibrin-fibrinogen split product formation during cardiopulmonary bypass: In the high-dose aprotinin group the concentration of the split products at the end of bypass was 1.5 +/- 0.6 micrograms/ml, compared with 3.4 +/- 3.0 micrograms/ml in the low-dose aprotinin group and 6.7 +/- 3.5 micrograms/ml in the control group (p < 00.5). Fibrinolytic activation on fibrin plates was also significantly reduced by aprotinin. Fibrin monomer formation was significantly diminished at the end of cardiopulmonary bypass in the high-dose group: 9.2 +/- 5.2 micrograms/ml compared with 21.6 +/- 14 micrograms/ml in the control group (p < 00.5). Elastase in complex with alpha 1-protease inhibitor at the end of bypass was increased to the same amount in the three groups: 784 +/- 278 ng/mL (control group), 693 +/- 189 ng/ml (low-dose aprotinin), and 719 +/- 270 ng/mL (high dose aprotinin) (no significant difference). Blood loss 6 hours postoperatively was significantly (p < 00.5) less in the high-dose group (99 +/- 32 ml/m2) than in the control group (164 +/- 87 ml/m2; low-dose group: 160 +/- 106 ml/m2). These observations suggest an attenuation of hemostatic activation during cardiopulmonary bypass with less plasmin formation and, because of inhibition of contact activation, less thrombin generation with aprotinin treatment. Thus the thrombotic-thrombolytic equilibrium is kept more balanced after cardiopulmonary bypass. High-dose aprotinin treatment is recommended for pediatric patients undergoing cardiac operations.

Sodium nitroprusside in patients with compromised left ventricular function undergoing coronary bypass: reduction of cardiac proinflammatory substances.

OBJECTIVE: The aim of the present study was to investigate whether the nitric oxide donor sodium nitroprusside can reduce the cardiac inflammatory response during coronary artery bypass grafting in patients with severely compromised left ventricular function. METHODS: Patients (n = 30) were assigned to receive placebo or sodium nitroprusside (0.5 microg. kg(-1). min(-1)) for the first 60 minutes of reperfusion. Interleukin 6, interleukin 8, and tumor necrosis factor alpha levels; platelet adhesion molecule CD41 and CD62 levels; and CD11b on leukocytes were determined in the radial artery and coronary sinus before cardiopulmonary bypass and during reperfusion (1, 5, 10, 35, and 75 minutes). RESULTS: At 1 minute of reperfusion, coronary venous levels of CD41-positive polymorphonuclear leukocytes were 8% lower than arterial levels in the placebo group and 18% higher in the sodium nitroprusside group (P =.021). At 5 minutes of reperfusion, the respective levels were 29% and 1% for interleukin 6 (P =.015), -5% and 20% for CD41-positive monocytes (P =.032), and -2% and 16% for CD11b-positive monocytes (P =.038). At 10 minutes of reperfusion, these levels were -14% and 21% for CD41-positive monocytes (P =.006). At 35 minutes of reperfusion, these levels were -13% and 7% for CD41-positive monocytes (P =.017), -41% and 23% for CD11b-positive monocytes (P =.001), and 7% and 25% for CD62-positive platelets (P =. 041). At 75 minutes of reperfusion, the levels were 15% and -7% for tumor necrosis factor alpha (P =.025) and -10% and 10% for CD62-positive platelets (P =.041). CONCLUSIONS: Transcardiac production of proinflammatory cytokines is reduced in patients undergoing coronary artery bypass grafting treated with the nitric oxide donor sodium nitroprusside. At the same time, less activated leukocytes and platelets are retained in the coronary circulation.

Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting.

BACKGROUND: Cardiopulmonary bypass causes inflammatory reactions leading to organ dysfunction postoperatively. This study was undertaken to determine whether using patients' own lungs as oxygenator in a bilateral circuit (Drew-Anderson Technique) could reduce systemic inflammatory response to cardiopulmonary bypass, improving patients clinical outcome following coronary artery bypass grafting. METHODS: A prospective randomized controlled trial involving 30 patients, divided in two groups of 15 patients each, undergoing elective coronary artery bypass grafting, was undertaken. In the Drew-group bilateral extracorporeal circulation using patient's lung as oxygenator was performed. The other patients served as control group, where standard cardiopulmonary bypass procedure was used. RESULTS: Pro-inflammatory and anti-inflammatory mediators were measured. Peak concentrations of proinflammatory interleukin-6, interleukin-8, were significantly lower in 15 patients undergoing Drew-Anderson Technique compared with the concentrations measured in 15 patients treated with standard cardiopulmonary bypass technique. Differences in patient recovery were analyzed with respect to time of intubation, blood loss, intrapulmonary shunting, oxygenation, and respiratory index. In patients undergoing uncomplicated coronary artery bypass grafting procedures bilateral extracorporeal circulation using the patients' own lung as oxygenator provided significant biochemical and clinical benefit in comparison to the standard cardiopulmonary bypass procedure. CONCLUSIONS: This prospective randomized clinical study has demonstrated that exclusion of an artificial oxygenator from cardiopulmonary bypass circuit significantly decreases the activation of inflammatory reaction, and that interventions that attenuate this response may result in more favorable clinical outcome.

Sodium nitroprusside during coronary artery bypass grafting: evidence for an antiinflammatory action.

BACKGROUND: It was the aim of the present study to investigate whether a nitric oxide donor can reduce systemic inflammation and the cardiac inflammatory response during coronary artery bypass grafting with cardiopulmonary bypass. METHODS: Patients undergoing elective coronary artery bypass grafting (n = 22) were randomly assigned to treatment with either sodium nitroprusside (0.5 microg x kg(-1) x min(-1)) or placebo (controls), both for the first 20 minutes of reperfusion. Interleukin-6 and interleukin-8 levels, the adhesion molecules CD41 and CD62 on platelets and CD41 on monocytes and PMN (as markers for coaggregate formation), CD11b on monocytes and PMN, as well as platelet and leukocyte counts were determined in radial artery and coronary sinus blood before cardiopulmonary bypass and during reperfusion (1, 5, 10, 25, and 35 minutes). RESULTS: A reduction of systemic interleukin-6 levels (15.4+/-3.5 pg/mL, 36.7+/-5.9 pg/mL, and 46.8+/-8.0 pg/mL versus 33.4+/-7.7 pg/mL, 76.7+/-13.2 pg/mL, and 106.0+/-26.5 pg/mL, respectively, at 1, 25, and 35 minutes of reperfusion) and interleukin-8 (29.6+/-4.5 pg/mL versus 54.0+/-9.4, pg/mL, resp., at 35 minutes of reperfusion) resulted from treatment with sodium nitroprusside. No intracardiac production of interleukin-8 in sodium nitroprusside-treated patients (-1.1+/-0.4 pg/mL and -2.8+/-2.2 pg/mL, resp., for the coronary sinus-radial artery difference at 5 and 25 minutes of reperfusion) was observed, whereas cardiac production of interleukin-8 was present in controls (2.5+/-1.5 pg/mL and 5.5+/-2.8 pg/mL, resp.). Retention of platelet/leukocyte coaggregates occurred during coronary passage in controls (coronary sinus-radial artery difference for CD41-positive monocytes at 1 and 10 minutes of reperfusion, -16.3%+/-8.5% and -8.8%+/-2.6%, resp.). This was reduced in sodium nitroprusside-treated patients (with 5.8%+/-5.2% and 0.0%+/-3.2%). Retention of platelets in controls (ratio of coronary sinus to radial artery platelet count at 5 and 10 minutes of reperfusion, 88%+/-6% and 91%+/-5%) was compared to washout in treated patients (108%+/-6% and 113%+/-7%). CONCLUSIONS: In patients undergoing routine coronary artery bypass grafting, administration of sodium nitroprusside during early reperfusion alleviates systemic inflammation and the cardiac inflammatory response.

Significant leukocyte and platelet retention during pulmonary passage after declamping of the aorta in CABG patients.

During reperfusion of the heart and the lungs in patients undergoing coronary artery bypass grafting, these organs have been shown to release inflammatory mediators. The present study was performed to quantitatively determine cellular retention or washout during pulmonary passage in early reperfusion. In 14 consecutive patients undergoing coronary artery bypass grafting blood was simultaneously drawn from right atrium and pulmonary vein at 1, 10 and 20 min reperfusion. The counts for platelets, leukocytes and the leukocyte subsets polymorphonuclear neutrophils (PMN), lymphocytes and monocytes were determined. Pulmonary veno-right atrial (transpulmonary) differences are given in percent with respective right atrial values being considered as 100%. Before CPB leukocyte counts were 4.7 +/- 0.5 in right atrium and 4.2 +/- 0.4 in pulmonary vein, x10(9)/l, resp. (transpulmonary difference of -8 +/- 3%). During reperfusion, pulmonary retention was in the range of 20-23% (p <0.01 vs. right atrial value). The basal values for PMN were 2.4 +/- 0.3 in right atrium and 1.9 +/- 0.3 in pulmonary vein, x10(9)/l, resp. (transpulmonary difference -15 +/- 8%). Thereafter, retention was in the range of 25-30% (p <0.01 vs. right atrium). Basal values for lymphocytes were 1.5 +/- 0.2 in right atrium and 1.6+/-0.3 in pulmonary vein, x10(9)/l, resp. (transpulmonary difference +6 +/- 10%). A tendency towards a washout of lymphocytes at 1 min reperfusion (+1 +/- 12%) was followed by retention of these cells at 10 and 20 min reperfusion (-14 +/- 12% and -10 +/- 5%, p <0.05 vs right atrium). Before ischemia monocyte counts were 0.7 +/- 0.2 in right atrium and 0.6 +/- 0.2 in pulmonary vein, x10(9)/l, resp. (transpulmonary difference -10 +/- 4%) and -9 +/- 9%, -27 +/- 12% (p <0.05 vs right atrium) and -22 +/- 14% at 1, 10 and 20 min reperfusion. During early reperfusion of the lungs after declamping of the aorta, significant amounts of leukocytes, platelets and the leukocyte subsets are retained in the pulmonary vascular bed. These retained cells may be responsible for the previously described pulmonary release of cytokines.

Effect of urapidil on the performance of ischaemic myocardium in anaesthetized dogs.

The effect of urapidil on the ischaemic myocardium was studied in eight anaesthetized dogs. Stenosis of the left descending coronary artery reduced blood flow and systolic contraction of the post-stenotic myocardium by about 50%; the end-diastolic length of the post-stenotic myocardium and the end-diastolic pressure increased, while aortic pressure slightly decreased. Subsequent administration of urapidil (0.25 + 0.25 + 0.5 + 1.0 mg/kg intravenously) did not affect the systolic shortening and end-diastolic length of the myocardium supplied by the left circumflux coronary artery, while the stroke volume and the systolic shortening of the ischaemic myocardium increased. The latter was correlated with a decrease in the heart rate (r = -0.92), but not with the reduction in aortic pressure. Urapidil by itself does not impair the performance of the ischaemic myocardium, but might be beneficial in decreasing the heart rate or suppressing reflex tachycardia during reduction of the afterload.