The effects of aprotinin and steroids on generation of cytokines during coronary artery surgery.

OBJECTIVE: To compare the efficacy of aprotinin and methylprednisolone in reducing cardiopulmonary bypass (CPB)-induced cytokine release, to evaluate the effect of myocardial cytokine release on systemic cytokine levels, and to determine the influence of cytokine release on perioperative and postoperative hemodynamics. DESIGN: Prospective, randomized clinical trial. SETTING: University teaching hospital and clinics. PARTICIPANTS: Thirty patients undergoing elective coronary artery bypass graft surgery. INTERVENTION: Patients were randomly allocated into groups treated with aprotinin (n = 10) or methylprednisolone (n = 10) or into an untreated control group (n = 10). Aprotinin-treated patients received aprotinin as a high-dose regimen (6 x 10(6) KIU), and methylprednisolone-treated patients received methylprednisolone (30 mg/kg intravenously) before CPB. MEASUREMENTS AND MAIN RESULTS: Patients were analyzed for hemodynamic changes and alveolar-arterial PO2 difference (AaDO2) until the first postoperative day. Plasma levels of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-6, and IL-8) were measured in peripheral arterial blood immediately before the induction of anesthesia, 5 minutes before CPB, 3 minutes after the start of CPB, 2 minutes after the release of the aortic cross-clamp, 1 hour after CPB, 6 hours after CPB, and 24 hours after CPB; and in coronary sinus blood immediately before CPB and 2 minutes after the release of the aortic cross-clamp. The hemodynamic parameters did not differ among the groups throughout the study. After CPB, AaDO2 significantly increased (p < 0.05) in all groups. A significant decrease in AaDO2 was observed in aprotinin-treated patients at 24 hours after CPB compared with the other groups (p < 0.05). TNF-alpha level from peripheral arterial blood significantly increased in control patients 1 hour after CPB (p < 0.01) and did not significantly increase in methylprednisolone-treated patients throughout the study. In all groups, IL-6 levels increased after the release of the aortic cross-clamp and reached peak values 6 hours after CPB. At 6 hours after CPB, the increase in IL-6 levels in methylprednisolone-treated patients was significantly less compared with levels measured in control patients and aprotinin-treated patients (p < 0.001). In control patients, IL-8 levels significantly increased 2 minutes after the release of the aortic cross-clamp (p < 0.05), and peak values were observed 1 hour after CPB (p < 0.01). IL-8 levels in control patients were significantly higher compared with patients treated with aprotinin and patients treated with methylprednisolone 1 hour after CPB (p < 0.05). CONCLUSION: This study showed that methylprednisolone suppresses TNF-alpha, IL-6, and IL-8 release; however, aprotinin attenuates IL-8 release alone. Methylprednisolone does not produce any additional positive hemodynamic and pulmonary effects. An improved postoperative AaDO2 was observed with the use of aprotinin.     

Glucocorticoid effects on the inflammatory and clinical responses to cardiac surgery

OBJECTIVE: To measure the effects of glucocorticoids on the systemic inflammatory response and clinical recovery after cardiac surgery. DESIGN: Randomized, prospective, double-blind, placebo-controlled clinical trial with concurrent comparison groups. SETTING: University medical center. PARTICIPANTS: Patients scheduled for elective coronary artery bypass graft surgery using normothermic cardiopulmonary bypass (CPB) and a standardized anesthetic. INTERVENTIONS: Participants randomly received either methylprednisolone, 15 mg/kg intravenously 1 hour before surgery and 0.3 mg/kg intravenously every 6 hours x 4 doses, or placebo. Comparison groups included cardiac surgical patients who received etomidate to lower endogenous cortisol during surgery and healthy volunteers who received methylprednisolone only. MEASUREMENTS AND MAIN RESULTS: Patients who received methylprednisolone had a significant reduction in circulating interleukin (IL)-6 at 60 minutes after CPB (p < 0.05) and on the morning of the 1st (p < 0.01) and 3rd (p < 0.05) postoperative days and a significant increase in circulating IL-10 at 60 minutes after CPB (p < 0.01) compared with the placebo group. Etomidate, given to lower cortisol during surgery, was associated with significantly decreased IL-6 and IL-10 responses to surgery compared with the placebo group, whereas methylprednisolone alone, given to healthy nonsurgical volunteers, had no effect on these cytokines. After adjusting for age, there were no significant differences in postoperative length of hospital stay between the methylprednisolone-treated (4.6 days) and placebo (6.1 days) groups or in the duration of mechanical ventilation (9.9 hours and 15.6 hours). No patient treated with methylprednisolone had nausea and vomiting on the 1st postoperative day compared with 33% of placebo-treated patients (p = 0.02). Glucose was significantly higher after methylprednisolone treatment at 1 hour after CPB (276 mg/dL v 210 mg/dL; p = 0.001) and at 2 hours (289 mg/dL v 213 mg/dL; p = 0.009) and 8 hours (247 mg/dL v 196 mg/dL; p = 0.02) after surgery. There were no differences in pain scores and no significant intergroup differences in lung peak expiratory flow rate or alveolar-arterial oxygen gradients after surgery. CONCLUSION: This study shows significant effects of glucocorticoids on the production of IL-6 and IL-10 in response to cardiac surgery but only minor effects on clinical recovery.     

Myocardial and lung injury after cardiopulmonary bypass: role of interleukin (IL)-10

BACKGROUND: Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8 play a key role in the inflammatory cascade after cardiopulmonary bypass (CPB) and may induce cardiac and lung dysfunction. Antiinflammatory cytokines such as IL-10 may also significantly limit these complications. Corticosteroid administration before CPB increases blood IL-10 levels and prevents proinflammatory cytokine release. This study examined the association of increased release of IL-10, stimulated by steroid pretreatment, with reduced myocardial and lung injury after CPB. METHODS: Twenty patients undergoing coronary artery bypass grafting (CABG) received either preoperative steroid (n = 10, protocol group) or no steroid (n = 10, control group). Perioperative care was standardized, and all caregivers were blinded to treatment group. Seven intervals of blood samples were obtained and assayed for TNF-alpha, IL-6, IL-8, and IL-10. Various hemodynamic and pulmonary measurements were obtained perioperatively. Levels of MB isoenzyme creatine kinase (CK-MB) were also measured. RESULTS: In the protocol group, proinflammatory cytokines were significantly reduced while IL-10 levels were much higher after CPB. The protocol group had a lower alveolar-arterial oxygen gradient and higher ratio of arterial oxygen pressure to fraction of inspired oxygen after CPB. Creatine kinase (CK) and CK-MB were reduced in the patients treated with steroid. Correlations were found between plasma cytokines levels and cardiac index, and CK-MB. CONCLUSIONS: This study confirms that corticosteroids abolish proinflammatory cytokines release and increase blood IL-10 levels after CPB. Our findings demonstrate a greater release of IL-10 induced by steroid pretreatment, and better heart and lung protection after CPB.     

Timing of steroid treatment is important for cerebral protection during cardiopulmonary bypass and circulatory arrest: minimal protection of pump prime methylprednisolone.

OBJECTIVES: The contact of cardiopulmonary bypass surface and patient's blood activates systemic inflammatory response which aggravates ischemia-reperfusion injury. This study evaluates the effects of cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) on cerebral protection using different steroid administration protocols. METHODS: Eighteen (n=6/group) 4 week-old piglets were divided in three groups. Methylprednisolone (30 mg/kg) was administered intravenously 4 h prior to CPB in Group I, or added in pump prime in group II. Group III received no steroid. All animals were cooled to 15 degrees C followed by 100 min of DHCA, then rewarmed over 40 min and sacrificed 6 h after CPB. Post-operative weight gain, bioelectrical impedance, colloid oncotic pressure (COP) and interleukin-6 (IL-6) were evaluated. Determination of cerebral trypan blue and immunohistochemical assays of transforming growth factor (TGF)-beta1 and caspase-3 activities were performed. RESULTS: Post-operative % weight gain (13.0+/-3.8 (I) versus 26.4+/-9.9 (II) versus 22.6+/-6.4 (III), P=0.02); % bioimpedance reduction (14.5+/-8.0 (I) versus 38.3+/-13.3 (II) versus 30.5+/-8.0 (III), P=0.003); mean COP (mmHg) (14.9+/-1.8 (I) versus 10.9+/-2.0 (II) versus 6.5+/-1.8 (III), P=0.0001) and systemic IL-6 levels (pg/ml) (208.2+/-353.0 (I) versus 1562.1+/-1111.4 (II) versus 1712.3+/-533.2 (III), P=0.01) were significantly different between the groups. Spectrophotometric analysis of cerebral trypan blue (ng/g dry weight) was significantly different between the groups (0.0053+/-0.0010 (I) versus 0.0096+/-0.0026 (II) versus 0.0090+/-0.0019 (III), P=0.004). TGF-beta1 scores were 3.3+/-0.8 (I) versus 1.5+/-0.8 (II) versus 1.5+/-0.5 (III), P<0.05, groups I versus II and I versus III. Remarkable perivascular caspase-3 activity was observed in groups II and III. CONCLUSION: Different timing of steroid administration results in different inflammatory mediator response. Steroid in CPB prime is not significantly better than no steroid treatment, while systemic steroid pre-treatment significantly decreases systemic manifestation of inflammatory response and brain damage.     

Effects of preoperative steroid administration on surgical stress in hepatic resection: prospective randomized trial

HYPOTHESIS: Preoperative administration of methylprednisolone sodium succinate can control surgical stress in patients undergoing hepatic resection. DESIGN: A prospective randomized trial. SETTING: A university hospital department of surgery. PATIENTS: Thirty-three patients who underwent hepatic resection were classified into 2 groups: a control group (n = 16) and a steroid group (n = 17) in which patients were intravenously administered 500 mg of methylprednisolone 2 hours before surgery. MAIN OUTCOME MEASURES: Perioperative levels of interleukin (IL)-6 and IL-10 (serum and peritoneal), immunosuppressive acidic protein, Candida antigen, and other laboratory and clinical variables were measured. RESULTS: Postoperative levels of serum and peritoneal IL-6 and levels of C-reactive protein were significantly lower in the steroid group than in controls. Furthermore, serum and peritoneal IL-10 levels were significantly higher in the steroid group. The total bilirubin value on postoperative day 1 was significantly lower in the steroid group than in controls. Postoperative immunosuppressive acidic protein levels were also significantly lower in the steroid group, as was the positive rate of serum Candida antigen. No differences were found in the incidence of postoperative complications. CONCLUSIONS: Preoperative steroid administration significantly elevated anti-inflammatory cytokine IL-10 levels, suppressed the levels of inflammatory cytokines IL-6 and C-reactive protein, and prevented postoperative elevation of total bilirubin values. Furthermore, postoperative elevation of immunosuppressive acidic protein levels and the positive rate of Candida antigen were suppressed, indicating that the immune response was maintained by preoperative steroid administration.     

Expression of adhesion molecules and cytokines after coronary artery bypass grafting during normothermic and hypothermic cardiac arrest

Objective: Cardiac surgery with cardiopulmonary bypass (CPB) results in vascular injury and tissue damage which involves leukocyte-endothelial interactions mediated by cytokines and adhesion molecules. This study was designed to demonstrate the effect of normothermic and hypothermic CPB to cytokine and soluble adhesion molecule levels in adults and to determine whether these levels correlate to the patients postoperative course. Design and patients: In 25 patients after normothermic and in 25 patients after hypothermic coronary artery bypass grafting with cardiopulmonary bypass (CPB), blood samples for cytokine and soluble adhesion molecule analysis were taken preoperatively, 24, 36, 48 h, and 6 days postoperatively. Soluble adhesion molecules (sE-selectin, sICAM-1) were measured by ELISA and cytokines (TNF-, IL-6, IL-8) by chemilumenscent-immunoassay. Clinical data were collected prospectively. Results: Postoperatively, adhesion molecule and cytokine levels were significantly elevated after CPB. Mean plasma levels of sICAM-1 was 2.4-fold higher after 6 days. Mean plasma concentration of sE-selectin peaked after 48 h with a 2-fold increase compared to normothermic conditions. In the hypothermia group sICAM-1, sE-selectin, IL-6, and IL-8 showed significantly higher levels (P<0.0057, P<0.0012, P<0.0419, P<0.0145) after 24 h compared to the normothermia group. No clinical differences were seen. Conclusion: Adhesion molecules and cytokines are elevated after CPB. Patients after hypothermic CPB show significant higher sICAM-1, sE-selectin, IL-6, and IL-8 levels after 24 h compared to normothermic conditions. These results are mainly due to longer CPB and crossclamp times but do not alter the patient's postoperative course.     

Profiles of inflammatory cytokines following colorectal surgery: Relationship with wound healing and outcome

Inflammation is an essential component of normal wound healing. This study has correlated systemic (plasma) and local (wound fluid) concentrations of inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-alpha [TNF-alpha], and IL-1beta) with wound healing and surgical outcome following elective colorectal surgery. Paired plasma and wound fluid samples were collected (n = 44) postoperatively (days 1, 3, 5, 7) and analyzed by enzyme-linked immunosorbent assay (pg/mL). Cytokine levels were significantly greater in drain fluid than plasma on each postoperative day (POD); e.g., POD 1 : IL-6; drain fluid, median, 77,050 pg/mL (range 9,928-456,408); plasma, 241 pg/mL (22-1,333). Daily profiles of IL-6 and TNF-alpha were similar in drain fluid and plasma; IL-6 levels peaked on POD 1 decreasing to POD 7, and TNF-alpha levels increased from PODs 1 to 7. However, IL-1beta in plasma peaked on POD 1 and plateaued, whereas drain fluid showed two peaks (PODs 1 and 7). Only plasma levels of cytokines correlated to clinical parameters; IL-6 levels significantly correlated with postoperative complications; e.g., POD 5, complications 92(1-597) and no complications, 14(2-217). IL-6 also correlated with tumor pathology (Dukes stage, tumor depth, vascular invasion), and TNF-alpha levels correlated with the estimated blood loss during surgery. We conclude that local wound levels of cytokines correlated with the stage of wound healing, whereas systemic levels correlated with postoperative complications and tumor pathology.     

Induction of higher expression of IL-beta and TNF-alpha,lower expression of IL-10 and cyclic guanosine monophosphate by pulmonary arterial hypertension following cardiopulmonary bypass

OBJECTIVE: Pulmonary arterial hypertension [PAH] and cardiopulmonary bypass [CPB] induce systemic inflammatory cytokines that are critical factors related to postoperative mortality of open heart surgery. We studied the expression of proinflammatory cytokines and cyclic guanosine monophosphate [cGMP] in patients suffering from PAH after CPB. METHODS: Seventy-six patients who underwent valve replacement surgery were recruited and divided into two groups according to their pulmonary arterial pressure [< 50 mmHg for Group A and > or = 50 mmHg for Group B]. Blood samples were taken to measure the concentrations of interleukin-1 beta [IL-1 beta], tumour necrosis factor alpha [TNF-alpha], interleukin-10 [IL-10] and cGMP.RESULTS: IL-1 beta and TNF-alpha were significantly higher in Group B [28.6 +/- 9.1 mmHg] than in Group A [65.8 +/- 10.2 mmHg] at baseline. After CPB, IL-1 beta of both groups rose significantly, while only TNF-alpha of Group B rose significantly higher. There were significant differences between the two groups after CPB. IL-10 and cGMP in Group B were lower than in Group A at baseline. They all decreased significantly after CPB. Significant differences were seen between the groups after CPB. CONCLUSION: Patients suffering from PAH had different levels of proinflammatory and anti-inflammatory cytokines compared to normal patients. PAH aggravates the production of IL-1 beta and TNF-alpha, while it decreases the production of IL-10 and cGMP after CPB.     

Endotoxin desensitization of human mononuclear cells after cardiopulmonary bypass: role of humoral factors

BACKGROUND: The ability of leukocytes to release proinflammatory cytokines on lipopolysaccharide stimulation in vitro is impaired after cardiopulmonary bypass (CPB). This study tested contribution and interaction of humoral factors in altered leukocyte responsiveness to lipopolysaccharide. METHODS: Whole blood and isolated peripheral-blood mononuclear cells (PBMCs) from 10 patients obtained after induction of anesthesia (T1) and 20 min (T2) and 24 h (T3) after CPB were cultured in the absence or presence of lipopolysaccharide and assessed for release of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta and their functional antagonists, IL-1 receptor antagonist (IL-1ra) and IL-10. In addition, dose-response characteristics and interaction of IL-10 and norepinephrine as modulators of TNF-alpha release were studied. RESULTS: Cardiopulmonary bypass induced release of antiinflammatory (T2: IL-10: median 25 pg/ml, 25th-75th percentile 9-42; IL-1ra: median 1,528 pg/ml, 25th-75th percentile 1,075-17,047; P < 0.05 compared with T1) but failed to induce proinflammatory cytokines (T2: TNF-alpha: median 0 pg/ml, 25th-75th percentile 0-6; IL-1beta: median 1 pg/ml, 25th-75th percentile 0-81; nonsignificant). Removal of plasma at T2 increased TNF-alpha response to lipopolysaccharide (+83.8%; P < 0.05), whereas it suppressed IL-10 (-36.8%; P < 0.05). Similarly, incubation of PBMCs (T1) with plasma obtained after CPB (T2) as well as addition of IL-10 or norepinephrine in concentrations present in plasma after CPB led to a reduced lipopolysaccharide-stimulated TNF-alpha and an increased IL-10 response. Coadministration of norepinephrine and IL-10 had synergistic effects. Although pretreatment with an anti-IL-10 antibody and labetalol before addition of plasma obtained at T2 largely restored the TNF-alpha response in vitro, their addition post-treatment failed to restore the monocytic TNF-alpha response. CONCLUSIONS: Plasma contains interacting factors that inhibit the release of TNF-alpha and increase the release of IL-10, presumably attenuating the inflammatory response to CPB. Although norepinephrine fails to induce a cytokine response in the absence of other stimuli, its administration seems to augment the antiinflammatory IL-10 response while attenuating the TNF-alpha response.     

Statins and biomarkers in claudicants with peripheral arterial disease: cross-sectional study

This exploratory substudy of The Iron (Fe) and Atherosclerosis Study (FeAST) compared baseline inflammatory markers, including cytokines, C-reactive protein (CRP), and ferritin, in subjects with peripheral arterial disease (PAD) taking statins with subjects with PAD who were not taking statins. Inflammatory markers in the serum of 47 subjects with PAD not taking statins and a healthy cohort of 21 medication-free men were compared with 53 PAD subjects taking statins at entry to the FeAST. Healthy subjects demonstrated lower levels of tumor necrosis factor (TNF)-R1, interleukin-6 (IL-6), and CRP. TNF-alpha R1 averaged 2.28 ng/mL versus 3.52 ng/mL, p = .0025; IL-6 averaged 4.24 pg/mL versus 16.61 pg/mL, p = .0008; and CRP averaged 0.58 mg/dL versus 0.92 mg/dL, p = .0192. A higher level of IL-6 was observed in PAD statin takers versus PAD subjects not taking statins: 19.47 pg/mL versus 13.24 pg/mL, p = .0455. As expected, total cholesterol and low-density lipoprotein levels were lower in the statin-treated group, p = .0006 and p = .0001, respectively. No significant differences in inflammatory cytokines were detected for varying doses of simvastatin. Additionally, no significant differences in inflammatory biomedical markers were found in subjects with PAD alone compared with those with concomitant coronary artery disease (CAD). Unexpectedly, serum inflammatory cytokine IL-6 levels were significantly higher in PAD subjects receiving statins. There was no difference in measured inflammatory markers in PAD subjects with concomitant CAD.     

Pulse low dose steroids attenuate post-cardiopulmonary bypass SIRS; SIRS I

BACKGROUND: Cardiopulmonary bypass (CPB) initiates inflammation that contributes to multiorgan dysfunction (SIRS). Steroids have been demonstrated to attenuate this response; however, resistance to use steroids remains because of potential adverse effects of the high doses used. This study examines a lower dose steroid protocol for safety and attenuation of SIRS. METHODS: Sixty patients undergoing CPB were randomized to pulse low doses of methylprednisolone (250 mg given twice IV) or placebo in this RCT. Outcomes pertaining to hemodynamics, ventilator requirement, arrhythmia, and metabolic derangements were recorded. Post-operative glucose control and gastrointestinal prohylaxis was instituted in all patients. RESULTS: IL-6 concentrations were lower in the steroid group at 4 and 8 h post-operatively (P < 0.0001). The steroid group demonstrated more normothermia (37.2 degrees C versus 37.6 degrees C, P = 0.002), better hemodynamic stability with less requirement for inotropes or vasopressors (0% versus 27.6%, P = 0.005), higher SVRIs (1840 versus 1340 DSm2/cm5, P = 0.002), and higher mean arterial pressures (79 versus 74 mmHg, P = 0.03). The steroid group had a shorter duration of intubation (7.7 versus 10.7 h, P = 0.02), a shorter length of ICU stay (1.0 versus 2.0 days, P = 0.03), and less blood loss (505 versus 690 ml, P = 0.04) with no difference in post-operative blood glucose levels or complications. CONCLUSIONS: Patients undergoing cardiopulmonary bypass receiving low pulse dose steroids had better hemodynamics, shorter mechanical ventilation times, less blood loss, and required less time in the ICU compared to those receiving placebo. Therefore, this study demonstrates that prophylactic low dose steroids attenuate the SIRS response to CPB without resulting in any untoward side-effects.     

The heart produces but the lungs consume proinflammatory cytokines following cardiopulmonary bypass.

OBJECTIVE: Proinflammatory cytokines, such as interleukin-6 (IL-6), and soluble adhesion molecules, such as E-selectin, may play an important role in patient response to cardiopulmonary bypass (CPB). We sought to define whether the heart and the lungs serve as important sources of these inflammatory mediators under clinical conditions of myocardial revascularization using CPB and cardioplegic arrest. METHODS: Plasma levels of IL-6 and E-selectin were measured in coronary sinus (CS), arterial, pulmonary arterial (PA) and left atrial (LA) blood samples taken from 12 consecutive patients (68.3 +/- 11 years; five females) undergoing coronary artery bypass grafting (CABG). Blood samples were collected preoperatively, after reperfusion, and 1, 6, 12 and 18 h following surgery. CS and LA blood was drawn using transcutaneous catheters. PA artery blood was obtained through a Swan-Ganz catheter. Cytokine levels were determined by standard enzyme linked immunosorbent assay (ELISA) technique. RESULTS: A mean of 3.8 +/- 1 coronary anastomoses were performed. The CPB time and aortic X-clamp time were 91 +/- 15 and 45 +/- 10 min, respectively. IL-6 levels increased significantly after CPB and peaked 6 h postoperatively. There was also a significant increase of E-selectin levels with an onset at 1 h and a peak at 12 h postoperatively. At all time points the IL-6 and E-selectin concentrations were significantly higher in the CS than in arterial blood. In contrast, the levels of both mediators measured in the LA were significantly lower than those in the PA. CONCLUSION: The reperfusion of ischemic myocardium during CABG results in a significant increase in plasma levels of IL-6 and E-selectin. Our data indicate that the myocardium, but not the lungs, is a predominant source of IL-6 and E-selectin release following CPB. The lungs may consume rather than release those mediators during reperfusion. Not the CPB per se, but the myocardial ischemia seems to be crucial in the pathogenesis of the inflammatory response observed following open heart surgery.     

Endothelial cell dysfunction after coronary artery bypass grafting with extracorporeal circulation in patients with type 2 diabetes mellitus.

OBJECTIVE: Type 2 diabetes mellitus is a well-known risk factor in patients with severe coronary artery disease undergoing coronary artery bypass grafting (CABG). The aim of the study was to analyze the endothelial dysfunction in these patients by evaluating postoperative soluble inflammatory cytokines. METHODS: Patients undergoing CABG without (n=15, group A) and with (n=14, group B) diabetes mellitus were analyzed for their release of E-selectin, interleukin-6 (IL-6), and tumor necrosis factor (TNF) up to 3 days postoperatively. A pharmacokinetic quantitative kinetic evaluation (Kinetica 2000) of maximum concentrations (c(max)), time to reach c(max) (t(max)), area under the curve (AUC(0-inf)), and terminal elimination half time (t(1/2)) was performed using a non-compartmental model. RESULTS: There was no difference in preoperative plasma concentrations of the cytokines and in the postoperative kinetic analyses of TNF when comparing both groups. However, the release of IL-6 was restricted with c(max) of 1055+/-543 pg/ml for group B versus 2112+/-1532 pg/ml for group A (p< or =0.05), paralleled by a decrease in the absolute amount (AUC(0-inf)) of IL-6. The t(1/2) remained unaffected (13.9+/-6.6h and 12.7+/-4.6h, respectively). The AUC(0-inf) of E-selectin decreased by a factor of 1.7 (p< or =0.05) with unchanged c(max) but reduced t(1/2) (12.9+/-10h for group B vs 33.1+/-20.4h for group A; p< or =0.01) referring to an augmented endothelial uptake and degradation of E-selectin. CONCLUSIONS: CABG with extracorporeal circulation could be used to verify a specific endothelial dysfunction in diabetic patients characterized by an impaired release of IL-6 and an increased turnover of E-selectin.     

High-dose aprotinin modulates the balance between proinflammatory and anti-inflammatory responses during coronary artery bypass graft surgery

OBJECTIVE: To rule out the effect of high-dose aprotinin in respect to the balance of proinflammatory and anti-inflammatory mediators induced by cardiopulmonary bypass (CPB). DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University-affiliated cardiac center. PARTICIPANTS: Twenty patients scheduled for coronary artery bypass graft surgery. INTERVENTIONS: In group A patients (n = 10), high-dose aprotinin was administered (2 x 106 KIU pre-CPB, 2 x 10(6) KIU in prime, 500,000 KIU/hr during CPB). In group C patients (n = 10), placebo was used instead. Proinflammatory interleukin (IL)-6, anti-inflammatory IL-1-receptor antagonist, and clinical parameters were measured 8 times perioperatively. The values are presented as mean +/- SEM. MEASUREMENTS AND MAIN RESULTS: Four hours after CPB, IL-6 concentration reached the maximum value, being significantly lower in group A patients as compared with group C patients (615 +/- 62 pg/mL v 1,409 +/- 253 pg/mL; p = 0.019). On the first postoperative day, the concentration of IL-6 in group A patients remained lower (219 +/- 24 pg/mL v 526 +/- 123 pg/mL; p = 0.015). In contrast, IL-1-receptor antagonist concentration was higher in group A patients as compared with group C patients after CPB (13,857 +/- 4,264 pg/mL v 5,675 +/- 1,832 pg/mL; p = 0.03). Total postoperative blood loss was lower in group A patients as compared with group C patients (648 +/- 64 mL v 1,284 +/- 183 mL; p = 0.002). CONCLUSIONS: High-dose aprotinin treatment reduced the inflammatory reaction and postoperative blood loss. The anti-inflammatory reaction was significantly enhanced in these patients, which suggests that the physiologic reaction of the organism to reduce the deleterious effects from CPB is more pronounced by using high-dose aprotinin.     

Comparative effectiveness of methylprednisolone and zero-balance ultrafiltration on inflammatory response after pediatric cardiopulmonary bypass

Studies have demonstrated that systemic inflammatory response syndrome (SIRS) remains one of the major causes of cardiopulmonary bypass (CPB)-associated organ injury during pediatric cardiac surgery. The purpose of this investigation was to compare the effectiveness of methylprednisolone (MP) and zero-balance ultrafiltration (ZBUF) on SIRS during pediatric CPB. Thirty infants undergoing open-heart surgeries were randomized to receive either MP in the priming solution (group M, n = 15) or ZBUF during CPB (group Z, n = 15). All the patients survived. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) were measured before CPB (T1), 5 min after the start of CPB (T2), at the termination of CPB (T3), the fourth hour (T4), and the eighth hour (T5) postoperatively. The results showed that the plasma concentrations of TNF-alpha in the Z group were significantly less than those in the M group at T4 and T5 (P < 0.05), and the plasma concentrations of IL-6 were significantly less than those in the M group at T4 (P < 0.05); the plasma concentrations of IL-8 in the Z group were significantly less than those in the M group at T5 (P < 0.05). There was no difference between two groups on the plasma concentrations of IL-10. The duration of postoperative mechanical ventilation was (9.6 +/- 0.8 h) in the M group and (7.8 +/- 0.4 h) in the Z group (P < 0.05). This study showed that application of ZBUF is more effective to decrease the level of inflammatory mediators including TNF-alpha, IL-6, and IL-8 than administration of MP after pediatric CPB.     

Preoperative high-dose steroid administration attenuates the surgical stress response following liver resection: results of a prospective randomized study

Background/Purpose Major abdominal surgery such as liver resection is associated with an excessive hyperinflammatory response and transient immunosuppression. We investigated the immunomodulating effect of preoperative pulse administration of high-dose methylprednisolone in patients undergoing hepatic resection without pedicle clamping. Methods Twenty patients who underwent hepatic resection were randomized into two groups: a steroid group (n = 10), in which patients were given 30 mg/kg per body weight (BW) methylprednisolone intravenously, and a control group (n = 10), in which patients received a placebo (sodium chloride) infusion. The main outcome parameter to assess systemic stress was the serum plasma level of interleukin-6 (IL-6). To evaluate cell-mediated immune function, human leukocyte antigen-DR (HLA-DR) expression on peripheral blood monocytes and lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) release by peripheral monocytes was measured. Other investigated serum parameters included C-reactive protein (CRP), total bilirubin, alanine aminotransferase (ALT), prothrombin time (PT)-INR, and cytokines such as IL-8 and IL-10 and TNF-α. Postoperative convalescence, complication rate, and length of hospital stay were compared between the groups. Results Postoperative plasma concentrations of IL-6 (days 1 and 2), IL-8 (days 2 and 3), and CRP (days 1–4) were significantly lower in the steroid than in the control group. The total bilirubin concentration was significantly lower on day 6 in the steroid than in the control group. Four hours after surgery, LPS-induced TNF-α secretion was significantly reduced in the steroid group, but it increased rapidly during the following days. HLA-DR, ALT, and PT-INR levels were not different between the two groups. The postoperative hospital stay in the steroid group was significantly lower compared to that in the control group (mean, 10.5 days versus 14.8 days; P < 0.05). No differences were found in the convalescence score or postoperative complication rate. Conclusions Intravenous methylprednisolone administration before hepatic resection significantly reduced systemic inflammatory cytokine release. No adverse effect on immunity was noted due to the methylprednisolone. We found no significant difference in the convalescence score, but a significantly shorter hospital stay in the steroid group. Further studies with more patients are needed to elucidate the clinical impact of preoperative steroid bolus therapy in liver surgery.     

Systemic steroid pretreatment improves cerebral protection after circulatory arrest.

BACKGROUND: This study evaluates whether systemic steroid pretreatment enhances neuroprotection during deep hypothermic circulatory arrest (DHCA) compared with steroid in cardiopulmonary bypass (CPB) prime. METHODS: Four-week-old piglets randomly placed into two groups (n = 5 per group) were given methylprednisolone (30 mg/kg) into the pump prime (group PP), or pretreated intravenously 4 hours before CPB (group PT). All animals underwent 100 minutes of DHCA (15 degrees C), were weaned off CPB, and were sacrificed 6 hours later. Postoperative changes in body weight, bioimpedance, and colloid oncotic pressure (COP) were measured. Cerebral trypan blue content, immunohistochemical evaluation of transforming growth factor-beta1 (TGF-beta1) expression, and caspase-3 activity were performed. RESULTS: Percentage weight gain (group PP 25.0% +/- 10.4% versus group PT 12.5% +/- 4.0%; p = 0.036), and percentage decrease in bioimpedance (PP 37.2% +/- 14.5% versus PT 15.6% +/- 7.9%; p = 0.019) were significantly lower, whereas postoperative COP was significantly higher in group PT versus group PP (PT 15.3 +/- 1.8 mm Hg versus PP 11.6 +/- 0.8 mm Hg; p = 0.003). Cerebral trypan blue (ng/g dry tissue) was significantly lower in group PT (PT 5.6 x 10(-3) +/- 1.1 x 10(-3) versus PP 9.1 x 10(-3) +/- 5.7 x 10(-4); p = 0.001). Increased TGF-beta1 expression and decreased caspase-3 activity were shown in group PT. CONCLUSIONS: Systemic steroid pretreatment significantly reduced total body edema and cerebral vascular leak and was associated with better immunohistochemical indices of neuroprotection after DHCA.     

Perioperative serum interleukins in neonates with hypoplastic left-heart syndrome and transposition of the great arteries

OBJECTIVE: The primary study objective was to examine the impact of diagnosis on the inflammatory response in neonates with congenital heart disease undergoing cardiac surgery. The secondary objective was to study the impact of the inflammatory response on postoperative outcome in these neonates. DESIGN: Observational study. SETTING: Tertiary care children's hospital heart center. PATIENTS: Neonates with hypoplastic left-heart syndrome (HLHS) undergoing stage I repair and patients with transposition of the great arteries (TGA) undergoing arterial switch operation. MEASUREMENTS AND MAIN RESULTS: There were 24 neonates with HLHS and 21 neonates with TGA. Serum samples to measure interleukin (IL)-6 and -10 were obtained before and after CPB at 1, 3, 6, and 24 hours postoperatively. Time to extubation, intensive care unit (ICU) length of stay, and peritoneal fluid drainage were compared between the groups. Serum IL-6 and IL-10 concentrations increased after CPB when compared to the preoperative concentration. Preoperative concentrations of IL-6 were significantly elevated in the HLHS group (HLHS: 32 [21.1, 69.6] pg/mL v TGA: 7.2 [3.6, 22.5] pg/mL [median, 25th, and 75th percentile], p = 0.003) and remained elevated immediately after CPB, and at 3 and 6 hours postoperatively. The IL-10 to IL-6 ratio was lower in the HLHS group preoperatively and immediately after CPB. ICU length of stay was significantly longer in the HLHS group (TGA 4 [3-6] days v HLHS 6 [5-8] days, p = 0.031). Mortality in the HLHS group (4/24) was associated with significantly higher IL-6 postoperatively (IL-6 immediately postoperatively: HLHS survivors 59.9 [34.3, 65.7] pg/mL v nonsurvivors 98.7 [94.4, 104.5] pg/mL, p < 0.011). CONCLUSIONS: All neonates with TGA or HLHS have a significant inflammatory response after CPB. Neonates with HLHS have evidence of an activated inflammatory response before CPB, which remains significant in the postoperative period. Accelerated interleukin expression and an abnormal cytokine balance correlate with longer time to extubation, longer ICU length of stay, and increased peritoneal fluid volume.     

Ganciclovir pharmacokinetics and cytokine dynamics in renal transplant recipients with cytomegalovirus infection

Ganciclovir is considered to be the first-line treatment for cytomegalovirus (CMV) in renal transplant recipients. This infection is also associated with elevations of specific plasma cytokines post-transplantation. To investigate daily cytokine response to therapy and ganciclovir pharmacokinetics, 4 transplant recipients (3 males, 1 female) with stable renal allograft function diagnosed with CMV infection were enrolled less than 4 months post-transplant. A creatinine clearance (ClCr) was generated by the Cockroft-Gault (C-G) equation (range: 42.3-68.5 mL/min) to determine ganciclovir dosing. Blood samples were collected for ganciclovir and cytokine [including interleukin (IL)-1beta, IL-2, IL-3, IL-4, IL-6, IL-8, IL-10, TNF-alpha, GM-CSF, and interferon (IFN)-gamma analyses after 7 d of intravenous (i.v.) ganciclovir (dosage range: 165-400 mg daily) therapy and again after 7 d of oral (p.o.) ganciclovir (dosage range: 1000 mg, 2-3 times daily) therapy. Pharmacokinetic ganciclovir was described with a two-compartment model. Total clearance of ganciclovir was consistently greater than ClCr, suggesting tubular secretion. Peak concentrations for i.v. ganciclovir averaged 8.39+/-1.87 microg/mL with minimum concentrations of 0.48+/-0.35 microg/mL. Plasma concentrations were lower but more sustained during a p.o. dosing interval (max=2.12+/-0.58 microg/mL, min=1.15+/-0.34 microg/mL). IL-6, IL-8, IL-10, and TNF-alpha were detectable at multiple times during the study periods while the remainder of the cytokines were only intermittently detectable. Average concentrations (i.v. versus p.o. study period) for TNF-alpha were 40.1+/-17.5 versus 22.1+/-11.2 pg/mL, for IL-8 were 17.1+/-15.6 versus 4.12+/-2.59 pg/mL, and for IL-10 were 7.39+/-5.54 versus 2.64+/-1.06 pg/mL. Concentrations were similar for IL-6 during both studies (9.39+/-5.42 versus 14.7+/-14.8 pg/mL). TNF-alpha, IL-8, and IFN-gamma appeared to correlate with CMV antigenemia. Further investigation of ganciclovir disposition and changes in plasma cytokines in renal transplant recipients during CMV infection may provide insight into variable antiviral responses in renal transplant recipients.