Crescenzia Rotunno

Protective Effects of Steroids in Cardiac Surgery: A Meta-Analysis of Randomized Double-Blind Trials

OBJECTIVE Cardiac surgery and cardiopulmonary bypass (CPB) induce an acute inflammatory response contributing to postoperative morbidity. The use of steroids as anti-inflammatory agents in surgery using CPB has been tested in many trials and has been shown to have good anti-inflammatory effects but no clear clinical advantages for the lack of an adequately powered sample size. The aim of this study was to evaluate the effects of steroid treatment on mortality and morbidity after cardiac surgery. DESIGN A systematic meta-analysis of randomized double-blind trials (RDBs). SETTING A university hospital. PARTICIPANTS Adult patients who underwent cardiac surgery. MEASUREMENTS AND MAIN RESULTS A trial search was performed through PubMed and Cochrane databases from 1966 to January 2009. Among 104 clinical trials reviewed, 31 RDB trials (1,974 patients) were considered suitable to be analyzed. A quality assessment of the trials was performed using the Jadad score. The types of steroid used in these trials were methylprednisolone (51.4%), dexamethasone (34.3%), hydrocortisone (5.7%), prednisolone (2.9%), or a combination of methylprednisolone and dexamethasone (5.7%). Steroid prophylaxis provided a protective effect preventing postoperative atrial fibrillation (odds ratio = 0.56; confidence interval [CI] 0.44-0.72, p < 0.0001), reducing postoperative blood loss (mean difference = -204.2 mL; CI from -287.4 to -121 mL; p < 0.0001), and reducing intensive care unit (mean difference = -6.6 hours; CI from -10.5 to -2.7 hours, p = 0.0007) and overall hospital stay (mean difference = -0.8 days; CI from -1.4 to -0.2 days, p = 0.01). Steroid prophylaxis had no effect on postoperative mortality, mechanical ventilation duration, re-exploration for bleeding, and postoperative infection. CONCLUSIONS A systematic review of RDB trials reveals that steroid prophylaxis may reduce morbidity after cardiac surgery and does not increase the risk of postoperative infections.

D-dimers are not always elevated in patients with acute aortic dissection.

In patients with acute aortic dissection, an early diagnosis is essential to anticipate aortic rupture, cardiac tamponade, organ ischemia and improve surgical results. A specific blood laboratory marker able to rule out the presence of aortic dissection has not been identified yet. Recently, several studies suggested using D-dimers as a negative predicting test to rule out diagnosis of acute aortic dissection in patients presenting with chest pain. In 61 patients with confirmed aortic dissection, preoperative D-dimers were assayed and correlated with time from symptom onset and extension of the false lumen dissection (according with De Bakey classification). Abnormal D-dimers values were considered those being greater than 400 μg/l. D-dimers values were above 400 μg/l in 50 patients (82%) and below 400 μg/l in 11 patients (18%). There was no correlation between preoperative D-dimers values and time from symptoms onset (r = −0.232; P = 0.1). We found that D-dimers are not always elevated in patients presenting with acute aortic dissection. Given the potential devastating effects of denying the diagnosis of acute aortic dissection with consequent delay of adequate treatment, a word of caution regarding the negative predictive value of D-dimer test in the diagnosis of aortic dissection seems warranted.

Hemostasis Alterations in Patients With Acute Aortic Dissection

BACKGROUND Surgery for acute aortic dissection (AAD) is frequently complicated by excessive postoperative bleeding and blood product transfusion. Blood flow through the nonendothelialized false lumen is a potential trigger for the activation of the hemostatic system; however, the physiopathology of the aortic dissection induced coagulopathy has never been precisely studied. The aim of the present study is the evaluation of the coagulation and fibrinolytic systems and platelet activation in patients undergoing surgery for AAD. METHODS Eighteen patients undergoing emergent surgery for Stanford type A AAD were enrolled in the study. The activation of the coagulation and fibrinolytic systems and platelet activation were evaluated at 6 different time points before, during, and after the operation, measuring prothrombin fragment 1.2 (F1.2), plasmin-antiplasmin complex, and platelet factor 4, respectively. RESULTS All measured biomarkers were increased before, during, and after the operations indicating a systemic activation of coagulation, fibrinolysis, and platelets. These changes were pronounced even preoperatively (T0), and soon after the beginning of cardiopulmonary bypass (T1) when the influence of hypothermia and prolonged cardiopulmonary bypass time were not yet involved. Time from symptom onset to intervention inversely correlated with preoperative F1.2 (r=-0.75; p=0.002) and plasmin-antiplasmin levels (r=-0.57; p=0.034). CONCLUSIONS Blood flow through the false lumen is a powerful activator of the hemostatic system even before the operation. This remarkable activation may influence postoperative outcome of AAD patients.

Anti-inflammatory strategies to reduce acute kidney injury in cardiac surgery patients: a meta-analysis of randomized controlled trials.

Acute kidney injury (AKI) after cardiac operations is a serious complication associated with postoperative mortality. Multiple factors contribute to AKI development, principally ischemia-reperfusion injury and inflammatory response. It is well proven that glucocorticoid administration, leukocyte filter application, and miniaturized extracorporeal circuits (MECC) modulate inflammatory response. We conducted a systematic review of randomized controlled trials (RCTs) in which one of these inflammatory system modulation strategies was used, with the aim to evaluate the effects on postoperative AKI. MEDLINE and Cochrane Library were screened through November 2011 for RCTs in which an inflammatory system modulation strategy was adopted. Included were trials that reported data about postoperative renal outcomes. Because AKI was defined by different criteria, including biochemical determinations, urine output, or dialysis requirement, we unified renal outcome as worsening renal function (WRF). We identified 14 trials for steroids administration (931 patients, WRF incidence [treatment vs. placebo]: 2.7% vs. 2.4%; OR: 1.13; 95% CI: 0.53-2.43; P = 0.79), 9 trials for MECC (947 patients, WRF incidence: 2.4% vs. 0.9%; OR: 0.47; 95% CI: 0.18-1.25; P = 0.13), 6 trials for leukocyte filters (374 patients, WRF incidence: 1.1% vs. 7.5%; OR: 0.18; 95% CI: 0.05-0.64; P = 0.008). Only leukocyte filters effectively reduced WRF incidence. Not all cardiopulmonary bypass-related anti-inflammatory strategies analyzed reduced renal damage after cardiac operations. In adult patients, probably other factors are predominant on inflammation in determining AKI, and only leukocyte filters were effective. Large multicenter RCTs are needed in order to better evaluate the role of inflammation in AKI development after cardiac operations.

Myocardial protection during aortic surgery: comparison between Bretschneider-HTK and cold blood cardioplegia.

The ideal cardioplegic strategy in thoracic aorta operations requiring long cardiopulmonary bypass and cross-clamp time has not been established. Suboptimal myocardial protection may lead to myocardial damage and possible post-operative complications. We evaluate post-operative cardiac Troponin I (cTnI) release, low cardiac output syndrome (LCOS) and mortality, using a cold crystalloid single-dose intracellular or cold blood multidose cardioplegia in 112 elective or emergent thoracic aorta operation patients. Fifty-four patients (HTK group) received Custodiol® cardioplegic solution and 58 received cold blood cardioplegia (CB group). Cross-clamp time, cardiopulmonary bypass (CPB) time and cTnI peak release were similar in both groups. No differences were found for atrial and ventricular arrhythmias, inotropic support, LCOS and in-hospital mortality. Two-way ANOVA analysis revealed an interactive effect on cTnI peak (p=0.012) of cardioplegic solution type across the cross-clamp time quintile. In the fifth quintile, cross-clamp time patient (>160 min) cTnI peak value was higher in CB patients (p=0.044). HTK and CB cardioplegic solutions assure similar myocardial protection in patients undergoing thoracic aorta operations. In long cross-clamp times, the lower post-operative cTnI release detected using HTK may be indicative of a better myocardial protection in these extreme conditions.

Perioperative steroids administration in pediatric cardiac surgery: a meta-analysis of randomized controlled trials

Objective: To evaluate the effects of prophylactic perioperative corticosteroid administration, compared with placebo, on postoperative mortality and clinical outcomes (renal dysfunction, duration of mechanical ventilation, and ICU length of stay) in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass. Data Sources: MEDLINE and Cochrane Library were screened through August 2013 for randomized controlled trials in which perioperative steroid treatment was adopted. Study Selection: Included were randomized controlled trials conducted on pediatric population that reported clinical outcomes about mortality and morbidity. Data Extraction: Eighty citations (PubMed, 48 citations; Cochrane, 32 citations) were identified, of which 14 articles were analyzed in depth and six articles fulfilled eligibility criteria and reported mortality data (232 patients), two studies reported ICU length of stay and mechanical ventilation duration (60 patients), and two studies reported renal dysfunction (49 patients). Data Synthesis: A nonsignificant trend of reduced mortality was observed in steroid-treated patients (11 [4.7%] vs 4 [1.7%] patients; odds ratio, 0.41; 95% CI, 0.14–1.15; p = 0.089). Steroids had no effects on mechanical ventilation time (117.4 ± 95.9 hr vs 137.3 ± 102.4 hr; p = 0.43) and ICU length of stay (9.6 ± 4.6 d vs 9.9 ± 5.9 d; p = 0.8). Perioperative steroid administration reduced the prevalence of renal dysfunction (13 [54.2%] vs 2 [8%] patients; odds ratio, 0.07; 95% CI, 0.01–0.38; p = 0.002). Conclusion: Despite a demonstrated attenuation of cardiopulmonary bypass–induced inflammatory response by steroid administration, a systematic review of randomized controlled trials performed so far reveals that steroid administration has potential clinical advantages (lower mortality and significant reduction of renal function deterioration). A larger prospective randomized study is needed to verify clearly the effects of steroid prophylaxis in pediatric patients.

Monitoring incomplete heparin reversal and heparin rebound after cardiac surgery.

OBJECTIVES To assess the incidence of incomplete heparin reversal and heparin rebound after cardiac surgery with cardiopulmonary bypass (CPB) and the ability of the activated coagulation time (ACT) and thromboelastography (TEG) to detect these phenomena. DESIGN Prospective single-center study. SETTING University hospital. PARTICIPANTS Forty-one patients undergoing elective cardiac surgery with CPB and with normal preoperative TEG parameters. INTERVENTIONS ACT, TEG, and plasma heparin levels were measured in all patients at 5 different times between 20 minutes and 3 hours after protamine administration. The variability of TEG reaction time (R) with and without heparinase (delta-R [DR]) was used to detect the presence of residual heparin. MEASUREMENTS AND MAIN RESULTS Plasma heparin expressed as anti-FXa activity was detected in 180 (88%) samples. At univariate analysis, ACT, R-kaolin (R-k), and DR significantly correlated with plasma heparin concentration (respectively, p = 0.007, p = 0.006, and p = 0.002). At multivariate analysis, R-k and DR remained associated with plasma heparin concentration (respectively, p = 0.014 and p = 0.004). Greater quartiles of heparin were associated with higher values of R-k and DR. Combined procedures had significantly lower DR than isolated procedures (p = 0.017), and CPB time and heparinization time positively correlated with R-k (respectively, p = 0.044 and p = 0.022). No association was observed between heparin concentration, ACT, and TEG parameters with postoperative bleeding and need for blood and blood components transfusions. CONCLUSIONS Heparin rebound and incomplete heparin reversal are very common phenomena after cardiac surgery with CPB; ACT is not able to detect residual heparin activity, whereas TEG analysis with and without heparinase allows the diagnosis of heparin rebound.

Pump blood processing, salvage and re-transfusion improves hemoglobin levels after coronary artery bypass grafting, but affects coagulative and fibrinolytic systems

Cell saving systems are commonly used during cardiac operations to improve hemoglobin levels and to reduce blood product requirements. We analyzed the effects of residual pump blood salvage through a cell saver on coagulation and fibrinolysis activation and on postoperative hemoglobin levels. Thirty-four elective coronary artery bypass graft (CABG) patients were randomized. In 17 patients, residual cardiopulmonary bypass (CPB) circuit blood was transfused after the cell saving procedure (cell salvage group). In the other 17 patients, residual CPB circuit blood was discarded (control group). Activation of the coagulative, fibrinolytic and inflammatory systems was evaluated pre-operatively (Pre), 2 hours after the termination of CPB (T0) and 24 hours postoperatively (T1), measuring prothrombin fragment 1.2 (PF 1.2), plasmin-anti-plasmin (PAP), plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6). The cell salvage group of patients had a significant improvement in hemoglobin levels after processed blood infusion (2.7 ± 1.7 g/dL vs 1.2 ± 1.1 g/dL; p=0.003). PF1.2 levels were significantly higher after infusion (T0: 1175 ± 770 pmol/L vs 730 ± 237 pmol/L; p=0.037; T1: 331 ± 235 pmol/L vs 174 ± 134 pmol/L; p=0.026). Also, PAP levels were higher in the cell salvage group, although not significantly (T0: 253 ± 251 ng/mL vs 168 ± 96 ng/mL; p: NS; T1: 95 ± 60 ng/mL vs 53 ± 32 ng/mL; p: NS). No differences were found for PAI-1, IL-6, heparin levels or for red blood cell (RBC) transfusions. The cell salvage group of patients had increased chest tube drainage (749 ± 320 vs 592 ± 264; p: NS) and fresh frozen plasma transfusion rate (5 (29%) pts vs 0 pts; p<0.04). Pump blood salvage with a cell saving system improved postoperative hemoglobin levels, but induced a strong thrombin generation, fibrinolysis activation and lower fibrinolysis inhibition. These conditions could generate a consumption coagulopathy.

Ochratoxin A inhibits the production of tissue factor and plasminogen activator inhibitor-2 by human blood mononuclear cells: Another potential mechanism of immune-suppression

The mycotoxin ochratoxin A (OTA), an ubiquitous contaminant of food products endowed with a wide spectrum of toxicity, affects several functions of mononuclear leukocytes. Monocytes/macrophages play a major role in fibrin accumulation associated with immune-inflammatory processes through the production of tissue factor (TF) and plasminogen activator inhibitor 2 (PAI-2). We studied the effect of OTA on TF and PAI-2 production by human blood mononuclear cells (MNC). The cells were incubated for 3 or 18 h at 37 degrees C with non toxic OTA concentrations in the absence and in the presence of lipopolysaccharide (LPS) or other inflammatory agents. TF activity was measured by a one-stage clotting test. Antigen assays were performed by specific ELISAs in cell extracts or conditioned media and specific mRNAs were assessed by RT-PCR. OTA had no direct effect on TF and PAI-2 production by MNC. However, OTA caused a dose-dependent reduction in LPS-induced TF (activity, antigen and mRNA) and PAI-2 (antigen and mRNA) production with >85% inhibition at 1 mug/ml. Similar results were obtained when monocyte-enriched preparations were used instead of MNC. TF production was also impaired by OTA (1 mug/ml) when MNC were stimulated with phorbol myristate acetate (98% inhibition), IL-1beta (83%) or TNF-alpha (62%). The inhibition of TF and PAI-2 induction might represent a hitherto unrecognized mechanism whereby OTA exerts immunosuppressant activity.

A Biocompatible Cardiopulmonary Bypass Strategy to Reduce Hemostatic and Inflammatory Alterations: A Randomized Controlled Trial

OBJECTIVE Cardiopulmonary bypass (CPB) systems without a venous reservoir rarely are adopted clinically. The effects of a biocompatible CPB system with a venous reservoir were evaluated on the activation of the coagulation and inflammatory systems. DESIGN A prospective, randomized controlled trial. SETTING A university hospital (single center). PARTICIPANTS Eighty-three coronary artery bypass graft (CABG) surgery patients were assigned to the Physio group (closed venous reservoir, phosphorylcholine coating, and no cardiotomy suction) or the Standard group (open, noncoated, and cardiotomy suction used). METHODS Blood samples were obtained at 6 different time points before, during, and after surgery. Nuclear factor-kB (NF-κB) was evaluated before surgery and 2 and 24 hours after surgery. Myocardial damage was evaluated measuring cardiac troponin I. MEASUREMENTS AND MAIN RESULTS Interleukin (IL)-6 (a marker of inflammation), prothrombin fragment 1-2 (PF-1.2, a marker of thrombin generation), plasmin-antiplasmin complex (PAP, a marker of fibrinolysis), and platelet factor 4 (PF4, a marker of platelet activation) were measured. The DNA binding activity of proinflammatory transcription factor NF-κB was quantified in the isolated lymphomonocyte cells. Surgery caused changes of all plasma biomarkers. This reaction was attenuated strongly in the Physio group; PF-1.2, PAP, and PF4 all were decreased significantly. In the Physio group, a significantly lower cardiac troponin I release was observed postoperatively. After surgery, NF-κB activity was reduced in the Physio group although this difference was not statistically significant. CONCLUSIONS A multimodal strategy using a closed and phosphorylcholine-coated CPB circuit together with the avoidance of cardiotomy suction reduced activation of the coagulation and fibrinolytic systems intraoperatively, although these changes did not persist postoperatively. However, no difference in clinical outcome was appreciated on a larger scale.