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Background: Endothelial injury occurring during cardiopulmonary bypass is a major contributing factor in the development of organ dysfunction, which leads to many of the postoperative complications occurring during cardiac surgery., Objective: This narrative review aims to summarize the main mechanisms of cardiopulmonary bypass - related disease, evaluating the unfavorable events leading to tissue injury, with a description of current pharmacologic and non-pharmacologic mechanisms to reduce CPB-related injury., Methods: A Medline/Pubmed/Scopus search was conducted using clinical queries with the key terms "cardiac surgery", "cardiopulmonary bypass", "inflammation" and "endothelial injury", and related MeSH terms, until July 2019. The search strategy included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the same key terms from https://patents.google.com/, www.uspto.gov, and www.freepatentsonline.com., Results: In this review, we discuss the current knowledge of the mechanisms of vascular endothelial cell injury, the acute inflammatory response, and the regulatory factors that control the extent of vascular injury during extracorporeal circulation, summarizing the main target of anti-inflammatory pharmacologic and non-pharmacologic strategies., Conclusion: Inflammatory response and endothelial dysfunction following cardiopulmonary bypass are the prices to pay for the benefits offered during cardiac surgery procedures. Counteracting the detrimental effect of extracorporeal circulation appears to be crucial to improve clinical outcomes in pediatric and adult cardiac surgery. The intrinsic complexity and the tight interplay of the factors involved might require a holistic approach against inflammation and endothelial response., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: During extracorporeal circulation (ECC) there is a great hemodynamic stress with possible impact on the microcirculation, including cochlear one. Previous studies have evaluated the effect of ECC on inner ear with contrasting results. The aim of this study is to evaluate possible modifications of the outer hair cells (OHC) function after open heart surgery (OHS) under ECC with transient evoked (TEOAEs) and distortion product otoacoustic emissions (DPOAEs)., Methods: Ten patients (5 F and 5 M), undergoing OHS with ECC, were subjected to an audiological assessment pre- and postoperatively. We compared the pre-operative and post-operative mean auditory thresholds, mean TEOAEs reproducibility and amplitude, and mean DPOAEs amplitude. Student's t-test was used to compare different values., Results: No significant differences were found between pre- and post-operative audiological assessment both in hearing level and in otoacoustic emissions., Conclusion: OHC function seems to be not affected by hemodynamic stress induced by ECC. Further studies on a larger scale will be necessary to confirm our preliminary data.

Endothelial progenitor cells (EPCs) are a subtype of hematopoietic stem cells, which contribute to the repair of injured endothelium. Treatment with atorvastatin has been shown to increase EPC count in patients with coronary artery disease. Therefore, we investigated whether atorvastatin augments the number of EPCs after cardiopulmonary bypass (CPB) surgery. We conducted a randomized double-blind, placebo-controlled, 2-way crossover trial in 50 patients undergoing elective coronary surgery. Patients received either 3-week treatment with atorvastatin or placebo. EPCs were quantitated by flow cytometric phenotyping on blood samples. Levels of interleukin, IL-6 and IL-8; tumor necrosis factor alpha; SDF-1alpha; granulocyte colony-stimulating factor; and vascular endothelial growth factor were determined at recruitment, preoperatively, post-CPB, and 6, 12, and 24 hours postoperatively. The atorvastatin group showed a significantly higher amount of EPCs both pre- and postoperatively compared with the placebo, with a >4-fold increase compared with the baseline values. CPB induced an increase in all cytokines, but the levels of proinflammatory cytokines were significantly lower in the atorvastatin group (P < 0.05). Statin did not affect levels of SDF-1alpha, granulocyte colony-stimulating factor, and vascular endothelial growth factor. However, no correlation was found between plasma levels of any cytokine and number of EPCs, with the exception of SDF-1alpha. Pretreatment with atorvastatin significantly increases the amount of EPCs after CPB, by a mechanism independent of plasma levels of cytokines and cholesterol.

Background: Abnormal erythrocyte deformability can cause severe complications during cardiopulmonary bypass (CPB) surgery, including both hemolysis and perfusion abnormalities., Objectives: The goals of this study were to evaluate changes in erythrocyte membrane fluidity and lipid peroxidation during CPB and to examine the effect of simvastatin treatment on these parameters., Methods: Patients undergoing cardiac surgery involving CPB were selected and randomized to receive either simvastatin 40 mg/d or placebo for 3 weeks before surgery. Three blood samples were obtained at different times during surgery for analysis of erythrocyte membrane fluidity, anion permeability, and lipid peroxidation. Erythrocyte ghosts were prepared and incubated with a lipophilic fluorescent probe (diphenyl-hexatriene), and fluorescence anisotropy was evaluated by spectrophotofluorimetric assay as a measure of membrane fluidity. Anion permeability was evaluated by the specific absorption of methemoglobin (CM) at 590 and 635 nm after treatment of heparinized blood with NaNO2. The formation of thiobarbituric acid-reactive substances was evaluated as an index of lipid peroxidation. Aspartate transaminase and lactate dehydrogenase were also measured as indices of hemolysis., Results: Forty patients met the inclusion criteria (20 simvastatin, 20 placebo). Their characteristics differed significantly at baseline only in terms of the lipid profile; the statin group had higher levels of high-density lipoprotein cholesterol (P = 0.01) and lower levels of low-density lipoprotein cholesterol (P = 0.001) than the placebo group. CPB was found to significantly modify characteristics of the erythrocyte membrane. Compared with preoperative values, CPB induced decreases in both mean (SD) erythrocyte membrane fluidity and anion permeability (preoperative CM: 0.69 [0.02]; 24-hour postoperative CM: 0.18 [0.02]; P < 0.001) and an increase in mean (SD) membrane lipid peroxidation (preoperative malonyl dialdehyde [MDA]: 0.21 [0.01] nmol/mL; postoperative MDA: 0.10 [0.02] nmol/mL; P < 0.001). Treatment with simvastatin was associated with a significant reduction in mean (SD) membrane lipid peroxidation both preoperatively and at 24 hours postoperatively compared with placebo (preoperative MDA: 0.07 [0.01] vs 0.10 [0.02] nmol/mL, respectively; P < 0.05; postoperative MDA: 0.10 [0.04] vs 0.21 [0.01] nmol/mL; P < 0.05). In addition, statin treatment was associated with significant increases in anion permeability preoperatively and postoperatively compared with placebo (preoperative CM: 0.79 [0.01] vs 0.69 [0.02]; P < 0.01; 24-hour postoperative CM: 0.30 [0.01] vs 0.18 [0.02]; P < 0.01)., Conclusion: The results of this study suggest that among these patients undergoing CPB surgery, use of simvastatin for 3 weeks before the surgery had significant beneficial effects on erythrocyte membrane fluidity, lipid peroxidation, and anion permeability., (Copyright 2007 Excerpta Medica, Inc.)

Aim: In this paper we report our clinical experience with extended utilization of axillary artery cannulation for cardiopulmonary bypass (CPB) and discuss the indications and the results of the procedure in terms of complications and usefulness., Methods: Between January 1999 and May 2004, 26 patients underwent right axillary artery cannulation for CPB. Fifteen patients presented acute type A aortic dissection and were operated urgently. Axillary cannulation was also used in 11 elective cases: 3 reoperative coronary surgery, 3 valve redo-operations and 5 cases of aortic valve regurgitation+aneurysm of the ascending aorta., Results: All axillary artery cannulations were successful (21 direct and 5 with a side graft) without neurologic or vascular injuries to the right upper extremities. Hospital mortality was 7.7% and included 2 patients operated in an emergency procedure because of acute type A aortic dissection. In all cases, this cannulation site provided adequate perfusion, with a range of peak flows from 4.1 to 5.7 L/min., Conclusion: Our preliminary results demonstrate that the right axillary artery may be considered an alternative cannulation site for achieving full CPB and providing antegrade flow, thus avoiding complications related to retrograde flow when femoral artery perfusion is performed. This safe and useful method may be used not only in aortic surgery but in other such complex cardiac procedures as redo-operations.

Objectives: Endothelial dysfunction has been shown to be a critical early component of organ injury after myocardial ischemia and reperfusion. Circulating levels of adhesion molecules have been regarded as a valid index of endothelial activation. Recent reports suggest that statins, widely used in the control of hypercholesterolemia, exert a protective effect on the endothelium reflected by a reduced level of circulating adhesion molecules. In this study, the effects of preoperative simvastatin treatment, at doses equivalent to those used orally for cholesterol control, were studied on plasma levels of VCAM-1, ICAM-1, and ELAM-1., Design: A case-control study., Setting: University hospital., Participants: Fifteen patients taking simvastatin with good control of cholesterol levels, 15 patients not responsive to the simvastatin treatment, and 15 normocholesterolemic patients (control) undergoing elective coronary artery bypass surgery., Measurements and Main Results: The plasma levels of VACM-1, ICAM-1, and ELAM-1 were evaluated at baseline; during cardiopulmonary bypass; and 6 hours, 24 hours, and 48 hours postoperatively. In the late postoperative samples, the plasma levels of ICAM-1 and ELAM-1 were lower in both simvastatin-treated patients compared with the control patients. No significant difference was found between the patients responsive to statin and those not responsive. Finally, no significant difference was found for VCAM-1 plasma levels between the control group and the 2 treatment groups., Conclusions: Pretreatment with simvastatin significantly reduces the increase of ICAM-1 and ELAM-1 after coronary artery bypass surgery, by a mechanism that seems not related to its efficacy in lowering cholesterol levels.

Objective: To investigate the effects of preoperative simvastatin treatment on leucocyte-endothelial interactions following coronary artery bypass surgery with cardiopulmonary bypass., Design: Double blind crossover study. Experiments on polymorphonuclear cells (neutrophils) were done at the end of cardiopulmonary bypass and one hour postoperatively. Endothelial P-selectin expression and neutrophil/endothelial adhesion were evaluated under either normoxic or hypoxic conditions., Setting: University hospital (tertiary referral centre)., Patients: Three groups of patients undergoing coronary bypass surgery: 20 patients taking simvastatin for cholesterol control, 16 patients not responsive to simvastatin, and 20 controls., Main Outcome Measures: Expression of neutrophil CD11b and endothelial P-selectin; adhesion of neutrophils to endothelium., Results: Cardiopulmonary bypass resulted in a significant increase in neutrophil CD11b expression in all groups. Similarly, the exposure of saphenous vein to hypoxia/reoxygenation induced an augmentation of endothelial P-selectin. However, both neutrophil CD11b expression and endothelial P-selectin exocytosis were less in the simvastatin groups than in the controls. Cardiopulmonary bypass and controlled hypoxia/reoxygenation stimulated neutrophil/endothelial adhesion, but the number of adhering cells was less in the simvastatin groups than in the controls, irrespective of the cholesterol concentration. Treatment of endothelial cells with L-NAME completely reversed the effects of simvastatin., Conclusions: Pretreatment with simvastatin reduces neutrophil adhesion to the venous endothelium in patients undergoing coronary surgery, irrespective of its efficacy at lowering cholesterol concentration.

Background: Granulocyte apoptosis is a key control process in the clearance of neutrophils from inflammatory sites, and its rate is modulated both in vitro and in vivo by a number of inflammatory mediators. In this study, we investigated the influence of cardiopulmonary bypass (CPB) on neutrophil apoptosis., Methods: Twenty patients undergoing coronary operation with CPB were studied. Patients undergoing off-pump (OP) coronary bypass and healthy subjects served respectively as stressed and normal groups. Interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha were assessed on plasma collected preoperatively, at the end of CPB, and after intervals of 4, 8, 12, and 24 hours. Neutrophil apoptosis was detected by light microscopy as well as by the annexin-V assay on postoperative samples. The polymorphonuclear leukocyte (PMN) apoptotic receptors, Fas and FasL, were studied together with the activity of caspase 3 in postoperative neutrophils., Results: Spontaneous apoptosis was significantly delayed in PMNs from CPB patients when compared with either the stressed or control patients. Neutrophils were activated, as indicated by increased surface expression of CD11b. Western blot analysis showed a normal expression of the apoptotic receptors Fas and FasL. Caspase 3 activity was found to be significantly reduced in neutrophils from CPB patients after 18 and 24 hours of culture. When control neutrophils were cultured in the presence of postoperative plasma from OP and CPB patients, apoptosis was significantly delayed. Depleting surgical plasma of IL-6 and IL-8 completely abolished this antiapoptotic effect., Conclusions: Inflammatory mediators during CPB prolong the functional lifespan of neutrophils through modulation of apoptosis, and potentiate the inflammatory response observed after coronary bypass operation.

Objective: Activation of both complement and neutrophils has been demonstrated to be involved in many pathological reactions following cardiopulmonary bypass (CPB). The aim of the present study is to evaluate the effect of normothermic and hypothermic CPB on both complement and neutrophil activation., Methods: Two groups of patients (n = 20 each) scheduled for elective coronary artery bypass grafting, underwent CPB with intermittent warm or cold blood cardioplegia. Plasma concentration of C3a, C5a and C5b-9, as well as nitro-blu tetrazolium (NBT) scores of circulating neutrophils were measured before anesthesia, 10 and 30 min after the beginning of CPB, and 8, 16 and 24 h, postoperatively., Results: In both groups, CPB determined a significant complement activation, evidenced as a significant increase in plasma concentration of C3a, C5a and C5b-9. This in turn triggered the neutrophil activation, documented as a significant increase of NTB scores in circulating neutrophils at the end of CPB and in the early postoperative period. Interestingly, in the warm group the extent of both complement and neutrophil activation was significantly higher compared with the cold group during the whole sampling period., Conclusion: In conclusion, our study clearly demonstrates that warm CPB is associated with an increased ability to activate complement and neutrophils in patients undergoing coronary surgery.