Dynamics of Vascular Protective and Immune Supportive Sphingosine-1-Phosphate During Cardiac Surgery

IntroductionSphingosine-1-phosphate (S1P) is a signaling lipid and crucial in vascular protection and immune response. S1P mediated processes involve regulation of the endothelial barrier, blood pressure and S1P is the only known inducer of lymphocyte migration. Low levels of circulatory S1P correlate with severe systemic inflammatory syndromes such as sepsis and shock states, which are associated with endothelial barrier breakdown and immunosuppression. We investigated whether S1P levels are affected by sterile inflammation induced by cardiac surgery.Materials and MethodsIn this prospective observational study we included 46 cardiac surgery patients, with cardiopulmonary bypass (CPB, n=31) and without CPB (off-pump, n=15). Serum-S1P, S1P-sources and carriers, von-Willebrand factor (vWF), C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) were measured at baseline, post-surgery and at day 1 (POD 1) and day 4 (POD 4) after surgical stimulus.ResultsMedian S1P levels at baseline were 0.77 nmol/mL (IQR 0.61-0.99) and dropped significantly post-surgery. S1P was lowest post-surgery with median levels of 0.37 nmol/mL (IQR 0.31-0.47) after CPB and 0.46 nmol/mL (IQR 0.36-0.51) after off-pump procedures (P<0.001). The decrease of S1P was independent of surgical technique and observed in all individuals. In patients, in which S1P levels did not recover to preoperative baseline ICU stay was longer and postoperative inflammation was more severe. S1P levels are associated with its sources and carriers and vWF, as a more specific endothelial injury marker, in different phases of the postoperative course. Determination of S1P levels during surgery suggested that also the anticoagulative effect of heparin might influence systemic S1P.DiscussionIn summary, serum-S1P levels are disrupted by major cardiac surgery. Low S1P levels post-surgery may play a role as a new marker for severity of cardiac surgery induced inflammation. Due to well-known protective effects of S1P, low S1P levels may further contribute to the observed prolonged ICU stay and worse clinical status. Moreover, we cannot exclude a potential inhibitory effect on circulating S1P levels by heparin anticoagulation during surgery, which would be a new pro-inflammatory pleiotropic effect of high dose heparin in patients undergoing cardiac surgery.

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Thrombin Generation during Cardiac Surgery: Is Heparin the Ideal Anticoagulant?

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649561 ◽

1993 ◽

Vol 70 (02) ◽

pp. 259-262 ◽

Cited By ~ 103

Author(s):

S J Brister ◽

F A Ofosu ◽

M R Buchanan

Keyword(s):

At Risk ◽

Cardiac Surgery ◽

Thrombin Generation ◽

Antithrombin Iii ◽

Experimental Studies ◽

High Dose ◽

Protamine Sulphate ◽

Elective Cardiac Surgery ◽

Post Surgery ◽

Dose Heparin

SummaryBlood samples were collected from 43 patients undergoing elective cardiac surgery to determine the extent of thrombin generation and inhibition in patients when receiving heparin while undergoing cardiopulmonary bypass (CPB). Plasma prothrombin fragment F1 + 2 and thrombin-antithrombin III (TAT) levels were measured as markers of thrombin generation and inhibition, respectively. Both F1 + 2 and TAT levels increased significantly during the course of CPB despite the heparin causing significant systemic anticoagulation, i.e. the activated coagulation time (ACT) was prolonged to greater than 400 s throughout the entire surgical procedure. The extent of thrombin generation increased with time on CPB but did not differ between patients receiving normothermic and hypothermic cardioplegia during CPB. Furthermore, thrombin generation increased following the neutralization of the heparin with protamine sulphate, and continued to be elevated significantly 24 h post surgery. The observation that high dose heparin did not prevent thrombin generation during CPB, is consistent with previous experimental studies demonstrating that thrombin bound to fibrin or other surfaces (e.g. the CPB conduit) is resistant to antithrombin III/heparin inhibition, and thus able to facilitate further thrombin generation. The observation that thrombin generation continued to be elevated post surgery i.e. 24 h after neutralizing the heparin with protamine sulphate, suggests that the high dose heparin did not inhibit effectively all of the thrombin that had been generated. Thus, CPB patients may be at risk not only of bleeding and other side-effects associated with the acute use of high dose heparin, but may also be at risk of further thrombosis-related events either acutely or chronically.

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Inflammatory and Hemostatic Activation in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029607308869 ◽

2008 ◽

Vol 14 (2) ◽

pp. 141-148 ◽

Cited By ~ 9

Author(s):

Brian R. Untch ◽

Walter P. Jeske ◽

Jeffrey Schwartz ◽

Sally Botkin ◽

Margaret Prechel ◽

...

Keyword(s):

Coronary Artery ◽

Plasminogen Activator ◽

Thrombin Generation ◽

Artery Bypass ◽

Plasminogen Activator Inhibitor ◽

Enzyme Linked Immunosorbent Assay ◽

Vascular Protection ◽

Plasminogen Activator Inhibitor 1 ◽

Off Pump ◽

Post Surgery

To characterize hemostatic differences imposed by 2 common cardiac surgeries, the authors studied patients undergoing coronary artery revascularization by off-pump (n = 13) or cardiopulmonary bypass on-pump (n = 26) technique. Blood samples collected to 4 days post-surgery were evaluated by flow cytometry and enzyme-linked immunosorbent assay. A significant inflammatory response occurred in both the groups after surgery shown by increased interleukin cytokines and C-reactive protein; however, levels peaked lower and hours later in the off-pump group. Platelets (P-selectin; platelet-leukocyte complexes) and leukocytes (CD11b) were activated only in on-pump patients. Thrombin generation was enhanced in both groups after surgery. Only in the on-pump patients, the thrombin-antithrombin complex, pro-thrombin fragment 1.2, and thrombomodulin (vascular integrity) decreased intraoperatively. Tissue plasminogen activator and plasminogen activator inhibitor-1 were greater in the on-pump patients. Off-pump surgery may place patients at higher risk of postoperative hypercoagulability because of normal platelet function, intraoperative thrombin generation, less fibrinolytic activity, and lack of vascular protection.

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Is there a difference in circulatory inflammatory response between on- versus off pump cardiac surgery?

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0031-1297578 ◽

2012 ◽

Vol 60 (S 01) ◽

Author(s):

S Lehmann ◽

J Garbade ◽

J Seeburger ◽

S Leontyev ◽

S Dhein ◽

...

Keyword(s):

Cardiac Surgery ◽

Inflammatory Response ◽

Off Pump

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Risk factors and incidence for postop delirium in patients undergoing cardiac surgery with cardiopulmonary bypass support vs. off pump surgery

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0032-1332398 ◽

2013 ◽

Vol 61 (S 01) ◽

Author(s):

O Dzemali ◽

K Graves ◽

H Loeblein ◽

A Zientara ◽

A Kostorz ◽

...

Keyword(s):

Risk Factors ◽

Cardiac Surgery ◽

Cardiopulmonary Bypass ◽

Off Pump

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High-dose Aprotinin in Cardiac Surgery—A Prospective, Randomized Study

Anaesthesia and Intensive Care ◽

10.1177/0310057x9402200505 ◽

1994 ◽

Vol 22 (5) ◽

pp. 529-533 ◽

Cited By ~ 20

Author(s):

M. J. Swart ◽

P. C. Gordon ◽

P. B. Hayse-Gregson ◽

R. A. Dyer ◽

A. L. Swanepoel ◽

...

Keyword(s):

Cardiac Surgery ◽

Placebo Group ◽

Blood Loss ◽

Artery Bypass ◽

Randomized Study ◽

Postoperative Blood Loss ◽

High Dose ◽

Maintenance Infusion ◽

Transfusion Requirements ◽

High Dose Aprotinin

Fifty patients undergoing primary coronary artery bypass surgery and 50 patients undergoing valve surgery received either high-dose aprotinin (2 million units loading dose, 2 million units added to the CPB prime, and 500,000 units/hr maintenance infusion) or placebo. Mean postoperative blood loss in the first six hours was reduced from 321 ml in the placebo group to 172 ml in the aprotinin group (95% confidence interval (CI) for difference = 95 to 189 ml). Seven patients in the placebo group and 16 patients in the aprotinin group did not require transfusion with homologous blood. This study adds to the growing body of evidence that the administration of high-dose aprotinin reduces blood loss and blood transfusion requirements associated with primary cardiac surgery.

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Off-Pump Technique May Prevent Worsening of Renal Function in CAD with CKD Undergoing CABG

Journal of Cardiac Critical Care TSS ◽

10.1055/s-0041-1723857 ◽

2021 ◽

Vol 05 (01) ◽

pp. 007-011

Author(s):

Shaheen Afsal ◽

K. Sujani ◽

Shashank Viswanathan ◽

Akshay Bhati ◽

Harish BR ◽

...

Keyword(s):

Renal Function ◽

Cardiac Surgery ◽

Serum Creatinine ◽

Renal Dysfunction ◽

Normal Renal Function ◽

Artery Bypass ◽

Significant Proportion ◽

Renal Dialysis ◽

Off Pump ◽

Preoperative Serum

AbstractCardiovascular disease (CVD) is a major cause for a significant proportion of all deaths and disability worldwide. Postoperative renal dysfunction following cardiac surgery is not an uncommon complication of cardiac surgery, which has serious implications with regard to morbidity, mortality, financial expenditure, and resource utilization. This study was performed to compare outcomes of patients with preoperative renal dysfunction with those having normal renal function undergoing off-pump coronary artery bypass grafting (OPCABG). Patients were divided into two categories, depending on their preoperative serum creatinine and glomerular filtration rate (GFR). The preoperative renal dysfunction was defined as serum creatinine >1.3 mg/dL and/or estimated GFR (eGFR) of <60 mL/min/1.73 m2. The category A patients had normal renal function defined as serum creatinine ≤1.3 mg/dL and/or eGFR of ≥60 mL/min/1.73 m2 while the category B patients had preoperative renal dysfunction that did not necessitate renal dialysis. Blood samples were collected from both category patients for serum creatinine prior to surgery, following surgery, on postoperative days 1, 2, 3, 4, 5, and on the day of discharge. The occurrence of acute kidney injury (AKI) was defined as an increase in the serum creatinine levels of ≥0.3 mg/dL within 48 hours or an increase of ≥1.5 above baseline known or presumed to have occurred within the previous 7 days based on Kidney Disease Improving Global Outcomes criteria. This study demonstrated that there was worsening of renal function in 7.4% of patients with normal renal function and 10.74% of patients with renal dysfunction that was not statistically different. Based on the results, we conclude that preoperative renal dysfunction may be a contributing predictor of AKI following OPCABG, and we recommend that the patients with more severe renal dysfunction with eGFR of 45–60 mL/min should be studied to demonstrate this hypothesis.

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Permissive Modulation of Sphingosine-1-Phosphate-Enhanced Intracellular Calcium on BKCa Channel of Chromaffin Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22042175 ◽

2021 ◽

Vol 22 (4) ◽

pp. 2175

Author(s):

Adonis Z. Wu ◽

Tzu-Lun Ohn ◽

Ren-Jay Shei ◽

Huei-Fang Wu ◽

Yong-Cyuan Chen ◽

...

Keyword(s):

Chromaffin Cells ◽

Low Dose ◽

Single Channel ◽

Cell System ◽

K Channel ◽

Lipid Mediator ◽

Bkca Channel ◽

High Dose ◽

Open Probability ◽

Sphingosine 1 Phosphate

Sphingosine-1-phosphate (S1P), is a signaling sphingolipid which acts as a bioactive lipid mediator. We assessed whether S1P had multiplex effects in regulating the large-conductance Ca2+-activated K+ channel (BKCa) in catecholamine-secreting chromaffin cells. Using multiple patch-clamp modes, Ca2+ imaging, and computational modeling, we evaluated the effects of S1P on the Ca2+-activated K+ currents (IK(Ca)) in bovine adrenal chromaffin cells and in a pheochromocytoma cell line (PC12). In outside-out patches, the open probability of BKCa channel was reduced with a mean-closed time increment, but without a conductance change in response to a low-concentration S1P (1 µM). The intracellular Ca2+ concentration (Cai) was elevated in response to a high-dose (10 µM) but not low-dose of S1P. The single-channel activity of BKCa was also enhanced by S1P (10 µM) in the cell-attached recording of chromaffin cells. In the whole-cell voltage-clamp, a low-dose S1P (1 µM) suppressed IK(Ca), whereas a high-dose S1P (10 µM) produced a biphasic response in the amplitude of IK(Ca), i.e., an initial decrease followed by a sustained increase. The S1P-induced IK(Ca) enhancement was abolished by BAPTA. Current-clamp studies showed that S1P (1 µM) increased the action potential (AP) firing. Simulation data revealed that the decreased BKCa conductance leads to increased AP firings in a modeling chromaffin cell. Over a similar dosage range, S1P (1 µM) inhibited IK(Ca) and the permissive role of S1P on the BKCa activity was also effectively observed in the PC12 cell system. The S1P-mediated IK(Ca) stimulation may result from the elevated Cai, whereas the inhibition of BKCa activity by S1P appears to be direct. By the differentiated tailoring BKCa channel function, S1P can modulate stimulus-secretion coupling in chromaffin cells.

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