Perioperative Elevation in Cell-Free DNA Levels in Patients Undergoing Cardiac Surgery: Possible Contribution of Neutrophil Extracellular Traps to Perioperative Renal Dysfunction

Background. This study aimed to determine the perioperative change in serum double-strand DNA (dsDNA) as a marker potentially reflecting neutrophil extracellular trap concentration in samples from patients undergoing cardiac surgery and to analyze a relationship between serum dsDNA concentrations and perioperative renal dysfunction. Methods. Serum dsDNA concentrations in samples that were collected during a previously conducted, prospective, multicenter, observational study were measured. Eighty patients undergoing elective cardiac surgery were studied. Serum samples were collected at baseline, immediately after surgery, and the day after surgery (POD-1). Results. Serum dsDNA concentration was significantly increased from baseline (median, 398 ng/mL [interquartile range, 372–475 ng/mL]) to immediately after surgery (median, 540 ng/mL [437–682 ng/mL], p<0.001), and they were reduced by POD-1 (median, 323 ng/mL [256–436 ng/mL]). The difference in serum creatinine concentration between baseline and POD-1 was correlated with dsDNA concentration on POD-1 (rs=0.61, p<0.001). Conclusions. In patients undergoing cardiac surgery, serum dsDNA concentration is elevated postoperatively. Prolonged elevation in dsDNA concentration is correlated with perioperative renal dysfunction. Further large-scale studies are needed to determine the relationship between serum concentration of circulating dsDNA and perioperative renal dysfunction

Soluble isoform of the receptor for advanced glycation end products as a biomarker for postoperative respiratory failure after cardiac surgery.

PURPOSE: Postoperative respiratory failure is a major problem which can prolong the stay in the intensive care unit in patients undergoing cardiac surgery. We measured the serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE), and we studied its association with postoperative respiratory failure. METHODS: Eighty-seven patients undergoing elective cardiac surgery were enrolled in this multicenter observational study in three university hospitals. Serum biomarker levels were measured perioperatively, and clinical data were collected for 7 days postoperatively. The duration of mechanical ventilation was studied for 28 days. RESULTS: Serum levels of sRAGE elevated immediately after surgery (median, 1751 pg/mL; interquartile range (IQR) 1080-3034 pg/mL) compared with the level after anesthetic induction (median, 884 pg/mL; IQR, 568-1462 pg/mL). Postoperative sRAGE levels in patients undergoing off-pump coronary artery bypass grafting (median, 1193 pg/mL; IQR 737-1869 pg/mL) were significantly lower than in patients undergoing aortic surgery (median, 1883 pg/mL; IQR, 1406-4456 pg/mL; p=0.0024) and valve surgery (median, 2302 pg/mL; IQR, 1447-3585 pg/mL; p=0.0005), and postoperative sRAGE correlated moderately with duration of cardiopulmonary bypass (rs  =0.44, p3 days. The optimum cutoff value for prediction of respiratory failure was 3656 pg/mL, with sensitivity and specificity of 62% and 91%, respectively. CONCLUSIONS: Serum sRAGE levels elevated immediately after cardiac surgery, and the range of elevation was associated with the morbidity of postoperative respiratory failure. Early postoperative sRAGE levels appear to be linked to cardiopulmonary bypass, and may have predictive performance for postoperative respiratory failure; however, large-scale validation studies are needed

Serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE) in the perioperative period.

<p>(A) Perioperative change in the levels of sRAGE in the entire study cohort. Serum levels of sRAGE were measured at three points: 1) after induction of anesthesia (Baseline); 2) at admission to the intensive care unit immediately after the operation (Post-Op); and 3) post-operative day 1 (POD 1); (B) Differences in Post-Op levels of sRAGE according to the type of operation. The operations were categorized as: 1) aortic surgery (<i>n</i> = 21); 2) valve surgery (<i>n = </i>33); and 3) off -pump coronary artery bypass grafting (OPCAB, <i>n</i> = 33); (C) Relationship between Post-Op sRAGE levels and duration of cardiopulmonary bypass. Patients were divided into three groups categorized by duration of cardiopulmonary bypass: 0 min; between 0 and 240 min; and ≥240 min. In panel B and C, Post-Op values were selected for comparison. Box-whisker plots show the 5th, 25th, 50th, 75th, and 95th percentile in each study condition. <i>p</i>-values for the three-group comparison were calculated using Tukey’s test. ns: not statistically significant.</p

Relationship between serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE) and the variables reflecting the condition of the lung.

<p>(A) Relationship between serum sRAGE and radiographic presentations scored by Murray’s chest X-ray score. Box-whisker plots show the 5th, 25th, 50th, 75th, and 95th percentile in each study condition. <i>p</i>-values for the three-group comparison were calculated using Tukey’s test; (B) Relationship between serum sRAGE levels and PaO₂/F_IO₂ on POD 1. Patients were divided into two groups using a cut-off value for PaO₂/F_IO₂ = 200. Box-whisker plots show the 5th, 25th, 50th, 75th, and 95th percentile in each study condition. The <i>p</i>-value was calculated using the Mann-Whitney U-test.</p

Multivariable analyses of association between postoperative levels of the serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE) and morbidity of prolonged mechanical ventilation (>3days).

<p>The serum levels of sRAGE (pg/mL) were natural log-transformed.</p>§1<p>Odds ratio per 1 natural log transformed sRAGE level.</p>*<p>Statistically significant at <i>p</i><0.05;</p>**<p>Statistically significant at <i>p</i><0.01.</p

Results of multiple regression analyses for the relationships between the serum levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE) and patients' conditions.

<p>The serum levels of sRAGE were natural log-transformed.</p>§1<p>1 unit of packed red cells is derived from 200 mL of donated blood.</p>§2<p>PBW: predicted body weight; male PBW (kg) = 50+0.91(height (cm) –152.4), and female PBW (kg) = 45.5+0.91(height (cm) –152.4).</p>*<p>Statistically significant at <i>p</i><0.05;</p>**<p>Statistically significant at <i>p</i><0.01.</p

Predictive performance of the post-operative levels of the soluble isoform of the receptor for advanced glycation end products (sRAGE) for postoperative respiratory failure and prolongation of stay in the intensive care unit (ICU).

<p>(A) Receiver operating characteristic (ROC) curve analysis for predicting performance of Post-Op levels of biomarkers (sRAGE and interleukin-8) and PaO₂/F_IO₂ on POD 1. ROC curves for sRAGE, interleukin-8, and PaO₂/F_IO₂ are shown with their area under the curve (AUC) calculations; (B) Relationship between serum levels of sRAGE and duration of mechanical ventilation; (C) Relationship between the serum levels of sRAGE and the length of stay in the ICU. In graph B and C, patients were dichotomized using the cut-off value of 3656 pg/mL, which was calculated from the ROC curve analysis shown in graph A. Patients with a high level of sRAGE (≥3656 pg/mL) showed a significantly longer duration of mechanical ventilation (<i>p</i> = 0.0001) and a longer stay in the ICU (<i>p</i><0.0001) than those with low sRAGE (<3656 pg/mL) (Mann-Whitney U-test). Spearman’s correlation coefficients (<i>r_s</i>) are shown with <i>p</i> values.</p

Flow chart for the enrollment of patients.

<p>Flow chart for the enrollment of patients.</p

Patient characteristics.

<p>OPCAB: off-pump coronary artery bypass grafting.</p>#<p><i>p</i><0.05 vs. aortic surgery group.</p>*<p><i>p</i><0.05.</p>$$<p><i>p</i><0.01 vs. OPCAB group.</p>**<p><i>p</i><0.01.</p>§1<p>PBW: predicted body weight; male PBW (kg) = 50+0.91(height (cm) –152.4), and female PBW (kg) = 45.5+0.91(height (cm) –152.4).</p>§2<p>1 unit of packed red cells or fresh frozen plasma is derived from 200 mL of donated blood.</p>§3<p>1 unit of packed platelet concentrate contains 2×10¹⁰ platelets.</p>§4<p>Data are shown as median with interquartile range.</p