Angiopoietin-2 is associated with capillary leak and predicts complications after cardiac surgery

Jakob Wollborn; Zilu Zhang; Julie Gaa; Moritz Gentner; Christian Hausmann; Felix Saenger; Karina Weise; Samuel Justice; Jean-Luca Funk; Hans Felix Staehle; Marie Thomas; Raphael R Bruno; Babak Saravi; Jan O Friess; Markus Marx; Hartmut Buerkle; Georg Trummer; Jochen D Muehlschlegel; Daniel Reker; Ulrich Goebel; Felix Ulbrich

doi:10.1186/s13613-023-01165-2

Angiopoietin-2 is associated with capillary leak and predicts complications after cardiac surgery

Ann Intensive Care. 2023 Aug 8;13(1):70. doi: 10.1186/s13613-023-01165-2.

Authors

Jakob Wollborn^{1

2

3}, Zilu Zhang⁴, Julie Gaa^{5

6}, Moritz Gentner^{5

6}, Christian Hausmann^{5

6}, Felix Saenger^{5

6}, Karina Weise^{5

6}, Samuel Justice⁷, Jean-Luca Funk^{5

6}, Hans Felix Staehle^{5

6}, Marie Thomas^{8

6}, Raphael R Bruno⁹, Babak Saravi⁷, Jan O Friess¹⁰, Markus Marx^{5

6}, Hartmut Buerkle^{5

6}, Georg Trummer^{8

6}, Jochen D Muehlschlegel⁷, Daniel Reker⁴, Ulrich Goebel^#^{5

11

6}, Felix Ulbrich^#^{5

6}

Affiliations

¹ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA. jwollborn@bwh.harvard.edu.
² Department of Anesthesiology and Critical Care, Medical Center, University of Freiburg, Breisgau, Germany. jwollborn@bwh.harvard.edu.
³ Faculty of Medicine, University of Freiburg, Freiburg, Germany. jwollborn@bwh.harvard.edu.
⁴ Department of Biomedical Engineering, Duke University, Durham, NC, USA.
⁵ Department of Anesthesiology and Critical Care, Medical Center, University of Freiburg, Breisgau, Germany.
⁶ Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁷ Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
⁸ Department of Cardiovascular Surgery, Medical Center, University of Freiburg, Freiburg, Germany.
⁹ Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine-University Duesseldorf, University Hospital Duesseldorf, Duesseldorf, Germany.
¹⁰ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, USA.
¹¹ Department of Anesthesiology and Critical Care, St. Franziskus-Hospital, Muenster, Germany.

^# Contributed equally.

Abstract

Background: Patients undergoing cardiac surgery are prone to numerous complications. Increased vascular permeability may be associated with morbidity and mortality due to hemodynamic instability, fluid overload, and edema formation. We hypothesized that markers of endothelial injury and inflammation are associated with capillary leak, ultimately increasing the risk of postoperative complications.

Methods: In this prospective, observational, multidisciplinary cohort study at our tertiary academic medical center, we recruited 405 cardiac surgery patients. Patients were assessed daily using body impedance electrical analysis, ultrasound, sublingual intravital microscopy, and analysis of serum biomarkers. Multivariable models, as well as machine learning, were used to study the association of angiopoietin-2 with extracellular water as well as common complications after cardiac surgery.

Results: The majority of patients underwent coronary artery bypass grafting, valvular, or aortic surgeries. Across the groups, extracellular water increased postoperatively (20 ± 6 preoperatively to 29 ± 7L on postoperative day 2; P < 0.001). Concomitantly, the levels of the biomarker angiopoietin-2 rose, showing a strong correlation based on the time points of measurements (r = 0.959, P = 0.041). Inflammatory (IL-6, IL-8, CRP) and endothelial biomarkers (VE-Cadherin, syndecan-1, ICAM-1) suggestive of capillary leak were increased. After controlling for common risk factors of edema formation, we found that an increase of 1 ng/mL in angiopoietin-2 was associated with a 0.24L increase in extracellular water (P < 0.001). Angiopoietin-2 showed increased odds for the development of acute kidney injury (OR 1.095 [95% CI 1.032, 1.169]; P = 0.004) and was furthermore associated with delayed extubation, longer time in the ICU, and a higher chance of prolonged dependence on vasoactive medication. Machine learning predicted postoperative complications when capillary leak was added to standard risk factors.

Conclusions: Capillary leak and subsequent edema formation are relevant problems after cardiac surgery. Levels of angiopoietin-2 in combination with extracellular water show promising potential to predict postoperative complications after cardiac surgery.

Trial registration number: German Clinical Trials Registry (DRKS No. 00017057), Date of registration 05/04/2019, www.drks.de.

Keywords: Acute kidney injury; Angiopoietin-2; Capillary leak syndrome; Cardiac surgery; Critical care; Endothelial permeability; Fluid balance.