Connecting hemosysis and visceral injury during cardiovascular surgery : studies on the causes, effects, and treatment of hemolysis-induced organ injury Citation for published version (APA): Vermeulen Windsant, I. C. (2012). Connecting hemosysis and visceral injury during cardiovascular surgery : studies on the causes, effects, and treatment of hemolysis-induced organ injury. Maastricht University. https://doi.org/10.26481/dis.20120928iv Document status and date: Published: 01/01/2012 DOI: 10.26481/dis.20120928iv Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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Download date: 28 Sep. 2021 Connecting hemolysis and visceral injury during cardiovascular surgery Studies on the causes, effects, and treatment of hemolysis‐induced organ injury © 2012 Iris Vermeulen Windsant, Maastricht ISBN: 978‐90‐9026809‐5 Layout: Tiny Wouters Cover: Xander Vermeulen Windsant XVW Architectuur Production: Datawyse Maastricht Printing of this thesis was financially supported by Stichting Hartsvrienden RESCAR Maastricht HaemoScan BV Groningen The studies presented in this thesis were performed at the Nutrition and Toxicology Research Institute Maastricht (NUTRIM), which participates in the Graduate School VLAG (Food Technology, Agro‐biotechnology, Nutrition and Health Sciences), accredited by the Royal Netherlands Academy of Arts and Sciences (KNAW). Furthermore, the studies presented in this manuscript were funded by Stichting Annadal and the Profileringsfonds of the MUMC+. Connecting hemolysis and visceral injury during cardiovascular surgery Studies on the causes, effects and treatment of hemolysis‐induced organ injury PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. dr. L.L.G. Soete, volgens het besluit van het College van Decanen, in het openbaar te verdedigen op vrijdag 28 september 2012 om 14.00 uur door Iris Catharina Vermeulen Windsant PROMOTORES Prof. dr. W.A. Buurman Prof. dr. M.J.H.M. Jacobs BEOORDELINGSCOMMISSIE Prof. dr. H. ten Cate (voorzitter) Prof. dr. P.J.E.H.M. Kitslaar Prof. dr. K.L.M. Leunissen Prof. dr. G. Marx (Universitäts Klinikum Aachen) Prof. dr. C.D.A. Stehouwer CONTENTS Chapter 1 General Introduction 7 Chapter 2 Circulating intestinal fatty acid binding protein as an early 27 marker of intestinal necrosis after aortic surgery; a prospective observational cohort study Chapter 3 Visceral injury and systemic inflammation in patients undergoing 47 extracorporeal circulation during aortic surgery Chapter 4 Cardiovascular surgery and organ damage; time to reconsider 67 the role of hemolysis Chapter 5 Hemolysis compromises nitric oxide‐dependent vasodilatory 89 responses in patients undergoing major cardiovascular surgery Chapter 6 Hemolysis is associated with acute kidney injury during major 105 aortic surgery Chapter 7 Hemolysis increases nitric oxide consumption and visceral 123 tissue damage after cardiac surgery Chapter 8 Blood transfusions increase circulating plasma free hemoglobin 141 levels and plasma nitric oxide consumption: a prospective observational pilot study Chapter 9 Hemolysis‐induced organ damage is reduced by nutritional 161 activation of the vagal anti‐inflammatory reflex Chapter 10 Summary and discussion 179 Nederlandse samenvatting 195 Dankwoord 205 Curriculum vitae 215 Publicatielijst 219 Abbreviations 223 General introduction Chapter 1 8 General introduction INTRODUCTION Cardiovascular disease is the major cause of death worldwide, claiming over 7.2 million lives in 2004 due to coronary heart disease alone.1 In the Netherlands, the total number of patients diagnosed with coronary heart disease was 730.400 in 2007 (RIVM). In 2008, 16.877 patients required open heart surgery to sufficiently treat coronary and/or cardiac valve disease.2 The introduction of the cardiopulmonary bypass (CPB) in the early nineteen sixties as a more routine technique during cardiovascular surgery led to a significant increase in treatment options for patients with serious cardiovascular disease, such as patients with multifocal coronary artery disease, cardiac valve disorders or patients with major vascular disease such as (thoracoabdominal) aortic aneurysms. CPB, also called extracorporeal circulation, enabled ongoing organ perfusion and oxygenation during extensive and time‐consuming operations of the heart and/or aorta. Nevertheless, despite major technical and medical refinements since its first introduction, CPB‐ assisted surgery is still associated with (relatively) high morbidity and mortality. Principally, major postoperative complications such as renal dysfunction (requiring dialysis), and pulmonary complications such as prolonged mechanical ventilation, ventilation assisted pneumonia or the adult respiratory distress syndrome, are relatively common.3‐6 Several CPB‐related factors, such as ischemia‐reperfusion injury, hemodilution, and initiation of a pro‐inflammatory response, have been extensively studied for their role in the development of these postoperative complications.7 Furthermore the impact of intravascular hemolysis caused by mechanical stress within the CPB system, among other factors, has been mentioned in the literature but not related to organ injury or patient outcome. This thesis aimed to elucidate the causes of acute hemolysis and its effects on the development of postoperative complications after (major) cardiovascular surgery. POSTOPERATIVE COMPLICATIONS OF CARDIOVASCULAR SURGERY WITH CARDIOPULMONARY BYPASS Open (thoraco)abdominal aortic aneurysm repair The term aneurysm denotes an abnormal dilatation of a blood vessel. Although theoretically any blood vessel may become aneurysmal, the infrarenal abdominal aorta (AAA) is most commonly affected. In contrast, the most extensive type of aneurysmal disease of the large arteries; the thoracoabdominal aortic aneurysm (TAAA) is a less commonly diagnosed phenomenon representing only 0.25% of all aortic aneurysms.8 Outward rupture of the weakened vessel wall represents the major risk of any aneurysmal blood vessel. Rupture of an aortic aneurysm is usually fatal due to severe 9 Chapter 1 hemorrhage and, if possible, requires emergency repair with concomitant high surgical morbidity and mortality.9 Depending on the type of TAAA, 2‐year survival rates of 24‐52% have been reported. The overall 5‐year survival rate is 17‐19%.10 Aneurysms can be surgically treated either through classical open reconstruction or by endovascular exclusion, depending on aneurysm anatomy, patient characteristics and preference and/or experience of the surgeon and hospital facilities. Despite the fact that elective surgical treatment is often imperative to improve survival, mortality rates remain high after open TAAA surgery; up to 15%.11 The primary causes of in‐hospital death are cardiac complications (46%), respiratory failure (15%), sepsis (12%) and coagulopathy (12%).12 The incidence of nonfatal complications after TAAA repair is accordingly high. Significant post‐operative complications occur in 77% of cases; 41% of patients have pulmonary complications, 28% renal complications, 21% liver dysfunction, or gastro‐intestinal complications in 7% (such as bowel ischemia, ileus, or peptic ulceration).13 Finally, spinal cord‐injury is seen in 12% of cases. A combination of these complications is often seen (31%) and, at worst, can progress into multiple organ failure (MOF). Nevertheless, successful open TAAA repair causes the 5‐year survival rate to triple or even quadruple to 66‐80%.11,12 Cardiac surgery The incidence of complications after cardiac surgery is largely dependent on the type of surgery performed, with higher incidence rates reported after complex cardiac surgery such as combined bypass and valve surgery, and ascending aortic aneurysm repair.14 The following incidence rates apply to patients undergoing cardiac surgery with CPB. Acute kidney