Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage

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Abstract

Introduction: Acute kidney injury (AKI) and intestinal injury negatively impact patient outcome after cardiac surgery. Enhanced nitric oxide (NO) consumption due to intraoperative intravascular hemolysis, may play an important role in this setting. This study investigated the impact of hemolysis on plasma NO consumption, AKI, and intestinal tissue damage, after cardiac surgery.

Methods: Hemolysis (by plasma extracellular (free) hemoglobin; fHb), plasma NO-consumption, plasma fHb-binding capacity by haptoglobin (Hp), renal tubular injury (using urinary N-Acetyl-β-D-glucosaminidase; NAG), intestinal mucosal injury (through plasma intestinal fatty acid binding protein; IFABP), and AKI were studied in patients undergoing off-pump cardiac surgery (OPCAB, N = 7), on-pump coronary artery bypass grafting (CABG, N = 30), or combined CABG and valve surgery (CABG+Valve, N = 30).

Results: FHb plasma levels and NO-consumption significantly increased, while plasma Hp concentrations significantly decreased in CABG and CABG+Valve patients ( p < 0.0001) during surgery. The extent of hemolysis and NO-consumption correlated significantly ( r ² = 0.75, p < 0.0001). Also, NAG and IFABP increased in both groups ( p < 0.0001, and p < 0.001, respectively), and both were significantly associated with hemolysis ( R _s = 0.70, p < 0.0001, and R _s = 0.26, p = 0.04, respectively) and NO-consumption ( R _s = 0.55, p = 0.002, and R _s = 0.41, p = 0.03, respectively), also after multivariable logistic regression analysis. OPCAB patients did not show increased fHb, NO-consumption, NAG, or IFABP levels. Patients suffering from AKI ( N = 9, 13.4%) displayed significantly higher fHb and NAG levels already during surgery compared to non-AKI patients.

Conclusions: Hemolysis appears to be an important contributor to postoperative kidney injury and intestinal mucosal damage, potentially by limiting NO-bioavailability. This observation offers a novel diagnostic and therapeutic target to improve patient outcome after cardiothoracic surgery.

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Most cited references 38

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Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study.

Andrea Lassnigg, Daniel Schmidlin, Mohamed Mouhieddine … (2004)

Acute renal failure increases risk of death after cardiac surgery. However, it is not known whether more subtle changes in renal function might have an impact on outcome. Thus, the association between small serum creatinine changes after surgery and mortality, independent of other established perioperative risk indicators, was analyzed. In a prospective cohort study in 4118 patients who underwent cardiac and thoracic aortic surgery, the effect of changes in serum creatinine within 48 h postoperatively on 30-d mortality was analyzed. Cox regression was used to correct for various established demographic preoperative risk indicators, intraoperative parameters, and postoperative complications. In the 2441 patients in whom serum creatinine decreased, early mortality was 2.6% in contrast to 8.9% in patients with increased postoperative serum creatinine values. Patients with large decreases (DeltaCrea or =0.5 mg/dl. For all groups, increases in mortality remained significant in multivariate analyses, including postoperative renal replacement therapy. After cardiac and thoracic aortic surgery, 30-d mortality was lowest in patients with a slight postoperative decrease in serum creatinine. Any even minimal increase or profound decrease of serum creatinine was associated with a substantial decrease in survival.

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The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.

Russell Rother, Leonard Bell, Peter Hillmen … (2005)

The efficient sequestration of hemoglobin by the red blood cell membrane and the presence of multiple hemoglobin clearance mechanisms suggest a critical need to prevent the buildup of this molecule in the plasma. A growing list of clinical manifestations attributed to hemoglobin release in a variety of acquired and iatrogenic hemolytic disorders suggests that hemolysis and hemoglobinemia should be considered as a novel mechanism of human disease. Pertinent scientific literature databases and references were searched through October 2004 using terms that encompassed various aspects of hemolysis, hemoglobin preparations, clinical symptoms associated with plasma hemoglobin, nitric oxide in hemolysis, anemia, pulmonary hypertension, paroxysmal nocturnal hemoglobinuria, and sickle-cell disease. Hemoglobin is released into the plasma from the erythrocyte during intravascular hemolysis in hereditary, acquired, and iatrogenic hemolytic conditions. When the capacity of protective hemoglobin-scavenging mechanisms has been saturated, levels of cell-free hemoglobin increase in the plasma, resulting in the consumption of nitric oxide and clinical sequelae. Nitric oxide plays a major role in vascular homeostasis and has been shown to be a critical regulator of basal and stress-mediated smooth muscle relaxation and vasomotor tone, endothelial adhesion molecule expression, and platelet activation and aggregation. Thus, clinical consequences of excessive cell-free plasma hemoglobin levels during intravascular hemolysis or the administration of hemoglobin preparations include dystonias involving the gastrointestinal, cardiovascular, pulmonary, and urogenital systems, as well as clotting disorders. Many of the clinical sequelae of intravascular hemolysis in a prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria, are readily explained by hemoglobin-mediated nitric oxide scavenging. A growing body of evidence supports the existence of a novel mechanism of human disease, namely, hemolysis-associated smooth muscle dystonia, vasculopathy, and endothelial dysfunction.

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Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

Mark Gladwin, Vandana Sachdev, Maria Jison … (2004)

The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. Copyright 2004 Massachusetts Medical Society

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Author and article information

Contributors

Iris C. Vermeulen Windsant: URI : http://community.frontiersin.org/people/u/129569

Jonas T. C. Sertorio: URI : http://community.frontiersin.org/people/u/180899

Annemarie A. van Bijnen: URI : http://community.frontiersin.org/people/u/170321

Journal

Journal ID (nlm-ta): Front Physiol

Journal ID (iso-abbrev): Front Physiol

Journal ID (publisher-id): Front. Physiol.

Title: Frontiers in Physiology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-042X

Publication date (Electronic): 08 September 2014

Publication date Collection: 2014

Volume: 5

Electronic Location Identifier: 340

Affiliations

[1] ¹Department of Surgery, Maastricht University Medical Center Maastricht, Netherlands

[2] ²NUTRIM School for Nutrition, Toxicology & Metabolism, Maastricht University Medical Center Maastricht, Netherlands

[3] ³Central Diagnostic Laboratory, Maastricht University Medical Center Maastricht, Netherlands

[4] ⁴Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paolo Ribeirao Preto, Brazil

[5] ⁵Department of Extracorporeal Circulation, Maastricht University Medical Center Maastricht, Netherlands

[6] ⁶Department of Anesthesiology, Maastricht University Medical Center Maastricht, Netherlands

[7] ⁷Cardiovascular Research Institute Maastricht, Maastricht University Medical Center Maastricht, Netherlands

[8] ⁸Department of Vascular Surgery, European Vascular Center Aachen-Maastricht, University Hospital Aachen Aachen, Germany

[9] ⁹Department of Cardiothoracic Surgery, Maastricht University Medical Center Maastricht, Netherlands

Author notes

Edited by: Magnus Gram, Lund University, Sweden

Reviewed by: Faikah Gueler, Hannover Medical School, Germany; David Ley, Lund University, Sweden

*Correspondence: Iris C. Vermeulen Windsant, Department of Cardiology, Catharina Hospital Eindhoven, Michelangelolaan 2, PO Box 1350, 5602 ZA Eindhoven, Netherlands e-mail: iris.vermeulenwindsant@ 123456cze.nl

This article was submitted to Oxidant Physiology, a section of the journal Frontiers in Physiology.

†Present address: Iris C. Vermeulen Windsant, Department of Cardiology, Catharina Hospital, Eindhoven, Netherlands;

Wim A. Buurman, School for Mental Health and Neuroscience, MHeNS, Maastricht University, Maastricht, Netherlands

Article

DOI: 10.3389/fphys.2014.00340

PMC ID: 4157603

PubMed ID: 25249983

SO-VID: 32bb924f-36a0-4c57-b347-7eda508d1681

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 17 June 2014

Date accepted : 20 August 2014

Page count

Figures: 3, Tables: 2, Equations: 0, References: 41, Pages: 9, Words: 6923

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Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage

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Most cited references 38

Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study.

The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

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