Eur J Cardiothorac Surg 1998;13:385-391
© 1998 Elsevier Science NL
von Willebrand factor and urinary albumin excretion are possible indicators of endothelial dysfunction in cardiopulmonary bypass
Geoffrey MK Tsang,
Simon Allen,
Domenico Pagano,
Carl Wong,
Timothy R Graham,
Robert S Bonser
Cardiothoracic Surgery Unit, University Hospital, Edgbaston, Birmingham B15 2TH, UK
Received 29 July 1997;
received in revised form 1 December 1997;
accepted 17 December 1997.
Corresponding author. Present address: Department of Cardiothoracic Surgery, Walsgrave Hospital, Coventry, CV2 2DX, UK. Tel.: +44 1203 602020; e-mail: g.m.k.tsang@bham.ac.uk
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Abstract
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Objective: Experimental evidence suggests that cardiopulmonary bypass (CPB) associated inflammatory response leads to endothelial injury and increased permeability, but this has been difficult to show clinically. We have investigated the use of von Willebrand factor (vWF), and urinary albumin excretion, as measured by the urinary albumin creatinine ratio (ACR), to demonstrate this. Methods: A total of 23 patients undergoing elective coronary artery bypass grafting were studied. Complement fragment C3a, leukotrienne B4 (LTB4), interleukin 6 (IL6), neutrophil elastase, vWF and ACR were measured on anaesthetic induction (baseline), 20 min after starting CPB, 5 min after cross-clamp removal, 5 min, 2, 6 and 24 h after termination of CPB. Anaesthetic, CPB and myocardial protection techniques were standardised. ANOVA was performed by using the distribution free Friedman test for each measured parameter. When significance differences were found (P<0.05), post hoc analysis with Wilconson signed rank test was used for comparison of each time point with the base line level and differences were only accepted as significant following the Bonferroni correction (P<0.008). Summary measures of peak versus peak and area under the cure were also analysed for ACR with vWF. Results: Peak vs. baseline levels for C3a were 4.9 vs. 2.1 µg/ml (P<0.0001), LTB4 was 800 vs. 20 pg/ml (P<0.0001), neutrophil elastase was 250 vs. 115 ng/ml (P<0.001), IL6 was 620 vs. 1.4 pg/ml (P<0.0001), vWF was 2.2 vs. 1.3 IU/ml (P<0.0001) and ACR was 17.6 vs. 2.0 mg/mmol (P<0.0001). C3a, LTB4 and ACR peaked during the operation. Neutrophil elastase peaked at 2 h following CPB. IL6 and vWF peaked at 6 h following CPB. The correlation coefficient between vWF and ACR following peak versus peak analysis was 0.48 (P=0.035), and area under the curve analysis was 0.6 (P<0.0l). Conclusion: These results demonstrate that endothelial permeability and injury, as measured by urinary albumin excretion and vWF, respectively, are related and the use of these easily detectable and sensitive biochemical markers warrants further investigation.
Key Words: Cardiopulmonary bypass • Endothelial dysfunction • von Willebrand factor • Urinary albumin excretion
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Introduction
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Patients undergoing cardiopulmonary bypass (CPB) manifest a systemic inflammatory type response. Thus, complement activation, elevated levels of cytokines and activation of neutrophils have been shown
[1]. These interrelated mechanisms are believed to cause generalised vascular endothelial dysfunction with resultant increases in permeability which has been implicated in end organ injury. However, these mainly experimental studies are difficult to replicate in humans and direct evidence for endothelial injury and dysfunction remain relatively limited in a clinical situation.
von Willebrand factor (vWF) is a glycoprotein synthesised by endothelium. Its functions include promotion of adhesion of endothelial cells to the vessel wall and following injury, to the endothelium bind and activate platelets to promote thrombus formation
[2]. High circulating plasma levels have been found in clinical conditions believed to be associated with endothelial injury
[3]
[4]
[5] and because of its specific origin, have been suggested as a useful marker of endothelial injury
[6].
Increased vascular permeability occurs in a variety of conditions as part of the acute inflammatory response, and is reflected in the kidney as a detectable increase in the excretion of large molecular weight plasma proteins such as albumin. Because of its large filtration area and high blood flow, the kidney is ideally placed to detect small changes in vascular permeability and because the tubular capacity to reabsorb filtered protein is limited, small increases in glomerular permeability will be amplified by the renal concentration mechanism, producing easily detectable changes in urinary excretion. These changes have been shown to be temporally and quantitatively related to the severity of the inflammatory stimulus
[7]
[8]
[9] and have been validated both experimentally and clinically as a marker of generalised vascular permeability
[10]
[11]. However, although increased urinary albumin excretion associated with CPB has been shown, its use as a marker of endothelial permeability and in particular, its relationship with endothelial injury and the inflammatory process has not been previously investigated in patients undergoing CPB.
We have therefore investigated the relationship between vWF and urinary albumin excretion with acute inflammatory response, complement activation, activation of the arachidonic acid cascade and neutrophil activation by measuring, respectively urinary albumin excretion, plasma vWF, interleukin 6 (IL6), complement fragment C3a, leukotrienne B4 (LTB4) and neutrophil elastase in patients undergoing CPB.
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Patients and methods
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A total of 23 patients, 18 males and 5 females, median age 57 years (range 48–67 years) with stable angina undergoing elective coronary bypass grafting were recruited into the study. All subjects gave informed consent. Patients with abnormal serum urea and creatinine, diabetes, hypertension or on current treatment with steroids or nonsteroidal anti-inflammatory drugs were excluded from the study. Standardised anaesthetic, CPB and myocardial protection techniques were used.
Patients were premedicated with temazepam 30 mg. Induction was by intravenous fentanyl 10 µg/kg, pancuronium 0.1 mg/kg and a ‘sleep dose’ of etomidate. Prior to CPB, the patients were ventilated with air and oxygen mixture with enflurane to maintain normocapnia. During CPB, total intravenous anaesthesia with propofol (10 mg/kg per h) and alfentanil (0.05 mg/kg per h) were used. Alfentanil (0–5 mg/h) and morphine (0-10 mg/h) were used as post operative analgesia. CPB was conducted with either a two stage or basket venous drainage and ascending aortic return. A roller pump (Cobe, CO), membrane oxygenator (Compactflo UK) and a 40 µm arterial line filter (Pall Biomedical Products, NY) were used. The circuit was primed with 2–2.5 l of Ringer’s lactate. Heparin was given at 3 mg/kg body weight to maintain an activated clotting time of >400 s during bypass. Bypass was conducted using pump flow rates of 2.4 l/min per m2 body surface area with pressure maintenance at 50–60 mmHg, by using 
-agonists or glyceryl trinitrate. The patients were cooled systemically to 28°C. Cardioplegic arrest was induced with 1 l of St. Thomas’ cold crystalloid cardioplegic solution, given antegradely into the aortic root for the construction of the distal anastomosis. Further doses were given as required. Topical cooling of the myocardium with ice slush was used during the cross clamp period. The proximal aorto-venous anastomosis was performed with the heart beating and reperfused during the rewarming phase of the operation. On discontinuation of bypass, heparin anticoagulation was reversed by protamine sulphate given at l mg/kg body weight.
Blood samples were collected into plain and ethylenediaminetetraacetic acid prepared tubes from an indwelling radial arterial line after: (A) induction of anaesthesia; (B) 20 min after the start of CPB; (C) 5 min after the removal of the aortic cross clamp; (D) 5 min; (E) 2; (F) 6; and (G) 24 h after termination of CPB. The blood samples were then immediately spun at 2000xg at 4°C for 10 min, the serum and plasma decanted and snap frozen and stored at -70°C for later analysis. A total of 5 ml of urine was collected from an indwelling urinary catheter inserted after anaesthetic induction at similar time points. The urine samples were also frozen at -70°C for later analysis.
C3a was measured by means of radioimmunoassay kits (Amersham, Arlington Height, IL). LTB4 was measured by enzyme immunoassay (Amersham). Neutrophil elastase was measured by an enzyme linked immunosorbent assay (ELISA) (Merck Diagnostics, UK). IL6 was measured by an enzyme amplified sensitivity immunoassay (Medgenix Diagnostics SA, Fleurus, Belgium). vWF levels were determined by ELISA using commercially available rabbit anti-human vWF antibodies (Dako, Bucks, UK). Urinary albumin concentration was measured by radioimmunoassay (Diagnostic Products, USA) and expressed as the albumin creatinine ratio (ACR) to correct for variations in urine flow
[12]. Plasma and urine samples were prepared according to manufacturers instructions. The intraassay and interassay variability, according to the manufacturers information, were, respectively <6.8 and 6.7% for C3a, <8.4 and 7.5% for LTB4, <8.1 and <20.1% for IL6, <8.1 and <7.8% for neutrophil elastase, <6.2 and <6.6% for vWF and <2.7 and 2.3% for urinary albumin. No corrections were made for the dilutional effects of CPB.
Levels of C3a, LTB4, neutrophil elastase, IL6, ACR and vWF were nonparametrically distributed, therefore median values and interquartile ranges have been used. The Friedman test was used as the distribution free analysis of variance with a critical level of 0.05. When a significant time effect was demonstrated, the Wilcoxon signed rank test was used as post hoc analysis to identify specific times at which differences existed when compared to base line levels. In these instances, the overall experimental of 0.05 was preserved by a modified Bonferroni procedure, that is, adjusted critical =0.05/N, where N is the number of post hoc analyses to be performed. The relationships between C3a, LTB4, neutrophil elastase, IL6, vWF and ACR were assessed by comparing the peak values and the area under the curve analysis
[13](Table 1). Spearman’s non-linear regression analysis was used for comparison of peak values and a linear regression analysis was used for comparison of area under the curve values.
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Results
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All patients received an internal mammary artery graft to the left anterior descending artery. The mean number of grafts was 2.4 per patient (range 2–4). The mean cardioplegic arrest and CPB times were 42±5 min (range 26–55 min) and 68±7 min (37–88 min), respectively. There was no difference between the preoperative and post-operative serum creatinine levels (96.5±3 µmol/l vs. 92.7±5 µmol/l). There was no operative or peri-operative mortality. All patients were discharged from the intensive care unit within 24 h of surgery. One patient developed chest infection requiring antibiotic treatment. All patients were discharged within 7 days of the operation.
The changes in levels of C3a, LTB4, elastase, IL6, ACR and vWF are illustrated in
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5 Fig. 6
. Within 20 min following the initiation of CPB, levels of LTB4 had risen dramatically and reached peak levels. LTB4 levels had returned to base line values at 5 min after the termination of CPB. C3a levels likewise, started to rise following the initiation of CPB with significant rises achieved 20 min after the start of CPB. Peak levels of C3a occurred at 5 min following the termination of CPB, but levels had returned to base line values by 6 h following the termination of CPB.
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Fig. 1. Levels of C3a measured at predetermined sampling points. Median values with interquartile ranges are shown. Sampling points (A) induction of anaesthesia, (B) 20 min after the start of CPB, (C) 5 min after the removal of the aortic cross clamp, (D) 5 min, (E) 2 h, (F) 6 h and (G) 24 h after termination of CPB. Friedman test for distribution free analysis of variance, P<0.0001. Post hoc analysis with Wilcoxon signed rank test when levels at each sampling point are compared to baseline levels (A). * P<0.001, ** P<0.0001.
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Fig. 2. Levels of LTB4 measured at predetermined sampling points. Median values with interquartile ranges are shown. Sampling points (A) induction of anaesthesia, (B) 20 min after the start of CPB, (C) 5 min after the removal of the aortic cross clamp, (D) 5 min, (E) 2 h, (F) 6 h and (G) 24 h after termination of CPB. Friedman test for distribution free analysis of variance, P<0.0001. Post hoc analysis with Wilcoxon signed rank test when levels at each sampling point are compared to baseline levels (A). * P<0.0001.
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Fig. 3. Levels of neutrophil elastase measured at predetermined sampling points. Median values with interquartile ranges are shown. Sampling points (A) induction of anaesthesia, (B) 20 min after the start of CPB, (C) 5 min after the removal of the aortic cross clamp, (D) 5 min, (E) 2 h, (F) 6 h and (G) 24 h after termination of CPB. Friedman test for distribution free analysis of variance, P<0.0001. Post hoc analysis with Wilcoxon signed rank test when levels at each sampling point are compared to baseline levels (A). * P<0.001, ** P<0.0001.
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Fig. 4. Levels of IL6 measured at predetermined sampling points. Median values with interquartile ranges are shown. Sampling points (A) induction of anaesthesia, (B) 20 min after the start of CPB, (C) 5 min after the removal of the aortic cross clamp, (D) 5 min, (E) 2 h, (F) 6 h and (G) 24 h after termination of CPB. Friedman test for distribution free analysis of variance, P<0.0001. Post hoc analysis with Wilcoxon signed rank test when levels at each sampling point are compared to baseline levels (A). * P=0.0002, ** P<0.0001.
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Fig. 5. Levels of vWF measured at predetermined sampling points. Median values with interquartile ranges are shown. Sampling points (A) induction of anaesthesia, (B) 20 min after the start of CPB, (C) 5 min after the removal of the aortic cross clamp, (D) 5 min, (E) 2 h, (F) 6 h and (G) 24 h after termination of CPB. Friedman test for distribution free analysis of variance, P<0.0001. Post hoc analysis with Wilcoxon signed rank test when levels at each sampling point are compared to baseline levels (A). * P=0.007, ** P<0.0037, *** P<0.0001.
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Fig. 6. Levels of ACR measured at predetermined sampling points. Median values with interquartile ranges are shown. Sampling points (A) induction of anaesthesia, (B) 20 min after the start of CPB, (C) 5 min after the removal of the aortic cross clamp, (D) 5 min, (E) 2 h, (F) 6 h and (G) 24 h after termination of CPB. Friedman test for distribution free analysis of variance, P<0.0001. Post hoc analysis with Wilcoxon signed rank test when levels at each sampling point are compared to baseline levels (A). * P=0.0003, ** P=0.0001, *** P<0.0001.
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Neutrophil elastase levels did not appear to rise until removal of the aortic cross clamp, with levels reaching significant and peak levels at 5 min and 2 h, respectively following the termination of CPB. Levels then gradually decreased, and although still elevated at 24 h following termination of CPB, this was not statistically significant. Base line levels of IL6 were barely detectable but showed a dramatic rise reaching peak levels at 6 h following termination of CPB. Levels were still highly significantly elevated 24 h following termination of CPB. Like IL6, vWF peak levels did not occur until 6 h following the termination of CPB. Circulating levels of vWF were still significantly elevated at 24 h following termination of CPB. Peak urinary albumin excretion occurred during CPB but was still highly significantly elevated at 2 h following the termination of CPB. Levels at 6 and 24 h post CPB were not significantly different to base line levels.
Peak versus peak and area under the curve analysis showed no correlation between C3a, LTB4, IL6, neutrophil elastase with ACR and vWF.
Fig. 7
illustrates the relationship between peak levels of vWF levels and urinary albumin excretion as measured by the ACR.
Fig. 8
illustrates the relationship between the total amount of vWF released into the circulation and the total amount of albumin excreted as calculated by area under the curve for each individual patient. The correlation coefficients between ACR and vWF for peak versus peak and area under the curve analysis were 0.48 (P=0.035) and 0.6 (P<0.01), respectively.
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Fig. 7. Correlation between peak versus peak values of vWF and ACR in individual patients. Correlation coefficient r=0.43, P=0.05.
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Fig. 8. Correlation between individual AUC analysis between vWF and ACR. Correlation coefficient r=0.6, P<0.01.
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Discussion
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These results confirm the multiple and interrelated pathways involved in the inflammatory process associated with CPB. Thus, complement activation, inflammatory mediator release from the arachidonic acid cascade and neutrophil activation have all been previously demonstrated
[1]. These mediators have been implicated in endothelial injury, increased endothelial permeability and subsequent end organ dysfunction
[1]
[14]
[15]
[16]. By using urinary albumin excretion and vWF as a relatively simple and easily detectable biochemical marker of endothelial permeability and endothelial injury, respectively, we have shown that there is an increase in endothelial permeability and it is associated with endothelial injury in patients undergoing CPB for coronary artery surgery.
vWF is stored in endothelial cell Weibel-Palade bodies and together with platelet factor 4 and ß-thromboglobulin in the granules in platelets
[17]. High circulating levels following CPB are believed to have originated from endothelial cells because the use of prostacyclin in CPB have been shown to reduce platelet activation as measured by ß-thromboglobulin levels without affecting vWF levels
[18]. It has also been estimated that following activation, platelet derived vWF can only contribute to 
15% of circulating levels
[19], whereas increases of 50% or greater have been seen following CPB
[18]
[20]
[21]
[22]. These observations, and the association of increased levels of vWF in diseases strongly suspected to have endothelial injury as a primary injury, have indicated that vWF may be used as a selective marker of endothelial injury
[6].
Experimental studies using histology, radioisotope labelling and direct measurement of lymphatic drainage
[1]
[24] have demonstrated endothelial injury and increased vascular endothelial permeability. However, many of these techniques are not suitable for routine use in the study of human subjects. Previous studies, of CPB associated organ dysfunction in patients, have used indirect measurements such as the respiratory index
[15]
[16] to assess pulmonary dysfunction, and urinary albumin excretion to assess glomerular permeability and function
[25]. Glomerular permeability can be dependent on inflammatory mediators and leucocyte activation and may reflect general endothelial permeability during CPB
[26]
[27]. In addition, following trauma, burn injury, surgery or ischaemia in which an acute inflammatory response occurs in association with increased vascular permeability, it was found that an increase in urinary protein excretion occurs
[7]
[8]
[9]
[10]. Because of its large filtration area and high blood flow, the kidney is ideally placed to detect small changes in vascular endothelial permeability, allowing large molecular weight proteins to enter the glomerular filtrate. Since the tubular capacity to reabsorb filtered proteins is limited, small increases in glomerular permeability will be amplified by the renal concentration mechanism, producing easily detectable changes in urine excretion. This effect can be seen following acute myocardial infarction and is sensitive enough to detect mild episodes of muscle ischaemia that occur in patients with intermittent claudication
[28].
Invasive experimental techniques, which are not suitable for routine use, are required to provide direct evidence of CPB associated endothelial injury in humans. Measuring biochemical markers of endothelial permeability and injury are relatively straight forward but their use for monitoring these processes has been limited. Urinary albumin excretion and vWF are arguably good biochemical markers of endothelial permeability and injury, but their relationship has not been previously determined in patients undergoing CPB. In conditions such as atherosclerosis, hypertension, diabetes mellitus and following myocardial infarction whereby endothelial injury and dysfunction are believed to play a central role in pathogenesis
[6]
[29]
[30], elevated levels of vWF and increased urinary albumin excretion have been seen, and are not only indicators of endothelial injury and dysfunction but are also predictors of long term morbidity and mortality. This relationship has been directly observed in patients with diabetes mellitus and is believed to play a central role in accelerated atheromatous disease seen in association with diabetes mellitus
[30]. In this study we have shown that there is some correlation between urinary albumin excretion and vWF release, reflecting a relationship between increased endothelial permeability and injury, respectively. It was however, surprising to find that urinary albumin excretion increased significantly and peaked prior to significant rises in vWF. It may be that the initial endothelial response to the circulating inflammatory mediators is an increase in permeability, which is followed by cell death, as in vitro studies have shown that cell lysis is required for vWF release
[18]
[23]. In this study, we have only measured a very limited number of inflammatory mediators. The lack of correlation between C3a, LTB4, IL6 and neutrophil elastase with ACR and vWF individually may mean that no single pathway predominates and that the summed effects of these various inflammatory pathways are important in causing increased endothelial permeability and injury following CPB.
We believe that the relationship between urinary albumin excretion and vWF release demonstrated in this study, may indicate a relationship between endothelial permeability and injury derived from a number of potential sources in patients undergoing CPB and because they are easily detectable and sensitive markers, their use to monitor this deleterious process warrants further investigation.
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Acknowledgments
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We would like to acknowledge the help of Dr D Wilshaw from the Department of Mathematics and Statistics, University of Newcastle Upon Tyne, UK.
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Abstract
Introduction
