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Ann Thorac Surg 1996;61:904-908
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Circulating Endothelin in Cardiac Operations: Influence of Blood Pressure and Endotoxin

Centre for Cardiopulmonary Surgery Amsterdam and Departments of Clinical Chemistry, Vrije Universiteit Hospital, Amsterdam, and University Hospital Leiden, Leiden, the Netherlands

Accepted for publication November 21, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Endothelin is involved in the control of cardiovascular and renal functions and acts as a neuromodulator.

Methods. In a prospective study among 15 male patients who underwent coronary artery bypass grafting, we investigated the release pattern and possible stimuli of circulating endothelin.

Results. We detected a steep increase in endothelin concentrations after the onset of cardiopulmonary bypass (CPB), and a second minor increase during CPB. The steep increase in endothelin concentrations correlated with the change in arterial pressures at the onset of CPB (r = -0.57; p < 0.03). The slow increase in endothelin concentrations during CPB, however, correlated with mean endotoxin levels during and after CPB (r = 0.60; p < 0.02).

Conclusions. The change in arterial pressure at the onset of CPB seems to induce a steep and fast increase in circulating endothelin level, which is probably mediated through the baroreceptors. The slow increase in endothelin level during CPB is associated with increased circulating endotoxin concentration. It may be that either endothelin-mediated vasoconstriction induces endotoxin transmigration from the intestine or endotoxin stimulates endothelin secretion from endothelial cells.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Endothelin-1, a 21-amino acid peptide, is a potent vasoconstrictor of mammalian vessels and is produced by many cell types, including endothelial cells, macrophages, and neurons in the paraventricular nucleus of the hypothalamus [1, 2]. Endothelin-1 is the first member of the endothelin family, originally described as an endothelial cell-derived peptide. Two additional highly homologous isoforms, endothelin-2 and -3, have been identified, which also have vasoactive properties. Endothelin-1 induces a slow and long-lasting constriction of almost all arteries and veins, and proliferation of various cell types such as smooth muscle cells [3]. Endothelin-1 is also a fast-acting circulating hormone involved in the regulation of arterial blood pressure [4] and cardiac output [5]. A fast increase in plasma endothelin-1 level was observed during upright posture and cooling, and a decrease was observed during blood volume expansion [6–8]. Production of endothelin-1 can be stimulated by physical stimuli such as shear stress and hypoxia, but also by receptor-operated mechanisms involving adrenalin, angiotensin II, thrombin, interleukin-1, and endotoxin [9–12].

Increased endothelin-1 plasma levels were measured during and after cardiopulmonary bypass (CPB) [13, 14]. After CPB, significantly higher circulating levels of endothelin-1 were observed in elderly patients and in patients with preexisting endothelial dysfunction [13, 14]. Higher endothelin-1 concentrations were associated with increased postoperative oxygen consumption [13]. During CPB, we and others detected significant amounts of circulating endotoxins [15–19]. Endotoxins are lipopolysaccharides that are present in the outer membrane of gram-negative bacteria. They elicit many potentially pathophysiologic effects on humoral and cellular systems [20], which may culminate in a systemic inflammatory response after cardiac operations. Several investigators suggested that hypoperfusion of the intestine induces transmigration of intestine-derived endotoxins into the blood and lymph circulation. Recently, Martinez-Pellús and associates [19] demonstrated that full selective decontamination of the intestine prevented circulating endotoxin during CPB. It may well be that endothelin, with its vasoconstrictive activity, plays a role in the intestinal hypoperfusion, which subsequently induces endotoxin transmigration during CPB. At the same time, endotoxin may stimulate the secretion of endothelin into the circulation.

In this prospective, descriptive study among 15 male patients undergoing elective coronary artery bypass grafting, we determined the concentration of immunoreactive endothelin (endothelin-1, 2-, and -3 together) and investigated possible stimuli for endothelin release, such as changes in arterial pressure and circulating endotoxin during cardiac operations.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients and Study Design
In this prospective study, 15 male patients (age, 45 to 75 years) suffering from ischemic coronary artery disease gave informed consent before undergoing nonurgent coronary artery bypass grafting. The study was performed at the Vrije Universiteit Hospital of Amsterdam, the Netherlands, and approved by the local medical ethical committee. None of the patients had a major organ dysfunction before coronary artery bypass grafting took place. Exclusion criteria were previous of intraaortic balloon counterpulsation, use of acetylsalicylic acid in the week before operation and corticosteroids or aprotinin during the operation, and creatinine plasma levels greater than 240 µmol•L^-1.

Technique of Anesthesia, Cardiopulmonary Bypass, and Intensive Care Treatment
On the morning of operation, all patients received 5 mg of lorazepam and their usual early morning dose of antianginal medication, consisting of ß-blockers, nitrates, and Ca²⁺-channel blockers. Anesthesia was performed with 0.2 mg•kg^-1 of fentanyl at induction and a maintenance rate of 0.3 µg•kg^-1•min•^-1 and 0.1 mg•kg^-1 of pancuronium bromide. No volatile anesthesia or nitrous oxide was used. Patients were ventilated with 40% oxygen and 5 cm H₂O positive end-expiratory pressure. Cardiopulmonary bypass was performed with moderate systemic hypothermia (28° to 30°C), nonpulsatile flow, and crystalloid cardioplegia. The CPB circuit consisted of a roller pump and a membrane oxygenator (Ultrox-1; Avecor, Plymouth, MN) with arterial filter and polyvinyl chloride tubing, which was primed with 2,000 mL of Ringer's lactate, 200 mL of human albumin 20%, 100 mL of 20% mannitol, 50 mL of 8.4% sodium bicarbonate, and 5,000 IU of heparin. A standard cannulation technique was used with a two-stage venous cannula and an arterial cannula in the ascending aorta, and venting was performed via the ascending aorta.

Parameters
Endothelin-like (endothelin-1, endothelin-2, and endothelin-3 together; further denoted as endothelin) immunoreactivity was measured after extraction of platelet-poor plasma on a SepPak C18 column (Waters, Millipore, MA) and by radioimmunoassay (Biomedica GmbH, Vienna, Austria). Sensitivity of the assay is 0.25 pg per tube, and cross-reactivity with endothelin-1 is 100%; endothelin-2, 142%; endothelin-3, 98%; and big endothelin, <1%. Blood for endothelin determination was collected in 5-mL tubes containing ethylenediaminetetraacetate as anticoagulant. Samples for endothelin determination were taken after induction of anesthesia (baseline), 10 minutes after onset of CPB, before and after aortic cross-clamp removal, after cessation of CPB, and 2 hours after arrival at the intensive care unit (ICU). Endotoxin levels were estimated with a chromogenic limulus amoebocyte lysate (LAL) assay (Coatest Endotoxin; Kabi-Chromogenix, Mölndal, Sweden; including ß-glucan insensitive LAL preparations, produced by Whittaker Bioproducts Inc, Walkersville, MD) as described before [15, 21]. Blood for the Limulus assay was collected in polystyrene tubes (Falcon 2063, Oxnard, CA), containing pyrogen-free heparin (Thromboliquine; Organon, Oss, the Netherlands) at a final concentration of 30 IU•mL^-1, and the tubes were immediately immersed in crushed ice. Platelet-rich plasma (PRP) was prepared and stored in duplicate portions at -70°C. Endotoxin concentrations are given in endotoxin units per milliliter of PRP (EU•mL^-1 PRP). The LAL test has a detection limit of 0.036 EU•mL^-1, ie, 3 ng•L^-1 with the LAL presently used. The clinical decision limit for endotoxin-positive sample was 0.060 EU•mL^-1. Endotoxin samples were taken after induction of anesthesia (baseline), 10 minutes after onset of CPB, before and after aortic cross-clamp removal, after cessation of CPB, and a half hour and 2 hours after arrival at the ICU.

Arterial blood pressures were measured in triplicate before and after onset of CPB.

Statistics
Statistical analysis was performed using Statview SE⁺ Graphics computer software (Abacus Concepts, Inc, Berkeley, CA). To analyze changes within the group, one-factor analysis of variance for repeated measures was performed, supplemented with the Scheffé post hoc test. Pearson's product moment test was performed to analyze correlations. A two-sided p less than 0.05 was considered to be statistically significant. Data are presented as means ± 95% confidence interval of the mean.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The group of patients consisted of 15 male patients with the following demographic and surgical data: age, 61 ± 4 years; height, 1.77 ± 0.03 m; weight, 81 ± 5 kg; body surface area, 1.98 ± 0.07 m²; preoperative left ventricular end-diastolic pressure, 12 ± 2 mm Hg; aortic cross-clamp duration, 79 ± 12 minutes; and CPB duration, 118 ± 16 minutes. No complications occurred; all patients survived and were dismissed from the ICU on the first postoperative day.

After the onset of CPB, a significant increase from baseline in immunoreactive endothelin concentrations was observed, which remained increased throughout the study period (Fig 1). After cessation of CPB, immunoreactive endothelin concentrations were significantly higher than after onset of CPB (p < 0.05), indicating that immunoreactive endothelin concentrations increased during CPB. Maximal endothelin levels of 7.1 ± 0.9 ng•L^-1 were reached at the end of the CPB period. At 4 hours in the ICU, endothelin levels were lower than at the end of CPB, but still increased compared with baseline levels.

View larger version (17K): [in this window] [in a new window]   Fig 1. . Immunoreactive endothelin and circulating endotoxin concentrations during and after cardiopulmonary bypass. Data are presented as means ± 95% confidence interval of the mean. Black triangle indicates cross-clamp removal. (EU•mL-1 PRP = endotoxin units per milliliter of platelet-rich plasma; + significant increase from baseline, * significant increase from onset of cardiopulmonary bypass (CPB) by one-factor analysis of variance for repeated measures supplemented with Scheffé's post hoc test, p < 0.05.)

To identify the possible associations between immunoreactive endothelin, arterial blood pressures, and circulating endotoxin, we correlated the percentage difference from baseline of arterial blood pressure after onset of CPB with circulating endothelin level after onset of CPB (Fig 2A), and the percentage increase in circulating endothelin during CPB with the mean of all measurement of circulating endotoxin during and after CPB (Fig 2B). Significant correlations were observed between the percentage change in arterial blood pressure at onset of CPB and immunoreactive endothelin concentrations after onset of CPB (r = -0.55; p = 0.03), and the percent change in immunoreactive endothelin (125% ± 17%) and the mean of all measurements of all endotoxin concentrations (0.192 ± 0.038 EU•mL^-1 PRP) during and after CPB (r = 0.60; p = 0.01).

View larger version (16K): [in this window] [in a new window]   Fig 2. . Correlations with immunoreactive endothelin concentrations. (A) Immunoreactive endothelin concentrations after onset of cardiopulmonary bypass (CPB) and percent change from baseline in arterial blood pressures at onset of CPB. (B) Immunoreactive endothelin level during CPB (percent change from onset of CPB at the end of CPB) and the mean of all endotoxin measurements during and after CPB. (EU•mL-1 PRP = endotoxin units per milliliter of platelet-rich plasma.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Previous studies demonstrated that the pattern of circulating endothelin in patients undergoing cardiac operations varies from an increase during CPB and high levels thereafter [13, 23] to no increases during operation and a small but continuous increase in the ICU [14]. This latest study was performed in children, who may respond differently to the CPB procedure than elderly patients [13, 14]. Inducers for circulating endothelin were not examined in these studies.

In this study most patients (10 of 15) had a significant drop in arterial blood pressures after onset of CPB, which correlated with the endothelin release into the systemic circulation. Previously, Shichiri and associates [6] showed that postural change and body fluid change affected circulating endothelin level (parallel with renin activity and aldosterone concentrations), which was suggested to be induced by activation of the baroreceptor reflex, and endothelin would be derived from the neurohypophysis [4]. Endothelin is synthesized in the paraventricular nuclear neurons and stored in the posterior pituitary [2], which makes fast release, as observed at onset of CPB, possible. Postural change increases the level of circulating endothelin, whereas volume expansion reduces the level of circulating endothelin; both mechanisms reflect the physiologic reaction after hemodynamic changes and the potential role of endothelin in blood pressure regulation [4]. From these observations, we conclude that the circulating endothelin after onset of CPB most likely originated from the neurohypophysis rather than from endothelial cells.

The slow systemic increase in endothelin level during CPB, however, may have originated from endothelial cells, and this increase might reflect the local production of endothelin by stimuli in the vascular bed. Systemic endothelin concentrations partly reflect the local production by endothelial cells. Endothelial cells in culture, however, preferentially release endothelin abluminally twice as much than luminally, because in vivo the potential target cells are the underlying smooth muscle cells [24]. Endotoxin as well as thrombin and hypovolemia (or a combination of these factors) could have been the stimulus that caused the increase in endothelin during CPB, but high local endothelin release, ie, from the intestine mucosa, might also contribute to the increase in systemic endotoxin. Several investigators [15, 16, 19] confirmed the early observation by Andersen and associates [18] and Rocke and colleagues [17] that circulating endotoxins are detected during CPB. More data have now appeared in the literature, supporting the early hypothesis that most of the circulating endotoxin is derived from the patients' own intestine. For instance, full selective decontamination of the intestine before operation completely prevented the appearance of endotoxins in the circulation during CPB [19]. Endotoxin transmigration is induced by reduced splanchnic perfusion and increased intestine-wall permeability [25–27]. In support of these observations, we found a correlation between the slow increase in endothelin level during CPB and circulating endotoxin concentration. Mesenteric arteries possess high concentrations of specific endothelin receptors, and blocking of these receptors improved hemorrhagic shock-induced gastric mucosal injury and mucosal microcirculation in rats [28, 29]. Circulating endothelin therefore may contribute to the impaired intestinal perfusion during CPB, causing endotoxin transmigration from the intestine. Future studies with full selective intestinal decontamination and no circulation endotoxin will reveal part of the mechanism. Does endotoxin stimulate endothelin production?

However, whether this circulating endothelin is physiologically functional remains to be determined, because endothelin-induced vasoconstriction is extremely sensitive to extracellular Ca²⁺ and Ca²⁺-channel blockers [1, 30, 31]. Because all patients received dihydropyridine-type Ca²⁺-channel blockers preoperatively, which seem to reverse endothelin-mediated vasoconstriction in human arteries [30, 31], we should find influences of Ca²⁺ antagonists on endothelin-induced hemodynamic changes. The aspect of Ca²⁺ antagonist treatment before cardiac operations and its hemodynamic consequences therefore need further study. But still, the release pattern of endothelin coincides with the nonphysiologic events at onset of CPB and the release of bacterial-derived endotoxins during cardiac operations, which suggests that circulating endothelin level may be a useful biochemical indicator for these events.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was financially supported by Janssen Pharmaceutica B. V., Tilburg, the Netherlands, protocol KTN-HOL-9012. Part of the endothelin kits were a kind gift of Sorin Biomedica, Amsterdam, the Netherlands. We thank Karin Joop and Yvonne Koen for technical assistance with the endotoxin assays and Hans Twaalfhoven for the endothelin assay.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr te Velthuis, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Department of Auto-Immune Diseases, PO Box 9190, 1006 AD Amsterdam, the Netherlands.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Piet G. M. Jansen Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Velthuis, H. t. Articles by Wildevuur, C. R. H. Search for Related Content PubMed PubMed Citation Articles by Velthuis, H. t. Articles by Wildevuur, C. R. H.