Ann Thorac Surg 2006;82:672-678
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Changes in Cerebral Vascular Reactivity Occur Early During Cardiopulmonary Bypass in the Rat
Thomas Modine, MDa,b,
Richard Azzaoui, MDa,b,
Thavarak Ouk, PhDb,
Georges Fayad, MDa,
Dominique Lacroix, MD, PhDa,b,
Henri Warembourg, MDa,
Regis Bordet, MD, PhDb,
Terence Gourlay, PhDc,*
a Service de Chirurgie Cardiovasculaire, Hôpital Cardiologique, Lille, France
b Laboratoire de Pharmacologie, Université de Lille 2, Faculté de Médecine, Lille, France
c Department of Cardiothoracic Surgery, Imperial College Faculty of Medicine, London, England
Accepted for publication March 22, 2006.
* Address correspondence to Dr Gourlay, Department of Cardiothoracic Surgery, Faculty of Medicine, Imperial College London, Hammersmith Campus, 2nd Floor B Block Hammersmith Hospital, DuCane Rd, London W12 ONN, UK. (Email: t.gourlay{at}imperial.ac.uk).
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Abstract
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BACKGROUND: Cardiopulmonary bypass (CPB) is known to cause cerebrovascular dysfunction. The etiology of these complications is complex, but disruption of normal cerebral endothelial function as a consequence of inflammatory or hypoperfusion phenomena have been implicated. The aim of this study was to investigate the effect of CPB time on cerebrovascular reactivity and to investigate the correlation of these findings with measured inflammatory markers.
METHODS: Cardiopulmonary bypass was carried out for 30 or 60 minutes on two groups of rats. Sham groups underwent the same surgical procedure without CPB. The middle cerebral artery was harvested and prepared for assessment of induced endothelial and vascular smooth muscle cell responses. Systemic inflammation was evaluated by measuring tumor necrosis factor-
and immunohistochemical staining for intercellular adhesion molecule-1.
RESULTS: Acetylcholine caused a dose-dependent vasodilation in the control groups that was absent in animals undergoing CPB (21.3% ± 1.3% increase in diameter at 30 minutes in the sham group compared with 5.4% ± 1.1% in the corresponding CPB group, p < 0.001). Significantly, this was apparent after only 30 minutes of CPB. Cardiopulmonary bypass did not alter the response to sodium nitroprusside (45.3% ± 8.6% after 30 minutes in the sham group compared with 57.8% ± 8.0% in the corresponding CPB group, p < 0.2). Furthermore, the contractile response to serotonin remained intact in all groups (32.9 ± 4.6 and 27.6 ± 2.6 at 30 and 60 minutes, respectively, in the sham groups compared with 23.1 ± 1.6 and 28.0 ± 4.4 in the corresponding CPB groups, p < 0.2). Cardiopulmonary bypass also led to an early and marked increase in tumor necrosis factor- and overexpression of intercellular adhesion molecule-1.
CONCLUSIONS: Cerebrovascular impairment appears early after the onset of CPB. The specific loss of acetylcholine-induced vasodilation suggests endothelial cell dysfunction rather than impaired vascular smooth muscle response to nitric oxide. This loss of endothelium-dependent regulatory factors after CPB may enhance vasoconstriction, impair cerebrovascular function, and contribute to neurologic injury after CPB.
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Introduction
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Neurologic injury has been a recognized pathophysiologic consequence of cardiopulmonary bypass (CPB) since its earliest application in clinical practice [1, 2]. This complication can be categorized as follows: type I, severe disorders (coma, stupor, stroke); and type II, mainly represented by a neurocognitive weakening [3, 4]. The mechanisms implicated in type I disorders are clear and involve ischemic or hemorrhagic events. However, those underlying type II disorders remain less well understood, but are thought to include microembolic and cerebral perfusion disorders together with the activation of inflammatory processes [5–7].
The systemic inflammatory response associated with CPB is the consequence of both ischemia-reperfusion events and blood contact with the foreign surfaces of the CPB circuit. Blood contact with the CPB circuitry has been shown to initiate humoral and cellular inflammatory responses [8, 9]. The sequence of events leading to this inappropriate activation of inflammatory processes has been well described, and may result in an increase in vascular permeability and hemodynamic changes mediated by the liberation of proinflammatory cytokines. Tumor necrosis factor- (TNF) and interleukin-1 (IL-1) promote vasodilatation and the expression of specific adhesion molecules such as E-selectin and intercellular adhesion molecule-1 (ICAM-1), promoting adhesion of leukocytes to endothelial cells. However, the neurologic impact of this inflammatory reaction is, as yet, not entirely understood, but it may be one of the mechanisms that lead to endothelial impairment in the brain, resulting in disruption of the brain microvessel vasomotor tonus and a diffuse cerebral hypoperfusion [10–13].
The endothelium has an important role to play in the maintenance of the blood-brain barrier, regulating inflammatory and thrombotic processes and vasomotor tonus. Animal experiments focusing on cerebral ischemia-reperfusion have already established a link between inflammation and impairment of brain vessel-dependent endothelial relaxation [14]. Under the influence of proinflammatory cytokines, endothelial cells overproduce membrane proteins (V-CAM, ICAM-1), leading to the adherence of neutrophil polynuclear cells to the vascular wall [15]. At this stage, these cells can free oxygen proteolytic enzymes and free radicals capable of disrupting the endothelium, resulting in the impairment of its vasomotor characteristics.
The purpose of this study was to investigate, using a rat model of CPB, the effect of CPB time on cerebral vascular reactivity, and whether inflammatory events correlate with this outcome.
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Material and Methods
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Animals
Thirty-two Male Sprague-Dawley rats, each weighing 422 ± 32 g, were anesthetized with a single intraperitoneal injection of chloral hydrate (300 mg/kg), and were allocated into one of four study groups (see experimental groups). This regimen provides at least 60 minutes of stable anesthesia and a satisfactory and uneventful recovery. Arterial pressure was continuously monitored through a femoral catheter. Central temperature was maintained with a warming mattress and a warming lamp directed onto the animal. Arterial blood gases were taken at 0, 15, 30, 45, and 60 minutes on bypass. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animal Resources" published by the National Institutes of Health (NIH publication 85–23, revised 1985).
CPB Circuit and Conduct of Bypass
All circuits were single use and set up under sterile conditions. The CPB circuit, described in a previous publication [16], consisted of a roller pump (101 U/R; Watson Marlow, Paris, France) and a 30-cm polyvinyl chloride (PVC) A-V loop with an internal diameter of 3 mm connected to the roller pump equipped with a 15-cm pump boot with a 5-mm internal diameter (Watson Marlow). Cardiopulmonary bypass was established at a flow rate of 100 mL · kg–1
· min–1. Venous return was drained by gravity into a 20-mL sterile syringe used as a venous reservoir. The membrane oxygenator (Pheresis Research, Erskine, Scotland) used during this procedure had been specifically conceived for rodent experimentation and approximated clinical apparatus in terms of surface area/body mass ratio and priming volume/blood volume ratio [16]. The entire circuit priming volume was 10 mL. and consisted of 5 mL of synthetic colloid and 5 mL of Ringer's Lactate. The circuitry was connected to the rat using a right transjugular approach, employing a 6.5F cannula for venous drainage, and caudal artery with a 20G catheter for arterial return. Cardiopulmonary bypass time was either 30 minutes or 60 minutes, depending on the experimental group. The pump output was set up at 100 mL · kg–1
· min–1 and adjusted to maintain acceptable arterial pressure (> 60 mm Hg). The central temperature was maintained at 35°C and was monitored rectally. Gas flow (O2 and medical air) was initiated at approximately 50 to 75 mL/min and adjusted in terms of sweep rate and FiO2 to maintain blood gasses in the physiologic range. At the termination of the CPB period, the animals were weaned from CPB, and the remaining priming volume reinfused before sacrifice.
Experimental Groups
The animals were allocated to one of four groups: group 1, 30 minutes of CPB; group 2, 60 minutes of CPB; group 3, 30 minutes of sham procedure; and group 4, 60 minutes of sham procedure.
Animals in the sham groups underwent the same experimental procedure as the CPB groups, but excluding the CPB. All animals were sacrificed 10 minutes after the CPB (or sham) period.
Experimental Protocols
Cerebral vascular reactivity study
Animals were sacrificed with a lethal dosage (300 µL/100 g) of 6% buffered sodium pentobarbital solution. In these animals (6 in each group), the brain was explanted and immediately placed in Krebs solution and maintained in an oxygenated state at 4°C. The right middle cerebral artery was carefully harvested and cleaned of any superficial tissue. The artery was handled with care by experienced technicians to avoid any mechanical damage.
Preparation of arterial segment and pressurized arteriograph system
Each segment of dissected middle cerebral artery was mounted in an arteriograph (Living Systems Instrumentation, Burlington, Vermont) using two glass cannulas and perfused with Krebs solution. Once mounted, the distal cannula was occluded in order to work in no-flow condition. The arteriograph chamber was continuously supplied with Krebs solution equilibrated with 5% CO2/95% O2 and maintained at 37°C and pH 7.4. The proximal cannula was connected to a pressure transducer, a miniature peristaltic pump, and a servo controller that continually measured and adjusted transmural pressure (TMP). The entire arteriograph system was positioned on the stage of an inverted microscope equipped with a video camera and a monitor. The lumen diameter was measured by image analysis with a video dimension analyser. The picture analysis allowed us to measure the diameter of the artery in addition to mechanical gauging (Model V91; Living System Instrumentation).
Measurement Procedure
All mounted arteries were pressurized to a TMP of 25 mm Hg for 1 hour to stabilize before experiments were conducted. The spontaneous contracting response of cerebral arteries to pressure contributes to autoregulation of cerebral blood flow and characterizes the myogenic tone. To evaluate myogenic reactivity, the TMP was increased in increments of 25 mm Hg from 25 to 100 mm Hg and arterial diameter was recorded at each step after a 5-minute equilibration period. At the end of each experiment and after another 25 mm Hg TMP equilibration period, TMP was once again increased in 25 mm Hg incremental steps from 25 to 100 mm Hg in the presence of papaverine (10 µM), a phosphodiesterase inhibitor, to record passive fully relaxed diameter. After this step, the TMP was adjusted to 75 mm Hg for the remainder of the experiment. Acetylcholine relaxing–dose response was determined by cumulative addition of acetylcholine (0.001 to 30 µM) on artery preparations that had been constricted by serotonin (1 µM induced 90% of the maximum constriction). Additionally, to test the nitric oxide mediated smooth muscle relaxation, a single concentration of sodium nitroprusside (10 µM) was added to the bath after preconstriction with serotonin (1 µM).
Inflammatory reaction study
The broad range of inflammatory markers commonly employed in clinical practice were not readily available for these rat studies. However, an enzyme-linked immunosorbent assay for TNF was available and was employed as a general marker of the inflammatory response. Immediately after anesthesia and during the course of the operative procedure, blood samples were taken, centrifuged, and the plasma removed and stored at –80°C to allow subsequent TNF assessment.
Immunohistologic study
In a separate population of 24 animals (6 in each group),all undergoing the same experimental procedures as described above, in-situ tissue fixation was achieved using intracardiac paraformaldehyde perfusion at the termination of the study period, and the brain was then explanted and set in a paraffin block. Ten sections of 5 µm thickness each were taken from the hippocampus for immunohistochemical assessment with an anti-ICAM-1 antibody.
Statistical Analysis
Results were expressed as mean values ± SE. Differences between the groups were determined by analyzing the univariate analysis of variance followed by, in cases of significant results, a Fisher's post-hoc Protected Least Significant Difference test, allowing the comparison. Significant threshold is p less than 0.05.
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Results
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Mean femoral arterial pressures were not significantly different between the CPB and sham animals throughout the experimental period (Fig 1). Venous pressure was not measured in either group; however, the adequacy of venous drainage in both CPB groups would suggest that there was no significant venous congestion present. In addition, there were no significant gradients when comparing caudal artery and carotid artery PaO2 and PaCO2 levels between the CPB and sham groups (Fig 2). The mean hematocrit was significantly lower in the CPB group than in the sham group (32.2 ± 4.2 versus 38.2 ± 0.8, p < 0.001) as a consequence of the hemodilution associated with priming (Table 1). Myogenic tonus assessment of middle cerebral arteries did not show any significant difference between the CPB and sham groups (Fig 3). There was an incremental increase in constriction in all groups to incrementally increasing TMP (from 8% to 25% in the 30-minute sham group over the TMP range of 25 to 100 mm Hg, compared with 18% to 32% in the corresponding CPB group, p > 0.05). The contractile response to a 10–6 M serotonin single dose did not reveal any significant difference between the groups (Table 2). The response was similar in magnitude in both the CPB and sham groups, and there was no apparent time-dependent effect (23.1% ± 1.6% contraction in the 30-minutes CPB group, compared with 28.0% ± 4.4% contraction in the 60-minutes CPB group (p < 0.1)). Dependent endothelial relaxation was, however, significantly altered within the CPB groups when compared with the sham groups (Fig 4). In all groups, there was a clear dose response to increasing concentrations of acetylcholine; however, the magnitude of the response was significantly different when comparing those animals in which CPB was performed with the sham animals. The level of relaxation increased from approximately 0.5% at the lowest concentration, to 5.4% ± 1.1% at the highest concentration in the 30-minutes CPB group, compared with approximately 4% to 21.3% ± 1.3% over the same concentration range in the corresponding sham group. The differences in response between CPB and corresponding sham groups was statistically significant at all concentrations, reaching p less than 0.001 at the peak acetylcholine concentration of 30 µM. Interestingly, this alteration appeared early, 30 minutes, after the onset of bypass, and there was no apparent significant time-dependent effect in the arterial response to acetylcholine beyond 30 minutes. There was no significant difference when comparing sham 30 to sham 60 animals or CPB 30 to CPB 60 animals at any concentration (p > 0.1).
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Fig 1. Arterial pressure in the cardiopulmonary bypass (CPB) and sham groups of animals. The mean femoral arterial pressures were not significantly different between the groups. The data are expressed as mean ± SD. (Triangles = carotid CPB; diamonds = carotid sham; squares = femoral CPB; circles = femoral sham.)
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Fig 2. Blood gas data in the cardiopulmonary bypass (CPB) and sham arms of the study. Both PaO2and PaCO2 are shown, and there were no statistically significant differences between the groups in terms of either factor. (Diamonds = carotid PaO2; triangles = caudal PaO2; squares = carotid PaCO2; X = caudal PaCO2; post-op = postoperative; pre-op = preoperative; T = time.)
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Fig 3. The myogenic tonus response in middle cerebral arteries, the contractile response to incrementally increasing transmural pressure (TMP), did not illicit any statistically significant differences between the groups. The data are expressed as mean ± SD and represent the percent (%) change in the precontracted tonus. (Squares = cardiopulmonary bypass [CPB] 30 minutes; diamonds = sham CPB 30 minutes; triangles = CPB 60 minutes; circles = sham CPB 60 minutes.)
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Fig 4. The response of precontracted middle cerebral artery to acetylcholine (ACHOL [endothelium-dependent vasoreactivity]). The results are shown as mean ± SD and represent the percent (%) relaxation of serotonin-induced preconstriction. The degree of relaxation was substantially diminished in the cardiopulmonary bypass (CPB) group, confirming an alteration in dependent vasoreactivity. (conc = concentration; gray boxes = CPB 30 minutes; black triangles = CPB 60 minutes; gray triangles = sham 30 minutes; black boxes = sham 60 minutes.)
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The relaxing response to a 10–5 M maximal dose of sodium nitroprusside was similar in both the CPB groups, and there were no significant differences observed when comparing these to the sham animals (57.8% ± 8.0% in the CPB 30 animals and 44.0% ± 11.7% in the CPB 60 animals, compared with 45.3% ± 8.6% and 41.2% ± 6.9% in the corresponding sham animals (p < 0.1; Table 2).
Tumor necrosis factor- plasma concentration was significantly higher in both CPB groups at the point of sacrifice than in the sham groups (p < 0.001), and there was no significant increase in TNF with increasing time when considering either the CPB animals or the corresponding shams (p > 0.1; Fig 5).
Anti–ICAM-1 immunostaining of cerebral sections revealed a clear overexpression of ICAM-1 on the vascular endothelium of cerebral vessels in both CPB groups compared with their respective sham groups (Fig 6a, b, c).
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Fig 6. Immunohistochemical analysis of brain sections. (a) Sections from the sham rats display the vascular wall with low intensity staining. (b) In contrast, cardiopulmonary bypass was associated with a significant enhancement of vascular wall staining in the 30-minute cardiopulmonary bypass (T30 CPB) group. (c) The negative control (sacrificed animals) shows no staining for intercellular adhesion molecule-1.
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Comment
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Small-animal models of CPB have been used in CPB research for a number of years, with a recent surge in this activity most likely driven by the emergence of reliable technology designed for this application and the associated cost advantage [16, 17]. In the present study, the rat CPB model functioned very reliably. All animals survived the procedure, and crucially, in the context of the focus of this study, blood gas and hemodynamic analysis did not show any differences between the carotid artery and caudal artery in any animal. We therefore consider this model to be a stable platform for the study of the pathophysiology of CPB.
In our vascular reactivity study, the middle cerebral artery's response to acetylcholine revealed a deep alteration in relaxation in the CPB groups even at low acetylcholine concentrations. At the same time, arterial response to sodium nitroprusside (nitric oxide provider) was comparable between the CPB and sham groups. Similarly, myogenic tonus assessment, which corresponds to the artery's resistance to contraction in the presence of intraluminal pressure increase, did not reveal any difference between the groups. Myogenic tonus is exclusively dependent on the smooth muscle, suggesting that it was undamaged by CPB. Finally, our study demonstrated that there was no difference in the middle cerebral artery's contractility between CPB and sham groups after a single 10–6 M serotonin dose. These observations in the immediate postoperative period suggest a marked alteration of the dependent endothelial relaxation while the smooth muscle dependent relaxation was perfectly well preserved. Our aim was to investigate the time course of these findings, and the studies confirmed that the middle cerebral artery lesions appear early (within 30 minutes) in the course of the CPB. Although considerable further study is required to define the mechanisms and the absolute time course of these events, the results suggest that early contact activation processes within the CPB system may be involved.
The two existing published studies concerning cerebral vascular reactivity changes associated with CPB have produced conflicting results. Sellke and colleagues [18] suggested that there is an isolated alteration of the dependent endothelium relaxation of the cerebral microvessels associated with extracorporeal circulation in the pig. On the other hand, Hindmann and associates [19] after similar procedures using a rabbit model, concluded that damaged smooth muscle accounted for the alteration they observed in independent endothelial relaxation. Despite the difference in experimental models, our results appear to fit the conclusions of Sellke and colleagues [18].
The mechanisms underlying endothelial damage have been studied largely in experimental models of cerebral ischemia-reperfusion [14, 20]. These studies have highlighted two factors involved in the evolution of this injury: oxidizing stress and inflammatory phenomena. Oxidizing stress directly results from ischemia-reperfusion events, implying the formation of oxygen free radicals. These can alter the endothelial cell while reducing, through complexation phenomena, nitric oxide availability to the smooth muscle cell [21]. Importantly, in our study, there were no ischemia-reperfusion sequences, which diminishes, but clearly, at this stage, does not eliminate the relative importance of oxidizing stress in our model. The sufficiency of the cerebral perfusion was further confirmed by the hemodynamic and blood gas assessments performed on the carotid axes, ruling out hypoxemia as an explanation for our observations. A significant hemodilution was detected in the CPB group compared with the control group, which must be considered, but the degree of hemodilution (hematocrit of approximately 30%) was absolutely typical of that encountered in clinical practice. However, the role of hemodilution in the inflammatory process cannot be ignored, and has been confirmed, particularly at high levels of dilution, in previous studies using a similar experimental approach [22].
The evaluation of more specific markers of oxidizing stress will be required to complete these data. Nonetheless, these observations appear to reduce the importance of oxidizing stress in the occurrence of endothelial dysfunction subsequent to CPB. However, CPB-related inflammation does not result solely from ischemia-reperfusion phenomena. It has been demonstrated that blood contact with the synthetic surfaces of the perfusion circuit generates a significant systemic inflammatory reaction [8, 23, 24]. Our study, in which TNF was employed as a marker of the systemic inflammatory response, is compatible with these findings insofar as it demonstrated an increase in TNF in the CPB groups when compared with sham groups [25]. Plasma TNF concentrations significantly increased in the blood samples obtained at sacrifice in all groups, but were significantly higher in the CPB groups (p < 0.005). Clinical and animal studies have shown that this inflammatory response can lead to a diffuse activation of endothelial cells, which overproduce cellular adhesion molecules (P-selectin, VCAM, ICAM) on their surface. Subsequently, endothelial cells become a neutrophil polynuclear cell target, which, once fixed to the vascular wall, can release proteolytic enzymes and free radicals, which can disrupt the integrity of the endothelium [11, 26, 27]. Immunohistochemical analysis of cerebral sections from animals after our CPB procedure has indeed demonstrated an ICAM-1 overexpression when compared with the sham groups. Although there was no statistical evidence supporting a correlation between the observations relating to I-CAM and TNF, and our observed vasomotor disruption, we believe that a larger study may confirm such a relationship.
Alteration of the dependent endothelial relaxation of cerebral arteries associated with CPB was clearly demonstrated in the present study, together with instability of the vasomotor tonus. We suggest that this may produce a diffuse cerebral hypoperfusion, which may lead to neurocognitive disorders.
Neurobehavioral studies using rat CPB models have already been published [17] showing a significant deterioration of neurobehavioral characteristics in animals subsequent to CPB. However, in these studies, in common with our own, the histomorphologic examination did not reveal any significant changes associated with CPB. To date, cerebral parenchyma damage directly related to CPB is sparsely documented, but these small animal studies offer an insight into the mechanism of brain injury during CPB.
Conclusions
Cerebrovascular impairment appears early after the onset of CPB. The specific loss of acetylcholine-induced vasodilation suggests endothelial cell dysfunction rather than impaired ability of vascular smooth muscle to respond to nitric oxide. We suggest that the loss of endothelium-dependent regulatory factors in the cerebral microcirculation after CPB may enhance vasoconstriction, leading to impaired cerebrovascular function, and that this may be an important mechanism underlying the development of neurologic injury after CPB.
Further studies are required to determine more fully the mechanisms underlying the fndings of the present study. However, our early studies suggest that the vasomotor disruption observed may, at least in part, have an inflammatory origin. That this ocurs early in the CPB procedure is very important, and further investigation is required to determine the exact time-frame of this CPB-related pathology.
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Acknowledgments
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This work was supported by the Federation Française de Cardiologie.
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References
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Abstract
Introduction
