BJA Advance Access originally published online on October 9, 2006
British Journal of Anaesthesia 2006 97(6):825-831; doi:10.1093/bja/ael270
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The effects of propofol on neutrophil function, lipid peroxidation and inflammatory response during elective coronary artery bypass grafting in patients with impaired ventricular function
Department of Anaesthesia and Intensive Care Medicine, Cork University/Mercy Hospitals and University College Cork Cork City, Ireland
*Corresponding author: Department of Intensive Care Medicine, Royal Perth Hospital, Wellington Street, Perth 6000, Western Australia. E-mail: mascor{at}bigpond.net.au
Accepted for publication August 23, 2006.
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Abstract |
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Background. Coronary artery bypass grafting (CABG) with cardiopulmonary bypass elicits a potent reperfusion injury and inflammatory response, more intense in patients with impaired myocardial function. Propofol has antioxidant properties which may attenuate such a response.
Methods. In total, 27 patients with impaired left ventricular function undergoing CABG were randomly allocated to receive either target-controlled infusion propofol (P) or saline (S) immediately before aortic cross-clamp release until 4 h after reperfusion. Troponin-I, Urinary 8-epi PGF-2
isoprostane, coronary sinus and systemic malondialdehyde concentrations, Interleukin-6 (IL-6), -8 and -10 concentrations and leucocytes function studies (neutrophil respiratory burst, phagocytosis, CD-11b and CD-18 expression) were measured.
Results. Propofol decreased MDA coronary sinus concentration at 1, 3 and 5 min after reperfusion (P<0.01); 60 min after reperfusion a significant difference between the two groups in systemic MDA concentrations was also seen. IL-6 concentration increases were significantly greater in Group S than Group P, 4 h after reperfusion [1118 (1333) pg ml–1 vs 228 (105) pg ml–1, P<0.01]. Serum IL-8 concentrations did not increase significantly in either group. Compared with baseline values IL-10 concentrations decreased after reperfusion but the values were higher in the propofol group than in the control group [22 (16) vs 11 (4) pg ml–1, P<0.05]. No difference in leucocyte function or urinary isoprostane concentrations was demonstrated.
Conclusion. Propofol attenuates free-radical-mediated lipid peroxidation and systemic inflammation in patients with impaired myocardial function undergoing CABG.
Keywords: anaesthetics, propofol; complications, reperfusion injury, inflammation; surgery, cardiovascular, CABG
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Introduction |
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Ischaemia–reperfusion injury is a very real occurrence during surgery for coronary artery bypass grafting (CABG). The mechanisms underlying this injury are becoming better appreciated but reactive oxygen species elaboration, free-radical mediated membrane injury, mitochondrial dysfunction and establishment of an inflammatory response are all central to the process.1 This results in varying combinations of myocardial dysfunction, myocardial necrosis and systemic inflammation.2 These abnormalities tend to be more common, severe and prolonged in patients who already have compromised myocardial function such as cardiac failure. Animal studies suggest that the failing heart is susceptible to a more severe reperfusion injury3 than the non-failing heart. The mechanism appears to be the deficiency of antioxidant enzymes and excessive mitochondrial production of oxygen free radicals4 in response to reperfusion stresses. These findings manifest as excessive intracellular hydroxyl ion accumulation and subsequent tissue injury. In man, baseline oxidant stress is shown to be greater in those with impaired cardiac function and cardiac failure,5 6 it correlates with functional status, and these patients may be prone to more severe reperfusion injury following CABG; manifestations vary from transient ventricular dysfunction (stunning) to severe unresponsive cardiogenic shock,7 a result of impaired ‘antioxidant-reserve’.
Systemic interleukins (IL-6 and -8), that reflect myocardial reperfusion injury, are elaborated by the injured myocardium8 and serve to drive systemic inflammation and upregulation of leucocyte adhesion molecules. IL-10, released primarily from the liver, acts as a counter-balance to these pro-inflammatory cytokines.9
Isoprostanes are a new class of compounds used with increasing frequency to document the occurrence of free-radical mediated tissue injury10 in cardiovascular diseases, and are complementary to other assays of free-radical injury, such as malondialdehyde (MDA)-lipid peroxidation.
The antioxidant properties of propofol should ameliorate free-radical injury in myocardial reperfusion and manifest as a less intense inflammatory response with less free-radical mediated tissue injury. These combined actions might be anticipated to attenuate the reperfusion injury, and if this is the case, then we should be able to detect this as alterations in the systemic inflammatory cascade, neutrophil function, oxidant stress and myocardial function as seen in the animal models.11 We aimed to assess these outcome variables in patients with impaired ventricular function.
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Methods |
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Twenty-seven ASA III patients, with a left ventricular ejection fraction <40%, undergoing elective CABG were studied. Exclusion criteria comprised clinically significant valvular dysfunction, myocardial infarction within the previous 6 weeks, diabetes mellitus, renal dysfunction, autoimmune disease, concurrent medication with anti-inflammatory or immunosuppressant agents, or a history of allergy to propofol. After obtaining institutional ethics committee approval and having received written informed consent, patients were randomly assigned to either control (Group S, n=13) or propofol (Group P, n=14) groups. Surgery was performed by two consultant cardiothoracic surgeons (without selection bias), and anaesthesia administered by one consultant anaesthetist. Investigators who undertook the assay procedures were unaware of the group from which the samples were obtained.
All patients received premedication with lorazepam 0.04 mg kg–1. After establishing standard monitoring procedures, anaesthesia was induced with fentanyl 15 µg kg–1 i.v. and inhalation of isoflurane 0.5%, with pancuronium 0.1 mg kg–1 i.v. to facilitate tracheal intubation. Intermittent positive pressure ventilation was commenced to maintain normoxia and normocapnia. Anaesthesia maintenance comprised isoflurane 1% in an oxygen–air mixture for the entire procedure. A further fentanyl 5 µg kg–1 was administered immediately prior to sternotomy. Approximately 15 min before the release of the aortic cross-clamp, patients in Group S received an infusion of normal saline 0.9%. At this time in Group P, a target-controlled infusion of propofol (DiprifusorTM) was commenced to achieve a steady-state target site concentration of 6–8 µg ml–1 at the time of cross-clamp release. This concentration was maintained until 5 min after aortic cross-clamp release, at which time it was decreased to 4 µg ml–1 and then maintained at 2–4 µg ml–1 until 4 h after aortic cross-clamp release. A morphine infusion, 10–40 µg kg–1 h–1 was commenced upon arrival in the intensive care unit.
Patients received either cold crystalloid antegrade cardioplegia, or cold antegrade and retrograde blood cardioplegia. In patients receiving cold blood cardioplegia (n=13), the coronary sinus was cannulated, permitting the administration of retrograde cardioplegia and blood sampling. In both groups cardiopulmonary bypass was performed at mild hypothermia (32°C nasopharyngeal temperature), using a membrane oxygenator (Quadrox, Jostra AG, Bellshill, Scotland, UK); non-pulsatile perfusion, maintained at 20–30 kPa and mean arterial pressure at 40–60 mm Hg, with a flow rate of 2.0–2.4 litre min–1 m–2.In both groups the time of termination of complete occlusion of the aorta was defined as the time of cross-clamp removal.
Blood samples were drawn from the radial artery cannula at eleven time points (Fig. 1). These were: T0, pre-induction; T1, approximately 15 min before aortic cross-clamp release, T2ar, T2br, T2cr, T2dr, T2er—1, 3, 5, 10 and 20 min after aortic cross-clamp release (or onset of reperfusion), and T3, T4, T5 and T6—1, 4, 24 and 36 h after aortic cross-clamp release. In the patients in whom a coronary sinus catheter had been inserted (n=13, 7 in Group P and 6 in Group S), samples were withdrawn from the coronary sinus at 1, 3, 5, 10 and 20 min after cross-clamp release (T2acs, T2bcs, T2ccs, T2dcs, T2ecs), for MDA analysis, corresponding to systemic samples, T2ar, T2br, T2cr, T2dr, T2er. Samples for neutrophil function studies were analysed immediately. Samples for MDA or cytokine analysis were stored at –85°C until processing. The timing of cytokine analysis was selected according to the documented pattern of release of these compounds.
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For MDA analysis, separated serum underwent a protein precipitation step, passed through a 0.44 µm filter (Millipore) and stored at –85°C until analysis. MDA levels were measured by high performance liquid chromatography (HPLC) as described by Bull and Marnett,12 using a reverse-phase, ion-pairing, isocratic elution by HPLC, a mobile phase comprising acetonitrile 14% in myristyl trimethylammonium bromide 50 mM (Sigma-Aldrich chemicals), and Na2HPO4 1 mM, adjusted to pH of 6.8 at a flow rate of 1.0 ml min–1, with effluent monitoring at 267 nm. The lower reliable detection limit for MDA was 15
mol per injectate, corresponding to concentrations of 1.5 µM in serum. Serum concentrations of IL-6 and -8 were measured at T1, T2er (and T2ecs), T3, T4 and T5. Serum concentrations of IL-10 were measured at T1, T4 and T6. All interleukin assays were performed on 96-well pre-coated antibody plates using commercially available kits (Quantikine® R&D Systems Europe Ltd, Oxon, UK), using a quantitative sandwich-enzyme-linked immunoassay technique (S-ELISA). The respective minimal detectable concentrations were IL-6<0.7 pg ml–1, IL-10=3.9 pg ml–1, IL-8<10 pg ml–1.
Leucocyte respiratory burst or phagocytic activity was determined using commercially available kits (Bursttest®, PHAGOTEST® Orpegen Pharma, Heidelberg, Germany) and flow cytometric analysis of gated leucocyte populations within 2 h. Leucocyte ß2 integrin expression was measured using (i) FITC-labelled mouse anti-human CD-18 or FITC-labelled mouse anti-human IgG1 (isotype control) or (ii) Phycoerythrin-labelled mouse anti-human CD-11b or IgG2 (isotype control) (Becton Dickinson, San Jose, CA, USA). Following leucocyte isolation, 10 000 cells were gated and analysed with a laser flow cytometer (FACScan/Lysis II, Becton Dickinson, Heidelberg, Germany) using blue/green excitation light (488 nm Argon Laser). Populations of monocytes and neutrophils were separately gated by scatter plotting. All leucocyte function studies were performed at T0, T1, T3 and T5.
Cardiac Troponin-I measurements were performed using a commercially available assay (AXSYM system, Abbott laboratories, IL, USA). This is a microparticle enzyme immunoassay with a sensitivity of 0.3 ng ml–1 at the 95% confidence level. Measurements were performed at T0 (immediately pre-induction), and at T5 (24 h after release of aortic cross-clamp).
In order to further clarify whole body oxidative stress, a urine sample was collected immediately post-induction, to serve as a baseline value. At the end of the infusion period (4 h after reperfusion), a urine collection was commenced for 20 h and urine produced during that period was collected and pooled. A pooled sample was then collected for isoprostane analysis. The two samples for each patient were then analysed by mass spectrometry and the concentration of 8-epi PGF2 isoprostane corrected for urinary creatinine concentration.
Data are expressed as mean (SD) unless otherwise stated. Categorical data were compared using 
2-tests and Fisher's exact test for small sample size. Non-parametric data were compared using Mann–Whitney U-tests for between group comparisons, for small sample sizes. Factorial ANOVA was used to examine the interaction of cardioplegia type both between and within treatment groups, and data was subsequently examined using two-way ANOVA. A post-hoc Tukey honest square difference correction was used for multiple comparisons. Repeat measures ANOVA was used to identify significant changes within groups using Dunnetts correction for comparison to a control group. P<0.05 was taken to indicate statistical significance. All data were analysed using Statistica software for Windows, Version 5.1 (Statsoft Inc., Tulsa, OK, USA).
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Results |
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The groups were similar in terms of patient characteristics and procedure variables (Table 1). Twenty-seven patients were recruited (Group S n=13, Group P n=14). Coronary sinus samples were obtained in 13 patients, 7 in Group P and 6 in Group S. These samples demonstrated a high serum MDA concentration in Group S at 1, 3 and 5 min after onset of reperfusion; minimal MDA was detected in Group P at these times (P<0.01) (Fig. 2A). This difference in coronary sinus concentrations did not persist at 10 or 20 min after reperfusion; 60 min after reperfusion a significant difference between the two groups in systemic MDA concentrations was observed (Fig. 2B).
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in the period up to extubation, median/range; 
difference between preoperative value and sample taken 24 h after aortic cross-clamp release—not significant
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The changes that occurred in serum cytokine concentrations are displayed in Table 2. T1 was used as the baseline value for comparison in all groups. IL-6 concentrations, increased significantly in both groups compared with baseline, at 4 h in Group S and at 24 h in Group P [1118 (1333) vs 53 (68) (P<0.01) and 1070 (1312) vs 47 (71) pg ml–1 (P<0.001) respectively]. Furthermore, IL-6 concentrations were significantly greater in Group S than Group P, 4 h after reperfusion [1118 (1333) vs 228 (105) pg ml–1, P<0.01]. Serum IL-8 concentrations, did not increase significantly in either group, and no difference in concentrations at any time was observed between the groups. Compared with baseline IL-10 concentrations decreased significantly in both groups 4 and 36 h after reperfusion; 36 h after reperfusion IL-10 concentrations were higher in Group P than in Group S [22 (16) vs 11 (4) pg ml–1, P<0.05].
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Changes in leucocyte function with time, expressed as mean fluorescence intensity are shown in Table 3. Extensive within group changes were observed for all leucocyte parameters. The only significant difference between treatment and control groups was seen at T0 (pre-induction), where neutrophil CD-11b expression was higher in Group S than in Group P. No difference between the groups was observed for urinary isoprostane concentrations, and urinary 8-epi PGF2
isoprostane concentration did not change in either group.
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Discussion |
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The most important finding of this study is that the use of clinically relevant concentrations of propofol in patients with impaired myocardial function attenuates cardiac free-radical-mediated injury. This action is associated with a decrease in the systemic inflammatory response and augmentation of the counter-inflammatory response to CABG.
In this study, we examined myocardial lipid peroxidation (as MDA production) in both coronary sinus and systemic blood. Coronary sinus samples permitted direct measurement of coronary effluent MDA. As coronary sinus sampling was possible only in those patients who received blood cardioplegia, we measured systemic concentrations of MDA in all patients. Peak coronary sinus MDA concentrations were detected at 1 min after reperfusion, and by 20 min its production had decreased. The administration of propofol exerted a significant effect upon MDA concentrations up to 5 min after reperfusion (Fig. 2A). The administration of propofol also attenuated systemic MDA 60 min after reperfusion (Fig. 2B). These findings are consistent with the explosive release of free radicals detected by spin traps occurring within seconds to minutes of reperfusion,13 and a potent antioxidant action of propofol in this setting. In a similar cohort of patients, Sayin and colleagues14 demonstrated a protective effect of propofol on tissue lipid peroxidation, using the arguably less sensitive TBARS assay. It is possible that our results may have been influenced by the use of two different cardioplegia techniques used in our study, but our subgroup analysis discounted this and the greatest effect that we have demonstrated was in patients, all of whom received the same cardioplegia technique. We are unable to explain the mechanism underlying the much greater effect of propofol on myocardial free-radical injury (coronary sinus MDA) than on systemic injury.
Tissue isoprostane concentrations increase in association with oxidative stress in coronary artery disease and concentrations reflect oxidative stress in myocardial ischaemia.15 Zhang and colleagues16 demonstrated that propofol can attenuate whole body oxidative stress, as measured by isoprostane analysis, in the 24 h following cardiopulmonary bypass. They did not measure organ-specific oxidative stress or inflammatory response. We compared pre-induction urinary 8-epi PGF2 isoprostane concentrations to the concentration in pooled urine from 4 to 24 h after reperfusion. No differences between the groups were identified. Although this is an unexpected finding given the intense level of oxidative stress we detected by MDA assay, it is in keeping with the emerging literature in this field. Serum levels are very volatile, and they increase and decrease quickly, particularly with cardiopulmonary bypass.17 It is likely that by 4 h after reperfusion, the majority of oxidative stress subsides and it is the events incited by free radicals (upregulation of cytokine secretion, injury of endothelium and activation of leucocytes) that begin to manifest systemically.
Pro-inflammatory cytokines drive the inflammatory response to CABG/CPB and are associated with postoperative myocardial dysfunction.8 18 The source of these may be the inflamed myocardium.19 We allowed 15 min before reperfusion (T2) as the baseline on the basis that a difference emerging after this would be attributable to the effects of treatment. In addition, we attempted to identify a transcardiac gradient for these cytokines (coronary sinus–serum concentrations). We did not demonstrate a significant increase in concentrations of IL-8 in either of the groups, nor did we demonstrate a transcardiac difference in IL-8 or IL-6 concentrations. It may be that the myocardium is not the site of origin of most IL-8 or that by the time of aortic cross-clamp release, IL-8 concentrations are already elevated to the extent that it is no longer possible to identify the increase attributable to reperfusion. In contrast, we demonstrated a very large increase in serum concentrations of IL-6 in patients in the control group 4 h after reperfusion, which remained elevated at 24 h (Table 2). Patients who received propofol did not demonstrate an increase compared with baseline until 24 h after reperfusion, and 4 h after reperfusion the concentrations in these patients was significantly lower than in the control group. One explanation for this is that propofol may have attenuated the IL-6 response to cardiopulmonary bypass and reperfusion or that the non-significant trend to higher IL-6 and -8 concentrations in the propofol group at 24 h merely represents a postponement of the inflammatory response. As with the previous investigators, we could not establish the presence of a transcardiac gradient for IL-6.20 21
The pro-inflammatory response during and after CABG elicits a counter-regulatory response, comprising increased IL-10 production which balances the increases in both IL-6 and -8. Recent study suggests that lymphatic cells infiltrating the reperfused myocardium secrete IL-10 and that this may have a major influence on myocardial recovery,22 perhaps by attenuating neutrophil–endothelial interactions. In our study, 36 h after reperfusion IL-10 concentrations were significantly higher in patients who received propofol, suggesting that propofol exerts an effect to maintain the anti-inflammatory response. Given the less intense pro-inflammatory response in patients who received propofol, the administration of propofol may have uncoupled the closely linked relationship between pro- and anti-inflammatory cytokines. If however, the explanation that propofol delays rather than abrogates the IL-6 and -8 responses, then a higher, more intense IL-10 response at 36 h is appropriate.
No identifiable pattern of alterations in neutrophil function emerged to provide any evidence of an effect of propofol. It is clear from our results that neutrophil function is volatile with significant intragroup variability. The changes that we observed may have been as a result of contact with the extracorporeal circuit, surgical trauma, or to an effect of anaesthetic vapour (isoflurane in this case).23
Some authors have claimed that a decrease in lethal reperfusion injury (as evident from alterations in Troponin-I concentrations) has only been demonstrated to occur with the use of volatile anaesthetic agents.24 25 The non-significant trend to higher Troponin-I concentrations in the propofol group that we have demonstrated may represent an aggravation of lethal reperfusion injury as other authors have postulated or perhaps the addition of propofol to vapour cannot augment myocardial protection any further. In that case it is the influence of propofol against non-lethal reperfusion injury that may define the difference between groups.
Thus, we have demonstrated in a cohort of patients with impaired preoperative left ventricular function undergoing elective CABG with CPB, that the administration and maintenance of a titrated, and clinically relevant dose of propofol from before aortic cross-clamp release, maintained until 4 h after reperfusion, can attenuate myocardial lipid peroxidation. This effect did not extend beyond 1 h after reperfusion, but was associated with a decrease in IL-6 production and a late augmentation of IL-10 release that is disproportionate to the pro-inflammatory cascade observed. No change in lethal reperfusion injury was observed although a trend to higher Troponin-I concentrations was demonstrated in the propofol group. We were unable to identify a leucocyte effect to account for these findings.
In conclusion, our findings suggest that the primary and greatest effect of propofol in this setting is an antioxidative action, with either an anti-inflammatory action or an inflammation-delaying action. These properties may be beneficial to patients undergoing elective CABG, although further studies with larger numbers of patients may offer further clarification of the influence of propofol on IL-6 and -8 release patterns. Whether this antioxidant action of propofol translates into a clinically important outcome, such as improved postoperative myocardial function remains to be determined.
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Acknowledgments |
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Financial support for this study was provided by Research registrar account, Department of Anaesthesia, University College Cork and European Association of Cardiothoracic Anaesthetists Grant support.
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