BJA Advance Access published online on January 16, 2007
British Journal of Anaesthesia, doi:10.1093/bja/ael366
Predictive value of IL-18 and SC5b-9 for neurocognitive dysfunction after cardiopulmonary bypass
Department of Anaesthetics and Intensive Care Medicine, Wales College of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
* Corresponding author: Department of Anaesthetics and Intensive Care Medicine, Wales College of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. E-mail: arunkumar{at}btinternet.com
Accepted for publication November 15, 2006.
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Abstract |
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BACKGROUND: Neurological injury after cardiopulmonary bypass (CPB) continues to be a major problem after cardiac surgery. The aim of this study was to investigate the predictive value of Interleukin-18 (IL-18) and SC5b-9 as biochemical markers of neurocognitive dysfunction after cardiac surgery.
METHODS: A total of 30 patients undergoing elective cardiac surgery using CPB were recruited. Blood samples were obtained for IL-18 and SC5b-9 concentrations before induction, 24, 48, 72, 96 and 120 h post-CPB and 6 weeks after operation. In addition, patients underwent a standard battery of neuropsychometric tests before operation and at day 5 and 6 weeks after operation.
RESULTS: Serum concentration of IL-18, but not SC5b-9, was significantly different between patients with and without neurocognitive dysfunction; serum IL-18 concentration significantly increased in patients with neurocognitive dysfunction (P = 0.018). Neurological outcome was significantly dependent on peak difference in IL-18 concentration at day 5 (P = 0.033), but not on peak difference in SC5b-9 concentration (P = 0.16). Eight patients had neurocognitive dysfunction at day 5 and three had neurocognitive dysfunction at 6 weeks. In a very small number of patients, no significant association was demonstrated between IL-18 or SC5b-9 concentrations and neurocognitive dysfunction at 6 weeks.
CONCLUSIONS: IL-18 has the potential as a useful marker of neurological dysfunction, requiring further investigation.
Keywords: blood, IL-18; blood, SC5b-9; brain, injury; heart, cardiopulmonary bypass; polypeptides, IL-18; polypeptides, SC5b-9
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Introduction |
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Neurological injury after cardiopulmonary bypass (CPB) remains a potentially devastating consequence of cardiac surgery. The incidence rate of type I outcome (non-fatal stroke, transient ischaemic attack, coma, or death) after coronary artery bypass grafting (CABG) is about 3%1 and that of type II outcome (deterioration in intellectual function, confusion, agitation, disorientation, memory deficit or seizure) may vary between 3 and 53%.1 2 Studies report very variable associations between serum markers such as S-100ß and neuron specific enolase and neuropsychometric tests after CPB.3–5
Interleukin-18 (IL-18) is a pro-inflammatory cytokine expressed by macrophages/Kupffer cells,6 keratinocytes,7 adrenal cortex,8 and myocardial cells.9 It is expressed in primary cultures of astrocytes and microglia, but not in neurons.10 In acute ischaemic stroke, serum IL-18 correlates with the extent of hypodense area in computed tomography.11 Cerebrospinal fluid (CSF) concentration of IL-18 is elevated in patients with traumatic brain injury,12 meningitis,13 and multiple sclerosis.14
SC5b-9 is the terminal complement complex generated by an assembly of C5 through C9 after complement activation. CSF concentration of SC5b-9 has been reported to be elevated in traumatic brain injury.15
The above studies suggest that IL-18 and SC5b-9 concentrations increase after the more potent type I cerebral injury. The behaviour of these markers after more subtle type II injury is not known. The aim of our study was to investigate the predictive value of serum IL-18 and SC5b-9 as markers of neurocognitive dysfunction after CPB.
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Methods |
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After approval from the local Ethics Committee and obtained written informed consent, 30 consecutive adults undergoing elective cardiac surgery using CPB were enrolled. An observational study of 30 patients was planned. All patients were ASA II or III. Preoperative exclusion criteria were: pre-existing cerebral damage (head injury) or previous brain surgery, brain pathology (tumours, cerebrovascular accident), significant carotid artery disease (carotid stenosis >50% on either side), previous psychiatric illness (e.g. schizophrenia), severe kidney, or liver disease (creatinine >200 µmol litre–1 and bilirubin >35 µmol litre–1), previous cardiac surgery, emergency surgery, and history of myocardial infarction in the last 6 months. Patients were also excluded from the study if they experienced perioperative complications such as need for intra-aortic balloon pump insertion, as this could potentially dislodge atheroma, or re-operation with CPB.
All patients received a standard oral premedication of either temazepam (20–30 mg) or lorazepam (1–3 mg). Anaesthesia was induced with etomidate (0.2 mg kg–1) and fentanyl 10–15 µg kg–1 with pancuronium (0.1 mgkg–1) for tracheal intubation. Anaesthesia was maintained with isoflurane 0–2%, fentanyl, and pancuronium as required. Heparin was administered before aortic cannulation at a loading dose of 300 units kg–1, with subsequent dosing guided by the activated clotting time.
CPB was started through cannulation of ascending aorta in all patients. CPB was maintained according to the local guidelines [i.e., non-pulsatile perfusion (2.4 litre min–1 m2) with a roller pump (Stockert S-III, Munich, Germany), hollow fibre membrane oxygenator (Medos Hilite 7000, Medos, Stolberg, Germany), polyvinyl chloride non-heparin-coated tubings, and an arterial line filter, with a clear priming solution of 1500 ml]. Vent suction was used and shed mediastinal blood was returned to the pump. Mild to moderate hypothermia (temperature approximately 32–35°C) was maintained. Mean arterial blood pressure was maintained above 50 mm Hg during CPB, with intermittent doses of phenylephrine or metaraminol if necessary and post CPB above 60 mm Hg with inotropes or vasopressors, according to the anaesthetist's discretion and the patient's requirements. Alpha-stat acid base management (i.e. no temperature correction) was used throughout. At the end of CPB, heparin was reversed with protamine given in a ratio of 1:1.
Patients were admitted to the cardiac intensive care unit after the procedure. Postoperative care followed standard protocols for extubation, ward transfer, mobilization, and discharge home. All data were collected prospectively for each patient. All patients underwent clinical and neurological assessment before operation and daily after operation until discharge.
Blood sampling
Blood samples (6–8 ml) were collected for IL-18 and SC5b9 at the following time points: induction of anaesthesia (baseline), 24, 48, 72, 96, 120 h post-CPB, and 6 weeks after operation. Blood samples were also collected for serum Troponin T levels before induction (baseline), at 24 and 48 h after operation. These blood samples were collected via existing arterial or venous cannulae or by venepuncture. IL-18 and SC5b-9 samples were immediately centrifuged at 2500 rpm for 15 min. Serum was separated and stored at –80°C until assayed. Samples were assayed in two batches, each consisting of complete patient sets. Each batch of samples was assayed by a single investigator in a single analytical run to obviate inter-assay variability. Blood was also obtained to assess renal function, liver function, and full blood count at the following time points: before operation, 24, 48, 72, 96 and 120 h post-CPB.
IL-18 assay
IL-18 was assayed using a quantitative human ELISA kit (Medical & Biological Laboratories Co., Ltd, Woburn, MA, USA) based on the principle of sandwich ELISA. The assay uses two monoclonal antibodies against two different epitopes of human IL-18. The concentration of human IL-18 was calibrated from a dose–response curve based on reference standards. The minimum concentration of IL-18 detected by the assay was 12.5 pg ml–1. The intra-coefficient of variation of the assay was <10% and the inter-coefficient of variation was <15%.
SC5b-9 assay
The enzyme immunoassay (Quidel Corp, San Diego, CA, USA) for the quantitation of SC5b-9 in human serum, plasma, or experimental samples is a three-step procedure utilizing a microassay plate coated with a mouse monoclonal antibody that binds specifically to SC5b-9. The standard control and test specimen absorbances are measured spectrophotometrically. The minimum concentration of serum SC5b-9 detected by the assay was 7.9 ng ml–1. Intra- and inter-assay coefficients of variation were <11%.
Neuropsychometric assessment
A battery of nine neuropsychometric tests were used to assess patients before operation, at day 5, and 6 weeks after operation. A qualified and trained examiner carried out the tests in a standardized method, in the same order. The battery included the core tests according to the recommendations of the ‘Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery’.16 The complete battery consists of: Rey auditory verbal learning test, part A of the trail making test, part B of the trail making test, digit symbol substitution test, digit span forward test, digit span backward test, grooved Pegboard test using dominant hand, grooved Pegboard test using non-dominant hand, and controlled oral word association test. The National Adult Reading Test (NART)17 was used to estimate pre-morbid full-scale intelligence quotient (IQ).
Statistical analysis
Data were entered onto an Excel spreadsheet and statistical analysis was performed using SPSS software (version 11.0, SPSS Inc., Chicago, IL, USA). Patient characteristics and clinical data are expressed as median [IQR] and percentages. Serum IL-18 and SC5b-9 concentrations are expressed as median [range]. The difference between maximum increase in IL-18 and SC5b-9 concentrations in patients with and without neurocognitive dysfunction was analysed by using Mann–Whitney U-test. Logistic regression was applied in order to assess whether peak differences of IL-18 and SC5b-9 had an effect on neurocognitive outcome. The dependent variable was the number of patients demonstrating neurocognitive dysfunction from the results of their neuropsychometric tests, and the independent variable was the peak difference of IL-18 or SC5b-9 concentration calculated from the peak and baseline values. P < 0.05 was taken as significant.
The definition of neurocognitive dysfunction used was based on the previous work carried out by our group.18 This previous study, looking at neurocognitive impairment after on-pump vs off-pump CABG, utilized the same battery of neuropsychometric tests. A patient was said to have had a major deterioration in an individual test (i.e. one of the nine tests if the score deteriorated by 1 SD of the baseline score for all patients). Neurocognitive dysfunction was defined as a major deterioration in two or more tests out of the nine tests.
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Results |
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Patient characteristics, operative, and clinical data for patients with and without neurocognitive dysfunction are shown in Tables 1 and 2. The mean (SD) NART for the study group was 117.03 (7.63) for predicted full-scale (IQ). Serum IL-18 and SC5b-9 concentrations are shown in Table 3. Maximum change in serum IL-18 concentration from baseline was significantly different between patients with and without dysfunction (P = 0.018). Median time to peak IL-18 concentration was 96 h; however, it was only possible to collect IL-18 samples from 22 of the 30 patients at this time point and consequently their peak serum concentration may have been missed. Maximum change in serum SC5b-9 concentration from baseline was not significantly different between patients with and without the dysfunction (P > 0.05).
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Eight out of 30 patients had type II neurocognitive dysfunction at 120 h. No patient had type I neurocognitive dysfunction. The medians and ranges of IL-18 and SC5b-9 for patients showing dysfunction and no dysfunction between baseline and at 6 weeks are shown in Tables 3 and 4. There was no relationship between serum SC5b-9 concentrations, whether the patient had dysfunction or not.
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Logistic regression revealed that neurocognitive dysfunction at 120 h was significantly dependent on peak difference in serum IL-18 concentration (P = 0.033). There was no relationship between peak difference in SC5b-9 concentration at 120 h and neurocognitive dysfunction (P = 0.16). Number of patients with neurocognitive dysfunction at 6 weeks was low in the patient group studied. Neurocognitive dysfunction persisted in only two patients at 6 weeks, with one additional patient having neurocognitive dysfunction at this time, and there was no relationship to the peak difference in IL-18 or SC5b-9 at 6 weeks (P-values 0.29 and 0.42, respectively). The probabilities of neurocognitive dysfunction at 120 h after operation predicted from peak difference in IL-18 and SC5b-9 concentrations, calculated by logistic regression are shown in Figures 1 and 2, respectively.
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Troponin T was measured in all patients at baseline and at 24 and 48 h in an attempt to exclude myocardial damage as a possible source of IL-18 after CPB. The threshold level of Troponin T for diagnosis of myocardial damage was 0.10 ng ml–1. Hepatic and renal functions were monitored in all patients until discharge. No patient had impaired liver function after operation. Only one patient developed acute renal failure in the postoperative period that required renal support using continuous veno-venous haemofiltration. This patient had a significant neurocognitive dysfunction on day 5. The most common postoperative complication was atrial fibrillation seen in 75% of patients with neurocognitive dysfunction as against 13% of patients without neurocognitive dysfunction.
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Discussion |
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This study demonstrates a significant relationship between the peak difference in IL-18 concentration measured over a 5-day period and neurocognitive dysfunction after CPB as assessed by neuropsychometric testing on day 5. Only 3 out of 30 patients (10%) had neurocognitive dysfunction at 6 weeks. Consequently, any relationship between IL-18 levels and neurocognitive dysfunction at 6 weeks could not be meaningfully explored. No significant relationship was found between peak difference in serum SC5b-9 concentration and neurocognitive dysfunction at day 5. The clinical implication of our study is the possibility of using IL-18 as a biochemical marker in the postoperative period to predict neurocognitive dysfunction after CPB. This is important, as early postoperative cognitive dysfunction has been shown to correlate with long-term cognitive deterioration both at 1 and 5 years.2 19
We were unable to demonstrate any relationship between neurocognitive dysfunction and SC5b-9 levels. Significant increase in SC5b-9 concentration has been reported after CPB with non-heparin-coated circuit.20 Though this study showed reduced release of SC5b-9 and preserved neuropsychological function with heparin-coated circuits compared with non-heparin coated, there was no statistically significant difference in the z scores for various cognitive domains between the groups. Perhaps, it is not surprising that we failed to demonstrate a relationship between SC5b-9 and neurocognitive dysfunction. SC5b-9 may not be a marker of the more subtle neurocognitive impairment after CPB, in spite of reported elevated concentrations in traumatic brain injury.15
The microglial cells in the central nervous system (CNS) have been shown to express the pro-inflammatory IL-18,21 and recent data suggest that IL-18 might be a key player in neuroinflammation and neurodegeneration.22 Binding of IL-18 to T lymphocytes, NK cells, macrophages, and neutrophils generate a Th1 or Th2 response. This promotes secretion of TNF-
, IL-1ß, IL-8 and, finally, induction of Interferon-
from T, B, and NK cells. IL-18 has an important dual role in determining the nature of the initial immune response by determining the nature of the cells and recruiting them to bring about a pro or anti-inflammatory response.23 The aetiology of CNS injury after cardiac surgery is multifactorial. It has been suggested that the profound systemic inflammatory response associated with CPB might be a contributory factor towards neurocognitive injury, rather than a causal one.24 The findings of our study raise the interesting question as to whether IL-18 is a marker or a causal agent in neurocognitive dysfunction after CPB.
One criticism of our study could be that we have used a marker that is potentially released from a number of other sources or as a part of an ongoing generalized inflammatory response to CPB. Plasma concentration of IL-18 has been reported to be elevated in patients with acute myocardial infarction.25 We attempted to address this possible source of IL-18 by measuring postoperative Troponin T that was not significantly different at 24 h between the group of patients with neurocognitive dysfunction and without neurocognitive dysfunction. The patients in our study did not demonstrate evidence to a generalized inflammatory response in the form of other organ dysfunction such as respiratory, hepatic, or gastrointestinal. An elevated urinary IL-18 concentration is reported to be an early predicator of acute renal failure after CPB.26 This raises the possibility that the data from one patient in our study who had neurocognitive dysfunction at postoperative day 5 and acute renal failure could be misleading.
Our study population consisted of patients for CABG (80%) and intracardiac procedures (20%) such as valve replacement and ASD repair. It has been shown that release of the serum marker, S-100ß, is more pronounced with intracardiac procedures;27 however, none of the patients having intracardiac procedures in our study developed adverse neurological outcome. The fact that the patients in our study were operated on by more than one surgeon, and the lack of assessment of the severity of aortic atherosclerosis is perhaps further limitation in the current study. Our findings of increased incidence rate of diabetes, pre- and postoperative atrial fibrillation and increased requirement for vasopressors or inotropes in patients with neurocognitive dysfunction are in agreement with the reported risk factors for adverse neurological outcome after CPB.28
If IL-18 does have a role in initiating the inflammatory cascade,29 then inhibition of IL-18 may abolish its deleterious effects and suggests the possibility of immunomodulation to improve patient outcome. Immunomodulation of IL-18 has already been demonstrated successfully in reducing myocardial dysfunction in vitro9 and in murine models of closed head injury.30 Our results suggest a potential role for IL-18 as a serum marker for predicting neurocognitive dysfunction after CPB. These are preliminary findings and need further exploration in larger studies.
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