Despite the declining incidence of complications following cardiac surgery, the reported incidence of postoperative cognitive decline (POCD) has remained largely unchanged, occurring in 30 to 65% of patients at hospital discharge.1–3 The incidence of POCD varies widely across different studies, depending on the criteria used to define POCD, the evaluation methods, the assessment time, the type of surgery and the patient characteristics. Because POCD signs are often subtle, a highly sensitive neuropsychological test battery must be used to detect POCD.4,5 POCD predominantly manifests as memory decline, decreased attention and decreased psychomotor speed.6 The occurrence of POCD is associated with increased mortality, reduced quality of life, early withdrawal from the workforce and significantly increased use of healthcare resources.7
POCD after cardiac surgery has been attributed to systemic inflammatory responses induced by the surgery itself and by the use of cardiopulmonary bypass (CPB). The latter causes disruption of the blood–brain barrier (BBB) and cerebral inflammation.1,5 The widespread inflammatory response to CPB is thought to be caused by several factors: by the activation of the immune system following contact between blood and the artificial materials of the bypass circuit, by ischaemia-reperfusion injury, or by complement activation following CPB.8 Contrary to the findings of Bruins et al., other studies found that postoperative circulating levels of inflammatory markers were similar regardless of the use of CPB during surgery.1,9 One proposed alternative explanation is that cerebral microemboli originating during CPB are responsible for POCD. However, several randomised studies were unable to identify any beneficial effect on cognitive function of avoiding CPB.10–12
If inflammation plays a role in the pathogenesis of POCD, suppression of the inflammatory response by corticosteroids might reduce the incidence or severity of POCD. Dexamethasone is a potent synthetic glucocorticoid with a long duration of action.13
C-reactive protein (CRP) is an acute-phase reactant and a well-recognised marker of systemic inflammation. Santonocito et al.14 have shown that the serum CRP increase within a few hours after surgery and remains increased until the third postoperative day when, in the absence of other inflammation, it begins to decrease towards the preoperative levels.
The S100β protein is expressed by astrocytes in the brain and does not reach the peripheral circulation of healthy individuals. S100β protein is a marker of BBB disruption and brain injury.15 It was shown that the S100β concentration was elevated for an extended duration after CPB (on-pump) relative to that observed after beating-heart (off-pump) surgery.16 However, the correlation between postoperative S100β levels and POCD remains uncertain.16–19
The aim of the current study was to assess the effects of preoperative dexamethasone on cognitive outcomes on the 6th day after surgery and also on the inflammatory response in patients who had undergone cardiac surgery. We hypothesised that the incidence of early POCD and the magnitude of the inflammatory response would be reduced in patients who received dexamethasone compared with those who received placebo.
Study design and participants
The current randomised, double-blind, placebo-controlled, parallel-arm trial was performed at the University Hospital of Split, Croatia between March 2015 and January 2016. Ethical approval for this study (Ethical Committee No. 2181-147-01/06/J.B.-16-2) was provided by the Ethical Committee of the University Hospital of Split (Chairperson Prof J. Bagatin) on 10 March 2015. All patients provided written informed consent.
The study enrolled patients aged between 41 and 84 years who were scheduled for elective coronary artery bypass graft surgery (CABG), heart valve surgery or combined surgery (CABG and valve surgery) with or without CPB. Exclusion criteria were any cerebrovascular incident in the last 3 years; mental illness; visual, hearing or motor impairment interfering with cognitive assessment; previous cardiac or carotid surgery; left ventricular ejection fraction of less than 35%; adrenal gland disease requiring steroid treatment for longer than 7 days in the past year; alcohol (>50 g day−1 or >500 g week−1) or controlled substance abuse; a preoperative Mini Mental State Examination (MMSE) score less than 26 points; a preoperative Beck Depression Inventory-Second Edition (BDI-II) score more than 19 points; a preoperative CRP level more than5 mg l−1; a preoperative white blood cell (WBC) count less than 4 or more than10 × 109 l−1; perioperative stroke and additional corticosteroid treatment throughout the study period. Stroke was defined as focal brain injury as detected via standard neurological examination and signs of new ischaemia-induced cerebral infarction on a computed tomography scan.20
Randomisation and masking
A random sequence generator was used to determine patient allocation. Patients were randomised (1 : 1) to receive a single intravenous bolus of 0.1 mg kg−1 dexamethasone or the same volume of placebo (0.9% NaCl) 10 h before surgery. The injections were performed by the attending anaesthesiologist. The pharmacy of the University Hospital of Split prepared the trial medication in computer-randomised blocks of five indistinguishable, sequentially numbered vials containing either a clear solution of dexamethasone (4 mg ml−1) or 0.9% NaCl. The patients, their treating physicians, the biochemists and the investigators were blind to the treatment allocation.
Surgery and anaesthesia
For all patients, the procedure began at 08:00. Anaesthesia was induced and subsequently maintained with fentanyl, midazolam, vecuronium and sevoflurane. The depth of anaesthesia was titrated to achieve a bispectral index (Aspect Medical Systems Inc., Newton, Massachusetts, USA) between 40 and 55. Surgical access to the heart was achieved via a median sternotomy. Heparin (1.5 mg kg−1) was administered prior to cannulation to achieve an activated clotting time greater than 280 s, and the effect of heparin was reversed with an equivalent dose of protamine sulphate at the time of decannulation. Myocardial protection was induced with cardioplegia via antegrade removal and retrograde reinfusion of cold blood (4 : 1 blood-crystalloid ratio) (Bichsel AG, Interlaken, Switzerland). CPB was performed using a non-pulsatile roller pump (Terumo Europe N.V., Eschborn, Germany) equipped with microporous membrane oxygenators containing integrated 40-μM arterial line filters and heparin-coated circuits (Carmeda; Medtronic Inc., Minneapolis, Minnesota, USA). During CPB, the alpha-stat technique was used along with maintenance of normothermia (35.5 to 36.5 °C) or spontaneous hypothermia (as low as 32 °C). A constant perfusion flow rate of 2.4 l min−1 m−2 was used. In patients undergoing surgery without CPB, distal anastomoses were performed with the help of an Octopus tissue stabiliser (Medtronic Inc.). Proximal anastomoses were fashioned onto the aorta by means of a single side-clamp. During beating-heart surgery, the same principles of heparinisation and neutralisation were used. An oesophageal probe and a forced warm air blanket were used to maintain the core temperature near normothermia (36 to 37 °C).
According to the Statement of Consensus on the Assessment of Neurobehavioral Outcomes after Cardiac Surgery,21 the investigators used a validated battery of five neuropsychological tests which included eight main variables to assess global cognitive status, short-term and intermediate-term memory, attention, concentration and psychomotor skills. The evaluation was based on the following tests: MMSE, Rey Auditory Verbal Learning Test, Wechsler Memory Scale and its three subscales (Visual Memory Span, Digit Span Forward, Digit Span Backward), Symbol Digit Modalities Test (SDMT)22 and computerised PsychE (simple reaction time) test.23 Alternative forms of all applied tests were used to reduce learning effects across sessions (refer to Table, Supplemental Digital Content 1, http://links.lww.com/EJA/A121, for an explanation of the different tests and the cognitive domains examined). Two days before the surgical procedure, neuropsychological tests and the BDI-II test22 were conducted to assess the participants. Neuropsychological tests were repeated on the 6th day after the surgical procedure when the patients were free of sedative and narcotic medications and chest drains and were able to walk and sit in a chair. A battery of tests requiring approximately 40 min was administered by a trained neuropsychologist from the University Hospital of Split in a standardised fashion at the same time of the day (10:00) and in the same silent room of the cardiac surgery ward.
Primary outcome measure
The primary endpoint of this analysis was the incidence of POCD on the 6th day after surgery. In our study, we used the same procedure as described by Ottens et al.24 to enable comparisons of the research findings between studies. We calculated the Jacobson and Truax Reliable Change Index (RCI) for each patient in the dexamethasone and placebo groups. The RCI is the sum of the Z-scores for the eight main variables. A greater RCI indicates higher cognitive test performance. POCD in an individual is defined as an RCI equal to or less than −1.96 on at least one test.25
Secondary outcome measures
The incidence of systemic inflammatory response syndrome (SIRS) was determined in both groups. SIRS is defined as the occurrence of any two of the following four criteria during the first 48 h after surgery: body temperature above 38 °C or below 36 °C, heart rate greater than 90 bpm, respiratory rate greater than 20 bpm or arterial carbon dioxide tension below 4.26 kPa (32 mmHg), and WBC count above 12 or below 4 × 109 l−1.26,27
CRP levels in the dexamethasone and placebo groups were determined at 12 h after surgery and on the 1st, 2nd and 3rd postoperative days (at 08:00). Serum CRP concentrations were assessed using the turbidimetry method (Architect ci16200; Abbott GmbH Diagnostics, Wiesbaden, Germany).
S100β protein levels were determined 6 and 30 h following the end of CPB or 3 h following the end of beating-heart surgery. Serum S100β levels were assessed using an electrochemiluminescence ‘sandwich’ immunoassay method (Cobas e601; Roche Diagnostics GmbH, Mannheim, Germany). The detection limit of this assay is 0.02 μg l−1. An S100β concentration higher than 0.12 μg l−1 was considered to be pathologically elevated.28
Data analysis was performed using IBM SPSS Statistics, version 24.0 (IBM Corp., Armonk, New York, USA). Analyses were conducted to compare the results between randomised groups over time. Categorical variables were expressed as numbers and (percentages). A chi-square test was used to determine the relationship between two categorical variables. Continuous variables were expressed as the means ± SD or medians and inter-quartile range, and the independent-samples t test or analysis of variance was used to evaluate statistical significance. We calculated the relative risk (RR) with 95% confidence intervals (CIs) and determined the differences among groups using the chi-square test. Subgroup analysis for the primary outcome measure was performed according to age group (two groups; cut-off value based on the mean age of the study population), surgical technique (with or without CPB), CPB duration (cut-off value based on the mean CPB duration in the study population), type of surgery (CABG versus other) and duration of mechanical ventilation during ICU stay (cut-off value based on the mean duration of mechanical ventilation in the study population) using Forest plot version 1.5.1 from the Rmeta package within RStudio (RStudio Inc., Boston, MA, USA). A significance level of 95% (P < 0.05) was applied.
We expected a difference in the incidence of POCD between the placebo (on-pump and off-pump) and dexamethasone (on-pump and off-pump) groups. We calculated the required sample size using the Pwr package within RStudio with input parameters for a 2 × 4 chi-square test with 3 degrees of freedom. We expected a moderate effect size and therefore set the value to 0.3. According to an effect size (w) of 0.3, an α of 0.05 and a power (1 − β) of 0.90, we required a total sample size (n) of 157 patients. Considering an estimated attrition rate of less than 5% at the time of hospital discharge,2 the final sample size was increased to a total of 169 patients.
Between March 2015 and January 2016, 169 patients were recruited. The Consort flow diagram for the patients through the study is shown in Fig. 1. Three patients in the dexamethasone group and two patients in the placebo group died in the early postoperative period. Two patients in the dexamethasone group and one patient in the placebo group experienced a stroke during the perioperative period. Ultimately, we analysed the data on 161 patients. The baseline demographic, clinical, surgical and postoperative characteristics of the patients are presented in Table 1.
On the 6th postoperative day, nine of the 80 (11.3%) patients in the dexamethasone group and 21 of the 81 (25.9%) patients in the placebo group fulfilled the diagnostic criteria for POCD. This difference in the incidence of POCD between groups was statistically significant (RR, 0.43; 95% CI, 0.21 to 0.89; P = 0.02). The patient scores on the different tests are presented in Table 2. Analysis of the neuropsychological test battery results showed statistically significant differences in the MMSE score, SDMT results and simple reaction time between the dexamethasone and placebo groups. On the 6th postoperative day, the RCI was 0.85 ± 1.5 in the dexamethasone group and 0.25 ± 1.0 in the placebo group (P = 0.01).
Figure 2 shows the results of the preplanned subgroup analyses of cognitive outcome. A differential effect of dexamethasone on the incidence of POCD on the 6th postoperative day was observed in two subgroups. Older age and a shorter duration of mechanical ventilation in the ICU were associated with a significantly reduced incidence of POCD in the dexamethasone group compared with the placebo group.
Twenty four of the 80 (30.0%) patients in the dexamethasone group and 47 of the 81 (58.0%) patients in the placebo group fulfilled the diagnostic criteria for SIRS (P < 0.001). Beating-heart surgery was associated with a slightly, but insignificantly, lower incidence of SIRS in both groups. Fifteen of the 42 (35.7%) patients in the dexamethasone on-pump group compared with nine of the 38 (23.7%) patients in the dexamethasone off-pump group developed SIRS (P = 0.24), whereas 22 of the 37 (59.5%) patients in the placebo on-pump group compared with 25 of the 44 (56.8%) patients in the placebo off-pump group developed SIRS (P = 0.81).
CRP levels prior to surgery were 1.9 ± 1.3 mg l−1 in the dexamethasone group and 1.7 ± 1.2 mg l−1 in the placebo group. Postoperative CRP levels are presented in Table 3. Patients who received dexamethasone had significantly lower CRP levels at all time points (P < 0.001). The differences in the postoperative levels of CRP between groups were not associated with the use of CPB.
The postoperative levels of S100β are presented in Table 3. At all time points, the S100β levels were in the pathologically elevated range (>0.12 μg l−1). The patients in the dexamethasone group had slightly lower S100β levels than those in the placebo group but these differences were not statistically significant: 6 h after on-pump surgery, P = 0.56; 30 h after on-pump surgery, P = 0.56; 3 h after off-pump surgery, P = 0.17. We noted a twofold decrease in S100β level from 6 h after CPB to 30 h after CPB. We did not find any correlation between S100β concentration and the incidence of POCD.
The current randomised trial including 169 cardiac surgery patients found a beneficial effect from the preoperative administration of dexamethasone on the incidence of early POCD compared with placebo treatment. In addition, this trial showed a significantly lower incidence of SIRS and postoperative CRP levels in the dexamethasone group than in the placebo group. To our knowledge, this is the second randomised trial to test, and the first to confirm, the hypothesis that suppressing the perioperative inflammatory response by using dexamethasone in cardiac surgical patients may improve postoperative cognitive outcome.
In recent years, several studies have investigated the effects of steroids on mortality and major adverse events following cardiac surgery. In the SIRS trial, cumulative doses of 500 mg of methylprednisolone were given intraoperatively (250 mg at the induction of anaesthesia and 250 mg at the initiation of CPB),29 whereas in the DECS trial only a single intraoperative (after the induction of anaesthesia) dose (1 mg kg−1) of dexamethasone was administered.30 Both studies failed to show any beneficial effect of steroids on most of the studied outcomes. Furthermore, the study by Ottens et al.24 found no beneficial effect of the intraoperative administration of high-dose dexamethasone (1 mg kg−1) on the incidence of POCD at either 1 month or 12 months after cardiac surgery. Contrary to Ottens et al. our study noted a beneficial effect after dexamethasone but, since we only examined early POCD, direct comparison of results is not possible. In addition, the cause of cognitive decline observed at a 12-month follow-up might include not only the effects of the surgery but also the effects of natural aging31 or the progression of cardiovascular disease or cerebrovascular disease, or the development of dementia.5,6 Significantly, other studies did not monitor the effects of corticosteroids on any inflammation-related laboratory parameters.24,29,30 A possible explanation for the discrepancy between the results of the previous studies and those of our study could be related to the different types and doses of steroids as well as the different modes of administration. We selected dexamethasone as it is a potent synthetic glucocorticoid with a long duration of action (biological half-life is 36 to 54 h).13 On the other hand, Whitlock et al.29 used methylprednisolone which is short-acting with low anti-inflammatory activity. Next, we administered only small doses of steroids (i.e. 0.1 mg kg−1) because high concentrations of glucocorticoids can be toxic to neural structures, especially the glucocorticoid receptor-rich hippocampus.32 Finally, we administered dexamethasone 10 h before surgery so that the anti-inflammatory effect of the steroid was expressed by the time of surgery and present throughout the early perioperative period.
The current study found a statistically significant difference between the dexamethasone and placebo groups in the incidence of POCD on the 6th postoperative day. In the current study, the incidence of POCD was lower than that observed in several other studies with similar designs.2,3 However, we excluded patients at high risk of POCD to show, as precisely as possible, the actual effects of steroids. Furthermore, we applied a strict definition of POCD (an individual RCI equal to or less than −1.96 on at least one test), whereas a similar study defined POCD more liberally (a decline of only 1 SD in performance on at least one of the applied tests).2 Analysis of our neuropsychological test battery results showed significant differences in the MMSE score, SDMT result and simple reaction time between the dexamethasone and placebo groups. Other tests did not show significant differences between groups, although the dexamethasone group showed better performance on all applied tests. The MMSE scores of the dexamethasone group indicate preservation of global cognitive status after surgery. The SDMT results and simple reaction time of the dexamethasone group suggest favourable influences of dexamethasone on the domains of psychomotor speed and information processing speed.
We also showed a beneficial effect of dexamethasone against the systemic inflammatory response induced by surgery. Piccoli et al.33 found significantly elevated CRP levels early after cardiac surgery in patients without clinical or laboratory signs of acute infection, suggesting that the systemic inflammatory response modulates CRP level. Considering the pharmacokinetics of CRP and the likelihood of perioperative infection,14 we analysed CRP levels at 12 h after surgery and on the 1st, 2nd and 3rd postoperative days. Since the SIRS criteria were evaluated within the first 48 h after the procedure this study analysed the data for the period that includes the anti-inflammatory effect of the corticosteroid. We showed that patients who received dexamethasone had a significantly lower SIRS incidence and CRP levels in the early postoperative period. Similar to the results of several other recent studies, we found no evident relationship among CPB, the systemic inflammatory response and POCD.1,9,11,12
S100β is normally present at low or undetectable levels in serum; thus, the preoperative S100β level was not determined in this study.15,16 In all measurements, the levels of S100β, a marker of BBB disruption and brain injury, were in the range considered to be pathologically elevated. Moreover, in all measurements, the S100β levels in the dexamethasone group were lower, although insignificantly so, suggesting less neuronal damage, than in the placebo group. Nevertheless, similar to two other studies,16,18 the current study did not reveal a precise relationship between elevated S100β level and cognitive decline. In contrast, two other studies did find such a correlation.17,19 This discrepancy is most likely due to methodological differences among studies in the timing of S100β sampling and neuropsychological test administration. These findings indicate the need for further studies on the relationship between S100β release and postoperative cerebral injury.
A strength of the current study is that no patients refused to participate on the 6th postoperative day and only eight patients (less than 5%) were lost to follow-up, a very satisfactory result that is comparable with the results of other studies reporting on cognitive outcomes after cardiac surgery.2,3
The current study has several limitations. This study evaluated the effects of dexamethasone only on early cognitive decline after cardiac surgery as this is a likely a harbinger of subsequent cognitive impairment.2 The incidence of POCD on the 6th postoperative day was lower than anticipated but the incidence of POCD varies widely across different studies because of inconsistent definitions of POCD and different methodology.1,4,5 Some might see the lack of a non-surgical control group in the current study as limitation, but the inclusion of a non-surgical control group may not be appropriate in light of the complicated physiological processes attributed to surgery and CPB.34 The definition of SIRS is not ideal for use with cardiac surgery patients; however, it is the only definition used in similar studies.27,35 Finally, differences in baseline demographics, and clinical and surgical characteristics between groups, represent another possible limitation of this study.
In conclusion, in this randomised clinical trial, including 169 cardiac surgical patients, the inflammatory response and the risk of early POCD were reduced by preoperative administration of dexamethasone. Therefore, we believe that the results of our study may prompt further research regarding the use of dexamethasone preceding surgery in patients who are scheduled to undergo elective cardiac surgical procedures.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: this study was supported by the Clinical Department of Anaesthesiology and Intensive Care, University Hospital of Split, Split, Croatia.
Conflicts of interest: none.
Presentation: preliminary data for this study were accepted as an oral presentation in the Best Abstract Prize Competition (BAPC) at the European Society of Anaesthesiology (ESA) Euroanaesthesia, 3 to 5 June 2017, Geneva.
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