Veerle Verheyden

Predictive models for kidney disease: improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery.

IntroductionAcute kidney injury (AKI) risk prediction scores are an objective and transparent means to enable cohort enrichment in clinical trials or to risk stratify patients preoperatively. Existing scores are limited in that they have been designed to predict only severe, or non-consensus AKI definitions and not less severe stages of AKI, which also have prognostic significance. The aim of this study was to develop and validate novel risk scores that could identify all patients at risk of AKI.MethodsProspective routinely collected clinical data (n = 30,854) were obtained from 3 UK cardiac surgical centres (Bristol, Birmingham and Wolverhampton). AKI was defined as per the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines. The model was developed using the Bristol and Birmingham datasets, and externally validated using the Wolverhampton data. Model discrimination was estimated using the area under the ROC curve (AUC). Model calibration was assessed using the Hosmer–Lemeshow test and calibration plots. Diagnostic utility was also compared to existing scores.ResultsThe risk prediction score for any stage AKI (AUC = 0.74 (95% confidence intervals (CI) 0.72, 0.76)) demonstrated better discrimination compared to the Euroscore and the Cleveland Clinic Score, and equivalent discrimination to the Mehta and Ng scores. The any stage AKI score demonstrated better calibration than the four comparison scores. A stage 3 AKI risk prediction score also demonstrated good discrimination (AUC = 0.78 (95% CI 0.75, 0.80)) as did the four comparison risk scores, but stage 3 AKI scores were less well calibrated.ConclusionsThis is the first risk score that accurately identifies patients at risk of any stage AKI. This score will be useful in the perioperative management of high risk patients as well as in clinical trial design.

Evaluation of multiple electrode aggregometry in whole blood using Multiplate® Mini Test cells

Multiple electrode aggregometry (MEA) enables rapid platelet function testing in whole blood using 600 μL disposable standard test cells (STC). However, newly available 350 μL mini test cells (MTC) could potentially be advantageous in some clinical settings where sample volume is limiting. In order to evaluate the diagnostic performance of MTC, we have estimated assay imprecision, correlation and agreement between area under curve (AUC) determined using MTC and STC in whole blood from healthy donors and from 119 cardiac surgery patients. Imprecision was similar with ADP, AA and TRAP test reagents using STC and MTC, but was markedly higher with the unvalidated ADR reagent. AUC determined using MTC and STC and the ADP, AA and TRAP reagents correlated strongly although MTC yield consistently lower AUC values reflecting fewer platelets in the smaller test cell. Agreement between AUC from STC and MTC was less strong, probably reflecting a composite effect of imprecision from both assay formats. MTC and STC are equally valid for MEA but AUC values obtained using one test format cannot be directly transformed to the other. Therefore, STC and MTC cannot be used interchangeably and AUC results must be compared to separately determined reference intervals.

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI-1 study

AIMS Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. METHODS We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. RESULTS Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, Cmax 189.4 ng ml−1 and t1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. CONCLUSIONS Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.

Trial protocol for a randomised controlled trial of red cell washing for the attenuation of transfusion-associated organ injury in cardiac surgery: the REDWASH trial.

Introduction It has been suggested that removal of proinflammatory substances that accumulate in stored donor red cells by mechanical cell washing may attenuate inflammation and organ injury in transfused cardiac surgery patients. This trial will test the hypotheses that the severity of the postoperative inflammatory response will be less and postoperative recovery faster if patients undergoing cardiac surgery receive washed red cells compared with standard care (unwashed red cells). Methods and analysis Adult (≥16 years) cardiac surgery patients identified at being at increased risk for receiving large volume red cell transfusions at 1 of 3 UK cardiac centres will be randomly allocated in a 1:1 ratio to either red cell washing or standard care. The primary outcome is serum interleukin-8 measured at 5 postsurgery time points up to 96 h. Secondary outcomes will include measures of inflammation, organ injury and volumes of blood transfused and cost-effectiveness. Allocation concealment, internet-based randomisation stratified by operation type and recruiting centre, and blinding of outcome assessors will reduce the risk of bias. The trial will test the superiority of red cell washing versus standard care. A sample size of 170 patients was chosen in order to detect a small-to-moderate target difference, with 80% power and 5% significance (2-tailed). Ethics and dissemination The trial protocol was approved by a UK ethics committee (reference 12/EM/0475). The trial findings will be disseminated in scientific journals and meetings. Trial registration number ISRCTN 27076315.

Near-patient coagulation testing to predict bleeding after cardiac surgery: a cohort study

Essentials Near‐patient testing improves coagulopathy diagnosis in cardiac surgery patients with severe bleeding. We investigated how well pre‐emptive near‐patient testing predicted severe bleeding. Severe bleeding could be predicted using both near‐patient tests and patient clinical characteristics. Near‐patient test results gave little additional predictive value over clinical characteristics alone.

Aprotinin revisited: rebuttal of comments by DeSantis and Lazaridis

Dear Editor, We appreciate the interest that DeSantis and Lazaridis [1] have expressed in our study [2]. We are indeed in agreement that the residual confounding which is introduced by covariate imbalance could have introduced bias into our estimates of the effects of aprotinin withdrawal on clinical outcomes. Although we provide readers with t-tests, we are also in agreement that they are an inappropriate metric of the covariate balance achieved through propensity matching. For this reason, we also present the accepted measure of covariate imbalance as defined by Rosenbaum and Rubin [3], namely standardised differences (standardised percentage bias). In the published manuscript, Fig. 1 and eTable 1 demonstrate that standardised differences were found to be \5 % in the all-patient analysis and \10 % in the high-risk analysis. This is within the accepted threshold for significant imbalance of 10 %. We are therefore confident that our results were not biased by residual confounding within the 24 key patient characteristics for which we matched patients. Of course, this parameter does not apply to the residual confounding which may have been introduced by imbalance in any unmeasured characteristics. However, in eTable 6 we model the effects of a number of potentially confounding unmeasured variables upon our results and demonstrate that they do not alter our conclusions. To clarify our methodology, to account for the intra-group correlation introduced by the propensity matching process, we computed errors which allow for this clustering effect (‘cluster confidence intervals’) for both our logistic regression and Cox regression (time-to-event analyses). We elected not to convert to generalised linear models since they are used to estimate risk differences, not odds ratios, which made it difficult to compare with our previously generated odds ratios and hazard ratios. In summary, our methodology anticipated that bias and confounding may have contributed to our results. Despite appropriate adjustments we demonstrated an increase in bleeding, morbidity and mortality that coincided with the withdrawal of aprotinin. Our results do not demonstrate cause and effect; however this real-world analysis highlights important limitations of the existing evidence relating to the indications for aprotinin in cardiac surgery.

Challenges of recruiting elderly patients undergoing cardiac surgery - our experience of recruiting 2500 participants in just 30 months at a single centre

Background Emergency operations, cancellations, changing operating theatre schedules, day of surgery arrivals and an aging population are all challenges facing the recruitment of cardiac surgery patients into studies. The observational Coagulation and Platelet Function Testing in Cardiac Surgery (COPTIC) study, which required patients to consent to give blood samples at the start and end of surgery, is the largest of its kind and the largest single study conducted at our hospital. We describe our experience of recruitment and retention and share our successful strategy.