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Adults undergoing cardiac surgery with cardiopulmonary bypass received either an intravenous balanced mixture of amino acids or placebo for up to 3 days. Amino acids reduced the occurrence of acute kidney injury.

Cardiopulmonary bypass initiates a systemic inflammatory response syndrome that is associated with postoperative morbidity and mortality. Steroids suppress inflammatory responses and might improve outcomes in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. We aimed to assess the effects of steroids in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. The Steroids In caRdiac Surgery (SIRS) study is a double-blind, randomised, controlled trial. We used a central computerised phone or interactive web system to randomly assign (1:1) patients at high risk of morbidity and mortality from 80 hospital or cardiac surgery centres in 18 countries undergoing cardiac surgery with the use of cardiopulmonary bypass to receive either methylprednisolone (250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients were assigned with block randomisation with random block sizes of 2, 4, or 6 and stratified by centre. Patients aged 18 years or older were eligible if they had a European System for Cardiac Operative Risk Evaluation of at least 6. Patients were excluded if they were taking or expected to receive systemic steroids in the immediate postoperative period or had a history of bacterial or fungal infection in the preceding 30 days. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcomes were 30-day mortality and a composite of death and major morbidity (ie, myocardial injury, stroke, renal failure, or respiratory failure) within 30 days, both analysed by intention to treat. Safety outcomes were also analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00427388. Patients were recruited between June 21, 2007, and Dec 19, 2013. Complete 30-day data was available for all 7507 patients randomly assigned to methylprednisolone (n=3755) and to placebo (n=3752). Methylprednisolone, compared with placebo, did not reduce the risk of death at 30 days (154 [4%] vs 177 [5%] patients; relative risk [RR] 0·87, 95% CI 0·70–1·07, p=0·19) or the risk of death or major morbidity (909 [24%] vs 885 [24%]; RR 1·03, 95% CI 0·95–1·11, p=0·52). The most common safety outcomes in the methylprednisolone and placebo group were infection (465 [12%] vs 493 [13%]), surgical site infection (151 [4%] vs 151 [4%]), and delirium (295 [8%] vs 289 [8%]). Methylprednisolone did not have a significant effect on mortality or major morbidity after cardiac surgery with cardiopulmonary bypass. The SIRS trial does not support the routine use of methylprednisolone for patients undergoing cardiopulmonary bypass. Canadian Institutes of Health Research.

Background Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery. Methods We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care ( n  = 15) or CytoSorb® HA ( n  = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors’ activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII). Results Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors’ adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes. Conclusions CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts. Trial registration ClinicalTrials.gov NCT02775123 . Registered 17 May 2016.

Background Cardiopulmonary bypass (CPB) triggers marked cytokine release often followed by a systemic inflammatory response syndrome, associated with adverse postoperative outcomes. This trial investigates the intraoperative use of haemoadsorption (HA) during cardiac surgery with CPB to assess its impact on postoperative systemic inflammatory response. Methods In this prospective randomised controlled trial (ethics approval no. 5094-14DRKS00007928), patients (> 65 years) undergoing elective on-pump cardiac surgery were randomised to intraoperative HA (CytoSorb) during CPB or standard care without HA. Primary outcome was the difference in mean interleukin (IL)-6 serum concentrations between groups on intensive care unit (ICU) admission. The secondary outcomes included various clinical and biochemical endpoints. Statistical methods included paired and unpaired t-tests, Wilcoxon, Mann–Whitney U-tests, and chi-square tests. Results Thirty-eight patients were allocated to receive either intraoperative HA (n = 19) or standard care (n = 19). The primary outcome, IL-6 levels on ICU admission, did not differ between the study group and controls (214.4 ± 328.8 vs. 155.8 ± 159.6 pg/ml, p  = 0.511). During surgery pre- versus post-adsorber IL-2, IL-6, IL-8, IL-10, heparan sulfate and myoglobin post- levels were reduced. Furthermore, IL-6 levels did not differ between the study groups on day 1 and 2 in the ICU. While sequential organ failure assessment scores, lactate levels, and C-reactive protein and procalcitonin (PCT) showed no statistically significant differences. Regarding haemodynamic stability in the treatment group the cardiac index (3.2 ± 0.7 vs. 2.47 ± 0.47 l/min/m 2 , p  = 0.012) on ICU day 2 increased, and lower fluid requirements as well as decreased fibrinogen requirement were observed. Need for renal replacement therapy did not differ though a shorter duration was observed in the treatment group. Time on ventilator, respiratory parameters, infectious complications, delirium scores, ICU and hospital lengths of stay, and mortality did not differ between groups. Conclusion HA did not reduce the IL-6 level on ICU admission or afterwards. Even though HA reduced cytokine load during cardiac surgery in the treatment group. There were no significant differences between groups in the postoperative course of other cytokine concentrations, organ dysfunction, ICU and hospital lengths of stay and mortality rates. Trial registration prospectively DRKS00007928 and published under: Baumann A, Buchwald D, Annecke T, Hellmich M, Zahn PK, Hohn A. RECCAS - REmoval of Cytokines during Cardiac Surgery: study protocol for a randomised controlled trial. Trials. 2016;17: 137. Graphical abstract

The dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio. We undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: NCT03532594). Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78-1.14] vs. 0.75 [IQR 0.57-0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75-245] vs. 135 [IQR 94-222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160-210] vs. 280 [IQR 250-300] mg; p < 0.001). Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C). Using a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients. ClinicalTrials.gov Unique identifier NCT03532594.

Patients undergoing cardiac surgery often receive red-cell transfusions, along with the associated risks and costs. Early intraoperative normovolemic hemodilution (i.e., acute normovolemic hemodilution [ANH]) is a blood-conservation technique that entails autologous blood collection before initiation of cardiopulmonary bypass and reinfusion of the collected blood after bypass weaning. More data are needed on whether ANH reduces the number of patients receiving allogeneic red-cell transfusion. In a multinational, single-blind trial, we randomly assigned adults from 32 centers and 11 countries who were undergoing cardiac surgery with cardiopulmonary bypass to receive ANH (withdrawal of ≥650 ml of whole blood with crystalloids replacement if needed) or usual care. The primary outcome was the transfusion of at least one unit of allogeneic red cells during the hospital stay. Secondary outcomes were death from any cause within 30 days after surgery or during the hospitalization for surgery, bleeding complications, ischemic complications, and acute kidney injury. A total of 2010 patients underwent randomization; 1010 were assigned to ANH and 1000 to usual care. Among patients with available data, 274 of 1005 (27.3%) in the ANH group and 291 of 997 (29.2%) in the usual-care group received at least one allogeneic red-cell transfusion (relative risk, 0.93; 95% confidence interval, 0.81 to 1.07; P = 0.34). Surgery for postoperative bleeding was performed in 38 of 1004 patients (3.8%) in the ANH group and 26 of 995 patients (2.6%) in the usual-care group. Death within 30 days or during hospitalization occurred in 14 of 1008 patients (1.4%) in the ANH group and 16 of 997 patients (1.6%) in the usual-care group. Safety outcomes were similar in the two groups. Among adults undergoing cardiac surgery, ANH did not reduce the number of patients receiving allogeneic red-cell transfusion. (Funded by the Italian Ministry of Health; ANH ClinicalTrials.gov number, NCT03913481.).

Purpose Cardiopulmonary bypass induces an ischaemia–reperfusion injury and systemic inflammatory response, which contributes to low cardiac output syndrome following cardiac surgery. Exogenous nitric oxide during cardiopulmonary bypass has shown potential to ameliorate such injury. We undertook a large randomised controlled trial to investigate the clinical effects of administering nitric oxide to the cardiopulmonary bypass circuit in children. Methods After written informed consent, children were randomised to receive 20 ppm nitric oxide to the gas inflow of the cardiopulmonary bypass oxygenator, or standard conduct of bypass. Results 101 children received nitric oxide and developed low cardiac output syndrome less frequently (15 vs. 31 %, p  = 0.007) than the 97 children who did not receive nitric oxide. This effect was most marked in children aged less than 6 weeks of age (20 vs. 52 %, p  = 0.012) and in those aged 6 weeks to 2 years (6 vs. 24 %, p  = 0.026), who also had significantly reduced ICU length of stay (43 vs. 84 h, p  = 0.031). Low cardiac output syndrome was less frequent following more complex surgeries if nitric oxide was administered (17 vs. 48 %, p  = 0.018). ECMO was used less often in the nitric oxide group (1 vs. 8 %, p  = 0.014). Conclusions Delivery of nitric oxide to the oxygenator gas flow during paediatric cardiopulmonary bypass reduced the incidence of low cardiac output syndrome by varying degrees, according to age group and surgery complexity. Clinical Trial Registration: ACTRN12615001376538.

Introduction Acute kidney injury (AKI) is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Renal near-infrared spectroscopy (NIRS) is used to evaluate regional oximetry in a non-invasive continuous real-time fashion, and reflects tissue perfusion. The aim of this study was to evaluate the relationship between renal oximetry and development of AKI in the operative and post-operative setting in infants undergoing cardiopulmonary bypass surgery. Methods In this prospective study, we enrolled 59 infants undergoing cardiopulmonary bypass surgery for congenital heart disease for univentricular ( n  = 26) or biventricular ( n  = 33) repair. Renal NIRS was continuously measured intraoperatively and for at least 24 hours postoperatively and analysed for the intraoperative and first 12 hours, first 24 hours and first 48 hours postoperatively. The renal oximetry values were correlated with the paediatric risk, injury, failure, loss, end (pRIFLE) classification for AKI, renal biomarkers and the postoperative course. Results Twenty-eight (48%) infants developed AKI based on pRIFLE classification. Already during intraoperative renal oximetry and further in the first 12 hours, 24 hours and 48 hours postoperatively, significantly lower renal oximetry values in AKI patients compared with patients with normal renal function were recorded ( P  < 0.05). Of the 28 patients who developed AKI, 3 (11%) needed renal replacement therapy and 2 (7%) died. In the non-AKI group, no deaths occurred. Infants with decreased renal oximetry values developed significantly higher lactate levels 24 hours after surgery. Cystatin C was a late parameter of AKI, and neutrophil gelatinase-associated lipocalin values were not correlated with AKI occurrence. Conclusion Our results suggest that prolonged low renal oximetry values during cardiac surgery correlate with the development of AKI and may be superior to conventional biochemical markers. Renal NIRS might be a promising non-invasive tool of multimodal monitoring of kidney function and developing AKI in infants undergoing cardiac surgery with cardiopulmonary bypass.

Whether remote ischaemic preconditioning, an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia, is beneficial for patients undergoing coronary artery bypass graft surgery is unknown. We did a single-blinded randomised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients. 57 adult patients undergoing elective coronary artery bypass graft surgery were randomly assigned to either a remote ischaemic preconditioning group (n=27) or to a control group (n=30) after induction of anaesthesia. Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia, induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg, with an intervening 5 min of reperfusion during which the cuff was deflated. Serum troponin-T concentration was measured before surgery and at 6, 12, 24, 48, and 72 h after surgery. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00397163. Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6, 12, 24, and 48 h after surgery. The total area under the curve was reduced by 43%, from 36·12 μg/L (SD 26·08) in the control group to 20·58 μg/L (9·58) in the remote ischaemic preconditioning group (mean difference 15·55 [SD 5·32]; 95% CI 4·88–26·21; p=0·005). We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning, using transient upper limb ischaemia.

Propofol has been shown to provide protection against renal ischemia/reperfusion injury experimentally, but clinical evidence is lacking. Here we studied the effect of propofol anesthesia on the occurrence of acute kidney injury following heart surgery with cardiopulmonary bypass. One hundred and twelve patients who underwent valvular heart surgery were randomized to receive either propofol or sevoflurane anesthesia, both with sufentanil. Using Acute Kidney Injury Network criteria, significantly fewer patients developed acute kidney injury postoperatively in the propofol group compared with the sevoflurane group (6 compared with 21 patients). The incidence of severe renal dysfunction was significantly higher in the sevoflurane group compared with the propofol group (5 compared with none). The postoperative cystatin C was significantly lower in the propofol group at 24 and 48h. Serum interleukin-6 at 6h after aorta cross-clamp removal, C-reactive protein at postoperative day 1, and segmented neutrophil counts at postoperative day 3 were also significantly lower in the propofol group. Thus, propofol anesthesia significantly reduced the incidence and severity of acute kidney injury in patients undergoing valvular heart surgery with cardiopulmonary bypass compared with sevoflurane. This beneficial effect of propofol may be related to its ability to attenuate the perioperative increase in proinflammatory mediators.