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Background It is unclear whether the innate immune response represents a therapeutic target for organ protection strategies in cardiac surgery. Methods A systematic review of trials of interventions targeting the inflammatory response to cardiac surgery reporting treatment effects on both innate immune system cytokines and organ injury was performed. The protocol was registered at the International Prospective Register of Systematic Reviews: CRD42020187239. Searches of the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase were performed. Random-effects meta-analyses were used for the primary analysis. A separate analysis of individual patient data from six studies (n=785) explored sources of heterogeneity for treatment effects on cytokine levels. Results Searches to May 2020 identified 251 trials evaluating 24 interventions with 20 582 participants for inclusion. Most trials had important limitations. Methodological limitations of the included trials and heterogeneity of the treatment effects on cytokine levels between trials limited interpretation. The primary analysis demonstrated inconsistency in the direction of the treatment effects on innate immunity and organ failure or death between interventions. Analyses restricted to important subgroups or trials with fewer limitations showed similar results. Meta-regression, pooling available data from all trials, demonstrated no association between the direction of the treatment effects on inflammatory cytokines and organ injury or death. The analysis of individual patient data demonstrated heterogeneity in the association between the cytokine response and organ injury after cardiac surgery for people >75 yr old and those with some chronic diseases. Conclusions The certainty of the evidence for a causal relationship between innate immune system activation and organ injury after cardiac surgery is low.

Background Patient blood management (PBM) interventions aim to improve clinical outcomes by reducing bleeding and transfusion. We assessed whether existing evidence supports the routine use of combinations of these interventions during and after major surgery. Methods Five systematic reviews and a National Institute of Health and Care Excellence health economic review of trials of common PBM interventions enrolling participants of any age undergoing surgery were updated. The last search was on June 1, 2019. Studies in trauma, burns, gastrointestinal haemorrhage, gynaecology, dentistry, or critical care were excluded. The co-primary outcomes were: risk of receiving red cell transfusion and 30-day or hospital all-cause mortality. Treatment effects were estimated using random-effects models and risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity assessments used I2. Network meta-analyses used a frequentist approach. The protocol was registered prospectively (PROSPERO CRD42018085730). Results Searches identified 393 eligible randomised controlled trials enrolling 54 917 participants. PBM interventions resulted in a reduction in exposure to red cell transfusion (RR=0.60; 95% CI 0.57, 0.63; I2=77%), but had no statistically significant treatment effect on 30-day or hospital mortality (RR=0.93; 95% CI 0.81, 1.07; I2=0%). Treatment effects were consistent across multiple secondary outcomes, sub-groups and sensitivity analyses that considered clinical setting, type of intervention, and trial quality. Network meta-analysis did not demonstrate additive benefits from the use of multiple interventions. No trial demonstrated that PBM was cost-effective. Conclusions In randomised trials, PBM interventions do not have important clinical benefits beyond reducing bleeding and transfusion in people undergoing major surgery.

Treatment guidelines recommend the routine use of point-of-care diagnostic tests for coagulopathy in the management of cardiac surgery patients at risk of severe bleeding despite uncertainty as to their diagnostic accuracy. We performed a systematic review and meta-analysis of studies that evaluated the diagnostic accuracy of viscoelastometry, platelet function tests, and modified thromboelastography (TEG) tests, for coagulopathy in cardiac surgery patients. The reference standard included resternotomy for bleeding, transfusion of non-red cell components, or massive transfusion. We searched MEDLINE, EMBASE, CINAHL, and Clinical Trials.gov, from inception to June 2019. Study quality was assessed using QUADAS-2. Bivariate models were used to estimate summary sensitivity and specificity with (95% confidence intervals). All 29 studies (7440 participants) included in the data synthesis evaluated the tests as predictors of bleeding. No study evaluated their role in the management of bleeding. None was at low risk of bias. Four were judged as low concern regarding applicability. Pooled estimates of diagnostic accuracy were; Viscoelastic tests, 12 studies, sensitivity 0.61 (0.44, 0.76), specificity 0.83 (0.70, 0.91) with significant heterogeneity. Platelet function tests, 12 studies, sensitivity 0.63 (0.53, 0.72), specificity 0.75 (0.64, 0.84) with significant heterogeneity. TEG modification tests, 3 studies, sensitivity 0.80 (0.67, 0.89), specificity 0.76 (0.69, 0.82) with no evidence of heterogeneity. Studies reporting the highest values for sensitivity and specificity had important methodological limitations. In conclusion, we did not demonstrate predictive accuracy for commonly used point-of-care devices for coagulopathic bleeding in cardiac surgery. However, the certainty of the evidence was low.

We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-seven adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI32. The group analysis indicated that protein translation-related pathways were downregulated in 25≤BMI≥32 compared with BMI32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI>32 group and α-ketoglutarate increasing in the BMI

ObjectiveTo identify research priorities that address the needs of people affected by cardiac surgery and those who support and care for them.DesignJames Lind Alliance (JLA) process—two surveys and a consensus workshop guided by an independent JLA adviser.SettingThe UK with international participation.ParticipantsThree stakeholder groups—heart surgery patients, carers and healthcare professionals involved in care delivery.MethodsThe initial survey was set to collect potential research questions in cardiac surgery as identified by stakeholders. Submitted questions were summarised into indicative questions. The existing evidence was searched to verify that these indicative questions had not been answered. In the second survey, stakeholders then voted for their top 10 from the list of unanswered questions. The top voted questions were taken forward for final ranking in a workshop.ResultsIn the initial survey, 629 respondents (28% patients/carers, 62% healthcare professionals) submitted 1082 potential questions. Of these, 797 in-scope questions were summarised into 49 indicative questions and of which 45 had not been answered by existing research. In the second survey, 492 respondents (43% patients/carers, 49% healthcare professionals) cast their votes with the top 12 from each of the three stakeholder groups totalling 21 questions advancing to the final priority setting workshop. The workshop attended by 25 delegates (10 patients/carers and 15 healthcare professionals) agreed on the top 10 research questions including long-term outcomes (quality of life), and aspects from preoperative personalised care (prehabilitation, frailty, comorbidities), intraoperative management (minimally invasive techniques), to prevention and management of postoperative complications (organ injury, atrial fibrillation, infection).ConclusionsThis Priority Setting Partnership (PSP) identified the priorities and unmet needs of patients and clinicians in cardiac surgery. The next step is to disseminate and implement the PSP results to ensure that these priorities shape future research and improve clinical services.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective: To identify and summarise the findings of RCTs evaluating interventions that target the inflammatory response to cardiac surgery and measure both markers of inflammation and clinical outcomes. Secondary objective: To evaluate whether interventions that target different drivers of inflammation during cardiac surgery influence the nature of the inflammatory response or clinical outcomes.

Background Experimental studies suggest that mechanical cell washing to remove pro-inflammatory components that accumulate in the supernatant of stored donor red blood cells (RBCs) might reduce inflammation and organ injury in transfused patients. Methods Cardiac surgery patients at increased risk of large-volume RBC transfusion were eligible. Participants were randomized to receive either mechanically washed allogenic RBCs or standard care RBCs. The primary outcome was serum interleukin-8 measured at baseline and at four postsurgery time points. A mechanism substudy evaluated the effects of washing on stored RBCs in vitro and on markers of platelet, leucocyte, and endothelial activation in trial subjects. Results Sixty adult cardiac surgery patients at three UK cardiac centres were enrolled between September 2013 and March 2015. Subjects received a median of 3.5 (interquartile range 2–5.5) RBC units, stored for a mean of 21 (sd 5.2) days, within 48 h of surgery. Mechanical washing reduced concentrations of RBC-derived microvesicles but increased cell-free haemoglobin concentrations in RBC supernatant relative to standard care RBC supernatant. There was no difference between groups with respect to perioperative serum interleukin-8 values [adjusted mean difference 0.239 (95% confidence intervals −0.231, 0.709), P=0.318] or concentrations of plasma RBC microvesicles, platelet and leucocyte activation, plasma cell-free haemoglobin, endothelial activation, or biomarkers of heart, lung, or kidney injury. Conclusions These results do not support a hypothesis that allogenic red blood cell washing has clinical benefits in cardiac surgery. Clinical trial registration ISRCTN 27076315.

Objectives Extracorporeal membrane oxygenation is a treatment for Persistent Pulmonary Hypertension of the Newborn with high mortality. Hypothesis the extracorporeal membrane oxygenation circuit results in inflammatory responses that mitigate against successful weaning. Design Single-center prospective observational feasibility study. Setting PICU. Patients Twenty-four neonates requiring extracorporeal membrane oxygenation support for Persistent Pulmonary Hypertension of the Newborn. Interventions None. Measurements and main results The reference outcome was death or more than 7 days of extracorporeal membrane oxygenation support. Other outcomes included serial measures of plasma-free hemoglobin and markers of its metabolism, leucocyte, platelet and endothelial activation, and biomarkers of inflammation. Of 24 participants recruited between February 2016 and June 2017, 10 died or required prolonged extracorporeal membrane oxygenation support. These patients were sicker at baseline with higher levels of plasma-free hemoglobin within 12 hours of cannulation (geometric mean ratio, 1.92; 95% CIs, 1.00-3.67; p = 0.050) but not thereafter, versus those requiring less than 7 days extracorporeal membrane oxygenation. Serum haptoglobin concentrations were significantly elevated in both groups. Patients who died or required prolonged extracorporeal membrane oxygenation support demonstrated elevated levels of platelet-leucocyte aggregation, but decreased concentrations of mediators of the inflammatory response: interleukin-8, C-reactive protein, and tumor necrosis factor α. Conclusions Clinical status at baseline and not levels of plasma-free hemoglobin or the systemic inflammatory response may determine the requirement for prolonged extracorporeal membrane oxygenation support in neonates.

Background: In an apparent paradox, morbidity and mortality are lower in obese patients undergoing cardiac surgery, although the nature of this association is unclear. We sought to determine whether the obesity paradox observed in cardiac surgery is attributable to reverse epidemiology, bias, or confounding. Methods: Data from the National Adult Cardiac Surgery registry for all cardiac surgical procedures performed between April 2002 and March 2013 were extracted. A parallel systematic review and meta-analysis (MEDLINE, Embase, SCOPUS, Cochrane Library) through June 2015 were also accomplished. Exposure of interest was body mass index categorized into 6 groups according to the World Health Organization classification. Results: A total of 401 227 adult patients in the cohort study and 557 720 patients in the systematic review were included. A U-shaped association between mortality and body mass index classes was observed in both studies, with lower mortality in overweight (adjusted odds ratio, 0.79; 95% confidence interval, 0.76–0.83) and obese class I and II (odds ratio, 0.81; 95% confidence interval, 0.76–0.86; and odds ratio, 0.83; 95% confidence interval, 0.74–0.94) patients relative to normal-weight patients and increased mortality in underweight individuals (odds ratio, 1.51; 95% confidence interval, 1.41–1.62). In the cohort study, a U-shaped relationship was observed for stroke and low cardiac output syndrome but not for renal replacement therapy or deep sternal wound infection. Counter to the reverse epidemiology hypotheses, the protective effects of obesity were less in patients with severe chronic renal, lung, or cardiac disease and greater in older patients and in those with complications of obesity, including the metabolic syndrome and atherosclerosis. Adjustments for important confounders did not alter our results. Conclusions: Obesity is associated with lower risks after cardiac surgery, with consistent effects noted in multiple analyses attempting to address residual confounding and reverse causation.

The clinical efficacy of organ protection interventions are limited by the redundancy of cellular activation mechanisms. Interventions that target epigenetic mechanisms overcome this by eliciting genome wide changes in transcription and signaling. We aimed to review preclinical studies evaluating the organ protection effects of histone deacetylase inhibitors (HDACi) with a view to informing the design of early phase clinical trials. A systematic literature search was performed. Methodological quality was assessed against prespecified criteria. The primary outcome was mortality, with secondary outcomes assessing mechanisms. Prespecified analyses evaluated the effects of likely moderators on heterogeneity. The analysis included 101 experimental studies in rodents (n = 92) and swine (n = 9), exposed to diverse injuries, including: ischemia (n = 72), infection (n = 7), and trauma (n = 22). There were a total of 448 comparisons due to the evaluation of multiple independent interventions within single studies. Sodium valproate (VPA) was the most commonly evaluated HDACi (50 studies, 203 comparisons). All of the studies were judged to have significant methodological limitations. HDACi reduced mortality in experimental models of organ injury (risk ratio = 0.52, 95% confidence interval 0.40–0.68, p < 0.001) without heterogeneity. HDACi administration resulted in myocardial, brain and kidney protection across diverse species and injuries that was attributable to increases in prosurvival cell signaling, and reductions in inflammation and programmed cell death. Heterogeneity in the analyses of secondary outcomes was explained by differences in species, type of injury, HDACi class (Class I better), drug (trichostatin better), and time of administration (at least 6 hours prior to injury better). These findings highlight a potential novel application for HDACi in clinical settings characterized by acute organ injury.

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link. Objectives: Micro-RNA, small noncoding RNA fragments involved in gene regulation, and microvesicles, membrane-bound particles less than 1 μm known to regulate cellular processes including responses to injury, may serve as disease-specific biomarkers of acute kidney injury. We evaluated the feasibility of measuring these signals as well as other known acute kidney injury biomarkers in a mixed pediatric cardiac surgery population. Design: Single center prospective cohort feasibility study. Setting: PICU. Patients: Twenty-four children (≤ 17 yr) undergoing cardiac surgery with cardiopulmonary bypass without preexisting inflammatory state, acute kidney injury, or extracorporeal life support. Interventions: None. Measurements and Main Results: Acute kidney injury was defined according to modified Kidney Diseases Improving Global Outcomes criteria. Blood and urine samples were collected preoperatively and at 6–12 and 24 hours. Microvesicles derivation was assessed using flow cytometry and NanoSight analysis. Micro-RNAs were isolated from plasma and analyzed by microarray and quantitative real-time polymerase chain reaction. Data completeness for the primary outcomes was 100%. Patients with acute kidney injury (n = 14/24) were younger, underwent longer cardiopulmonary bypass, and required greater inotrope support. Acute kidney injury subjects had different fractional content of platelets and endothelial-derived microvesicles before surgery. Platelets and endothelial microvesicles levels were higher in acute kidney injury patients. A number of micro-RNA species were differentially expressed in acute kidney injury patients. Pathway analysis of candidate target genes in the kidney suggested that the most often affected pathways were phosphatase and tensin homolog and signal transducer and activator of transcription 3 signaling. Conclusions: Microvesicles and micro-RNAs expression patterns in pediatric cardiac surgery patients can be measured in children and potentially serve as tools for stratification of patients at risk of acute kidney injury.

Background and objectives To review preclinical and clinical studies that have evaluated the effects of red cell rejuvenation in vivo and in vitro and to assess the potential risks and benefits from their clinical use. Materials and methods A systematic review and narrative synthesis of the intervention of red cell rejuvenation using a red cell processing solution containing inosine, pyruvate, phosphate and adenine. Outcomes of interest in vitro were changes in red cell characteristics including adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG), deformability and the accumulation of oxidized lipids and other reactive species in the red cell supernatant. Outcomes in vivo were 24-h post-transfusion survival and the effects on oxygen delivery, organ function and inflammation in transfused recipients. Results The literature search identified 49 studies evaluating rejuvenated red cells. In vitro rejuvenation restored cellular properties including 2,3-DPG and ATP to levels similar to freshly donated red cells. In experimental models, in vivo transfusion of rejuvenated red cells improved oxygen delivery and myocardial, renal and pulmonary function when compared to stored red cells. In humans, in vivo 24-h survival of rejuvenated red cells exceeded 75%. In clinical studies, rejuvenated red cells were found to be safe, with no reported adverse effects. In one adult cardiac surgery trial, transfusion of rejuvenated red cells resulted in improved myocardial performance. Conclusion Transfusion of rejuvenated red cells reduces organ injury attributable to the red cell storage lesion without adverse effects in experimental studies in vivo. The clinical benefits of this intervention remain uncertain.

Background We evaluated the effects of two interventions that modify the red cell storage lesion on kidney and lung injury in experimental models of transfusion. Methods White–landrace pigs (n = 32) were allocated to receive sham transfusion (crystalloid), 14-day stored allogeneic red cells, 14-day red cells washed using the red cells washing/salvage system (CATS; Fresenius, Germany), or 14-day red cells rejuvenated using the inosine solution (Rejuvesol solution; Zimmer Biomet, USA) and washed using the CATS device. Functional, biochemical, and histologic markers of organ injury were assessed for up to 24 h posttransfusion. Results Transfusion of 14 day red cells resulted in lung injury (lung injury score vs. sham, mean difference −0.3 (95% CI, −0.6 to −0.1; P = 0.02), pulmonary endothelial dysfunction, and tissue leukocyte sequestration. Mechanical washing reduced red cell–derived microvesicles but increased cell-free hemoglobin in 14-day red cell units. Transfusion of washed red cells reduced leukocyte sequestration but did not reduce the lung injury score (mean difference −0.2; 95% CI, −0.5 to 0.1; P = 0.19) relative to 14-day cells. Transfusion of washed red cells also increased endothelial activation and kidney injury. Rejuvenation restored adenosine triphosphate to that of fresh red cells and reduced microvesicle concentrations without increasing cell-free hemoglobin release. Transfusion of rejuvenated red cells reduced plasma cell-free hemoglobin, leukocyte sequestration, and endothelial dysfunction in recipients and reduced lung and kidney injury relative to 14-day or washed 14-day cells. Conclusions Reversal of the red cell storage lesion by rejuvenation reduces transfusion-associated organ injury in swine.

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.

Introduction: AKI is very common in paediatric cardiac surgery patients. The diagnosis relies on changes in serum creatinine and urine output, which lack specificity and sensitivity especially in newborns and premature infants. Diagnostic changes also occur late in the injury phase when interventions have limited effectiveness. Microvesicles (MV) are small particles ( Hypothesis: MV and associated miRNA provide specific and early-detection markers for AKI and a tool to investigate AKI pathogenesis. Methods: Study subjects were 24 children ( Results: AKI was diagnosed in 14 patients and was confirmed by urinary NGAL increase at 6 hours after the operation (25±3.45 ng/ml vs 10.44±2.9 ng/ml; p 0.006). Patients with AKI were younger, underwent longer CPB, received higher volumes of red blood cells, and required higher inotrope support (Table). AKI subjects had increased levels of monocyte and B1-integrin MV. That correlated well with IL-8 and MCP-3 levels and monocyte activation. These changes were also reflected in miRNA profile in both groups. Conclusions: MV and miRNA could potentially serve as early AKI markers in children and their analysis reveals mechanistic parallels with adults.

Introduction: Allogeneic red blood cell (RBC) transfusion in cardiac surgery patients increases the risk of pulmonary and renal morbidity. These associations are attributable to the ‘storage lesion’ - accumulation of metabolites in the RBC supernatant that includes pro-inflammatory lipids, cell-free hemoglobin and energy depletion. Hypothesis: Storage lesion components trigger different events that lead to organ injury. Reducing storage lesion by RBC washing or rejuvenation will reduce organ injury. Methods: Samples from 60 cardiac patients participating in a randomized controlled trial of RBC washing prior to transfusion versus standard care were analysed for inflammatory markers. In a complementary experiment, 4 groups of pigs received crystalloid infusion or 14-day old RBC that were left untreated, washed or rejuvenated (Rejuvesol, Citra Labs, IN). Inflammatory markers, free hemoglobin and iron were measured in blood. Leukocyte invasion was determined by immunohistochemistry. The results were verified and further analysed in an in vitro inflammatory model. Results: Transfusion of stored RBC (~22 days) into humans or pigs was associated with leukocyte activation, and attenuated by washing. That was attributed to oxidised lipids on transfused RBC derived microvesicles that activated monocytes and platelets, as revealed in depletion experiments. Unexpectedly, transfusion of washed RBC increased kidney injury, which correlated with higher free haemoglobin levels, oxidative stress (confirmed by HMOX-1 levels and protein carbonylation), and endothelial injury in washed RBC recipients. Oxidative stress triggered non-standard endothelial activation defined by expression of VLA5 and fibronectin retention. Either pathway was reduced when rejuvenated blood was transfused. Conclusion: Monocytes/platelets and endothelium are activated by oxidized lipids/MV and reactive free haem, respectively, and can be alleviated by RBC rejuvenation.

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.