Nishith N. Patel

Indications for red blood cell transfusion in cardiac surgery: a systematic review and meta-analysis

BACKGROUND Good blood management is an important determinant of outcome in cardiac surgery. Guidelines recommend restrictive red blood cell transfusion. Our objective was to systematically review the evidence from randomised controlled trials and observational studies that are used to inform transfusion decisions in adult cardiac surgery. METHODS We did a systematic review by searching PubMed, Embase, Cochrane Library, and DARE, from inception to May 1, 2015, databases from specialist societies, and bibliographies of included studies and recent relevant review articles. We included randomised controlled trials that assessed the effect of liberal versus restrictive red blood cell transfusion in patients undergoing cardiac and non-cardiac surgery, and observational studies that assessed the effect of red blood cell transfusion compared with no transfusion on outcomes in adult cardiac patients after surgery. We pooled adjusted odds ratios using fixed-effects and random-effects meta-analyses. The primary outcome was 30-day mortality. FINDINGS We included data from six cardiac surgical randomised controlled trials (3352 patients), 19 non-cardiac surgical trials (8361 patients), and 39 observational studies (232,806 patients). The pooled fixed effects mortality odds ratios comparing liberal versus restrictive transfusion thresholds was 0.70 (95% CI 0.49-1.02; p=0.060) for cardiac surgical trials and 1.10 (95% CI 0.96-1.27; p=0.16) for trials in settings other than cardiac surgery. By contrast, observational cohort studies in cardiac surgery showed that red blood cell transfusion compared with no transfusion was associated with substantially higher mortality (random effects odds ratio 2.72, 95% CI 2.11-3.49; p<0.0001) and other morbidity, although with substantial heterogeneity and small study effects. INTERPRETATION Evidence from randomised controlled trials in cardiac surgery refutes findings from observational studies that liberal thresholds for red blood cell transfusion are associated with a substantially increased risk of mortality and morbidity. Observational studies and trials in non-cardiac surgery should not be used to inform treatment decisions or guidelines for patients having cardiac surgery. FUNDING None.

Prevention of post-cardiopulmonary bypass acute kidney injury by endothelin A receptor blockade.

Objective:The aim of this study was to determine whether administration of a specific endothelin A receptor antagonist, sitaxsentan sodium, would prevent the development of post-cardiopulmonary bypass acute kidney injury in swine. Design:Experimental study. Setting:Cardiovascular Research Institute. Interventions:Adult pigs (n = 8 per group) were randomized to undergo a sham procedure, cardiopulmonary bypass, or cardiopulmonary bypass plus administration of endothelin A receptor antagonist (RA), with recovery and reassessment at 24 hrs. Measurements and Main Results:Cardiopulmonary bypass resulted in a significant reduction in creatinine clearance relative to sham pigs (mean difference for cardiopulmonary bypass vs. sham, −50.3 mL/min [95% confidence interval −89.2 to −11.4 mL/min], p = .008). This was reversed by the administration of endothelin A RA during cardiopulmonary bypass (mean difference for cardiopulmonary bypass + endothelin A RA vs. cardiopulmonary bypass, +43.3 mL/min [95% confidence interval +3.3 to +83.4 mL/min], p = .030). Cardiopulmonary bypass also resulted in a significant rise in the specific urinary biomarker of acute kidney injury interleukin-18 compared to sham procedures (mean difference +209 pg/mL [95% confidence interval +119 to +299 pg/mL], p < .001) that was reversed by endothelin A receptor antagonist administration. Post-cardiopulmonary bypass kidney injury was associated with vascular endothelial injury and dysfunction, reduced nitric oxide bioavailability, inflammation, and a significant increase in the expression of the paracrine vasoconstrictors adenosine and endothelin-1. In post-cardiopulmonary bypass kidneys at 24 hrs there was persistent hypoxia at the level of the outer medulla, cortical adenosine triphosphate depletion, and evidence of proximal tubule epithelial cell stress manifest as phenotypic change. There was no evidence of acute tubular necrosis. Administration of endothelin A RA to cardiopulmonary bypass pigs reversed endothelial dysfunction, regional hypoxia, inflammation, and tubular changes. Conclusion:In this model, post-cardiopulmonary bypass acute kidney injury is associated with endothelial dysfunction, regional tissue hypoxia, and proximal tubular epithelial cell stress but not acute tubular necrosis. Antagonism of the endothelin-1 A receptor reversed these changes and may represent a therapeutic target for the prevention of post-cardiac surgery acute kidney injury.

Meta-analysis of colloids versus crystalloids in critically ill, trauma and surgical patients.

There is uncertainty regarding the safety of different volume replacement solutions. The aim of this study was systematically to review evidence of crystalloid versus colloid solutions, and to determine whether these results are influenced by trial design or clinical setting.

Phosphodiesterase-5 inhibition prevents postcardiopulmonary bypass acute kidney injury in swine.

BACKGROUND Acute kidney injury after cardiac surgery is common, has no effective treatments, and is associated with adverse outcomes. The aim of this study was to determine whether administration of the phosphodiesterase-5 inhibitor sildenafil citrate (SDF) would prevent the development of post-cardiopulmonary bypass (CPB) acute kidney injury in swine. METHODS Adult pigs (n = 8 per group) were randomized to undergo sham procedure, CPB, or CPB plus administration of SDF, with recovery and reassessment at 24 hours. RESULTS Cardiopulmonary bypass resulted in a significant reduction in creatinine clearance relative to sham pigs (mean difference CPB versus sham, -47.9 mL/min; 95% confidence interval [CI]: -93.7 to -2.2; p = 0.039). This was prevented by the administration of SDF during CPB (mean difference CPB+SDF versus CPB, +55.6 mL/min; 95% CI: +6.5 to +104.7; p = 0.024). Cardiopulmonary bypass also resulted in a significant rise in the urinary biomarker interleukin-18 compared with sham procedures (mean difference 209.3 pg/mL; 95% CI: 120.6 to 298.1; p < 0.001) that was prevented by SDF administration. Post-CPB kidney injury was associated with vascular endothelial injury and dysfunction, reduced nitric oxide bioavailability, medullary hypoxia, cortical adenosine triphosphate depletion, inflammation, and evidence of proximal tubule epithelial cell stress manifest as phenotypic change. Administration of SDF to CPB pigs preserved nitric oxide bioavailability and prevented endothelial dysfunction, regional hypoxia, inflammation, and tubular changes. CONCLUSIONS In this model, phosphodiesterase-5 inhibition using SDF prevented post-CPB acute kidney injury by the preservation of nitric oxide bioavailability, and warrants evaluation as a renoprotective agent in clinical trials.

Reversal of anemia with allogenic RBC transfusion prevents post-cardiopulmonary bypass acute kidney injury in swine

Anemia during cardiopulmonary bypass (CPB) is strongly associated with acute kidney injury in clinical studies; however, reversal of anemia with red blood cell (RBC) transfusions is associated with further renal injury. To understand this paradox, we evaluated the effects of reversal of anemia during CPB with allogenic RBC transfusion in a novel large-animal model of post-cardiac surgery acute kidney injury with significant homology to that observed in cardiac surgery patients. Adult pigs undergoing general anesthesia were allocated to a Sham procedure, CPB alone, Sham+RBC transfusion, or CPB+RBC transfusion, with recovery and reassessment at 24 h. CPB was associated with dilutional anemia and caused acute kidney injury in swine characterized by renal endothelial dysfunction, loss of nitric oxide (NO) bioavailability, vasoconstriction, medullary hypoxia, cortical ATP depletion, glomerular sequestration of activated platelets and inflammatory cells, and proximal tubule epithelial cell stress. RBC transfusion in the absence of CPB also resulted in renal injury. This was characterized by endothelial injury, microvascular endothelial dysfunction, platelet activation, and equivalent cortical tubular epithelial phenotypic changes to those observed in CPB pigs, but occurred in the absence of severe intrarenal vasoconstriction, ATP depletion, or reductions in creatinine clearance. In contrast, reversal of anemia during CPB with RBC transfusion prevented the reductions in creatinine clearance, loss of NO bioavailability, platelet activation, inflammation, and epithelial cell injury attributable to CPB although it did not prevent the development of significant intrarenal vasoconstriction and endothelial dysfunction. In conclusion, contrary to the findings of observational studies in cardiac surgery, RBC transfusion during CPB protects pigs against acute kidney injury. Our study underlines the need for translational research into indications for transfusion and prevention strategies for acute kidney injury.

Pharmacological strategies for the prevention of acute kidney injury following cardiac surgery: an overview of systematic reviews.

CONTEXT Post cardiac surgery acute kidney injury (AKI) is common, poorly understood and associated with a significant increase in morbidity and mortality. OBJECTIVES An overview of systematic reviews that have evaluated pharmacological agents for the prevention of AKI post cardiac surgery. DATA SOURCES We searched electronic databases (PubMed and the Cochrane Database of Systematic Reviews) from inception to January 2014. STUDY SELECTION Systematic reviews of randomized controlled trials that have evaluated pharmacological agents for the prevention of AKI in adult patients undergoing cardiac surgery. DATA ANALYSIS Numbers needed to treat (NNT) or harm (NNH) were calculated from pooled events given in each meta-analysis. Primary outcome measures were defined as (i) mortality, (ii) need for renal replacement therapy (RRT), and (iii) acute kidney injury. RESULTS Data from 7 systematic reviews evaluating 6 different pharmacological renoprotective agents were included. Dopamine, fenoldopam and N-acetylcysteine did not demonstrate any benefit in terms of mortality, need for RRT or incidence of AKI. Atrial natriuretic peptide reduced the need for RRT (NNT = 22 (95% CI: 13 to 73) and brain natriuretic peptide reduced the incidence of AKI (NNT = 11 (95% CI: 6 to 32), although both agents did not demonstrate any effect on mortality. Loop diuretics demonstrated increased incidence of AKI (NNH = 8 (95% CI: 5 to 15). CONCLUSION There is a paucity of effective renoprotective agents that can be used in adult cardiac surgical patients. There is an urgent need to develop novel renoprotective strategies.

Interactions of cardiopulmonary bypass and erythrocyte transfusion in the pathogenesis of pulmonary dysfunction in Swine.

Background:Allogeneic erythrocyte transfusion in cardiac surgical patients is associated with a fourfold increase in pulmonary complications. Our understanding of the processes underlying these observations is poor and there is no experimental model of transfusion-related acute lung injury that shows homology to cardiac surgical patients. Our objective was to develop a novel swine recovery model to determine how two clinical risk factors, allogenic erythrocyte transfusion and cardiopulmonary bypass, interact in the genesis of postcardiac surgery acute lung injury. Methods:Thirty-six pigs were infused with allogeneic 14- or 42-day-old erythrocytes or they underwent cardiopulmonary bypass with or without transfusion of 42-day erythrocyte. Controls received saline. All pigs were recovered and assessed for pulmonary dysfunction, inflammation, and endothelial activation at 24 h. Results:Transfusion of stored allogeneic erythrocytes in pigs compared with sham caused pulmonary dysfunction characterized by reduced lung compliance (mean difference −3.36 [95% CI, −5.31 to −1.42] ml/cm H2O), an increase in protein levels in bronchoalveolar lavage fluid, histological lung injury inflammation, and endothelial activation. Transfusion of blood stored for up to 42 days resulted in greater protein levels in bronchoalveolar lavage fluid, macrophage infiltration, platelet activation, and depletion of T-lymphocytes in recipient lungs versus 14-day-old blood. Transfusion interacted with cardiopulmonary bypass to increase lung injury in the absence of platelet activation. Conclusions:In this novel large animal model of allogeneic erythrocyte transfusion, pulmonary dysfunction occurs in the absence of any priming event, is increased when combined with other inflammatory stimuli, and is mediated by monocyte activation and T-lymphocyte depletion.

Long-term survival after surgical aortic valve replacement among patients over 65 years of age

Objective Surgical aortic valve replacement (AVR) remains the gold standard therapy for severe aortic stenosis. Long-term survival data following AVR is required. Our objective was to provide a detailed contemporary benchmark of long-term survival following AVR among elderly patients (≥65 years) in the UK. Methods We conducted a retrospective cohort study of 1815 adult patients undergoing surgical AVR± coronary artery bypass graft (CABG) surgery at a single UK centre between 1996 and 2011. Our main outcome was patient survival, which was assessed by linkage to census records at the Office for National Statistics. Results The mean age of the cohort was 75 (±5.6) years. Patients in the AVR alone group had a slightly higher median survival of 10.9 (95% CI 10.5 to 11.8) years than the AVR+CABG group which had a median survival of 9.6 (95% CI 8.7 to 10.1) years (p=0.001 of log-rank test (LRT) for equality of survivor functions). The presence of chronic kidney disease, severely impaired left ventricular function or being a current smoker were each associated with a ≥50% increased risk of long-term mortality. Comparison of our study cohort patients and the reference (operation year, age and gender matched) UK population suggested no difference in survival probability up to 8 years (p=0.55). However, for longer periods of follow-up, the difference became increasingly significant (p<0.0001). Conclusions Long-term survival following surgical AVR in patients over 65 years of age is excellent and up to 8 years is comparable to the matched general population.

Changes in renal medulla gene expression in a pre-clinical model of post cardiopulmonary bypass acute kidney injury

BackgroundAcute kidney injury (AKI) is a common and serious complication of cardiac surgery using cardiopulmonary bypass (CPB). The pathogenesis is poorly understood and the study of AKI in rodent models has not led to improvements in clinical outcomes. We sought to determine the changes in renal medullary gene expression in a novel and clinically relevant porcine model of CPB-induced AKI.ResultsAdult pigs (n = 12 per group) were randomised to undergo sham procedure, or 2.5 hours CPB. AKI was determined using biochemical (Cr51 EDTA clearance, CrCl, urinary IL-18 release) and histological measures. Transcriptomic analyses were performed on renal medulla biopsies obtained 24 hours post intervention or from sham group. Microarray results were validated with real-time polymerase chain reaction and Western Blotting.Of the transcripts examined, 66 were identified as differentially expressed in CPB versus Sham pig’s kidney samples, with 19 (29%) upregulated and 47 (71%) down-regulated. Out of the upregulated and downregulated transcripts 4 and 16 respectively were expression sequence tags (EST). The regulated genes clustered into three classes; Immune response, Cell adhesion/extracellular matrix and metabolic process. Upregulated genes included Factor V, SLC16A3 and CKMT2 whereas downregulated genes included GST, CPE, MMP7 and SELL.ConclusionPost CPB AKI, as defined by clinical criteria, is characterised by molecular changes in renal medulla that are associated with both injury and survival programmes. Our observations highlight the value of large animal models in AKI research and provide insights into the failure of findings in rodent models to translate into clinical progress.

Long-term survival after off-pump versus on-pump coronary artery bypass graft surgery. Does completeness of revascularization play a role?

BACKGROUND We sought to compare the incidence of incomplete revascularization (IR) and long-term survival (up to 20years) after off-pump (OPCAB) versus on-pump (ONCAB) coronary artery bypass in a high OPCAB volume centre where OPCAB was introduced in 1996 and has become the preferred strategy over the years. METHODS AND RESULTS From 1996 to 2015 a total of 7,427 OPCAB and 7128 ONCAB procedures were performed at Bristol Heart Institute, United Kingdom. We obtained 5423 propensity matched pairs for final comparison. Mixed effect Cox model accounting for clustering due to different surgeon was used to investigate the treatment effect on mortality. RESULTS OPCAB was associated with higher rate of incomplete revascularization 13.3% versus 6.7%; P<0.0001). Mean follow-up time was 7.8±4.6year [max 17.3]. At 12years OPCAB was associated with a marginal but significant +3% increase in overall mortality (67.4%[95%CI 65.8-69.1] vs 64.4%[95%CI 62.7-66.2]; stratified log-rank P=0.03). When compared to ONCAB with complete revascularization, OPCAB with IR (HR 1.74;95%CI 1.53-1.99; P<0.001) and ONCAB with IR (HR 1.29; 95%CI 1.06-1.57; P=0.01) but not OPCAB with complete revascularization (HR 1.02;95%CI 0.94-1.11; P=0.63) were associated with increased risk of late mortality. CONCLUSION Despite completeness of revascularization was achieved in the majority of OPCAB cases, OPCAB remained associated with a significantly higher rate of incomplete revascularization. This translated into a marginal but significant reduction in late survival rates after OPCAB when compared to ONCAB.