Blood and urinary cytokine balance and renal outcomes at cardiac surgery.

BACKGROUND: Increased perioperative pro-inflammatory biomarkers, renal hypoperfusion and ischemia reperfusion injury (IRI) heighten cardiac surgery acute kidney injury (CS-AKI) risk. Increased urinary anti-inflammatory cytokines attenuate risk. We evaluated whether blood and urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation, hypoperfusion and IRI are increased in CS-AKI patients. METHODS: Preoperative and 24-h postoperative blood and urinary pro-inflammatory and anti-inflammatory cytokines, blood VEGF and H-FABP (hypoperfusion biomarkers), and MK, a biomarker for IRI, were measured in 401 cardiac surgery patients. Pre- and postoperative concentrations of biomarkers and selected ratios thereof, were compared between non-CS-AKI and CS-AKI patients. RESULTS: Compared with non-CS-AKI, blood pro-inflammatory (pre- and post-op TNFα, IP-10, IL-12p40, MIP-1α, NGAL; pre-op IL-6; post-op IL-8, MK) and anti-inflammatory (pre- and post-op sTNFsr1, sTNFsr2, IL-1RA) biomarkers together with urinary pro-inflammatory (pre- and post-op uIL-12p40; post-op uIP-10, uNGAL) and anti-inflammatory (pre- and post-op usTNFsr1, usTNFsr2, uIL-1RA) biomarkers, were significantly higher in CS-AKI patients. Urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation (blood and urine), hypoperfusion (blood H-FABP and VEGF) and IRI (blood MK) were decreased in CS-AKI. In contrast, blood anti-inflammatory biomarkers expressed as similar ratios with blood biomarkers were increased in CS-AKI. CONCLUSIONS: The urinary anti-inflammatory response may protect against the injurious effects of perioperative inflammation, hypoperfusion and IRI. These finding may have clinical utility in bioprediction and earlier diagnosis of CS-AKI and informing future therapeutic strategies for CS-AKI patients.

Acute kidney injury risk in orthopaedic trauma patients pre and post surgery using a biomarker algorithm and clinical risk score.

Acute kidney injury (AKI) after major trauma is associated with increased mortality. The aim of this study was to assess if measurement of blood biomarkers in combination with clinical characteristics could be used to develop a tool to assist clinicians in identifying which orthopaedic trauma patients are at risk of AKI. This is a prospective study of 237 orthopaedic trauma patients who were consecutively scheduled for open reduction and internal fixation of their fracture between May 2012 and August 2013. Clinical characteristics were recorded, and 28 biomarkers were analysed in patient blood samples. Post operatively a combination of H-FABP, sTNFR1 and MK had the highest predictive ability to identify patients at risk of developing AKI (AUROC 0.885). Three clinical characteristics; age, dementia and hypertension were identified in the orthopaedic trauma patients as potential risks for the development of AKI. Combining biomarker data with clinical characteristics allowed us to develop a proactive AKI clinical tool, which grouped patients into four risk categories that were associated with a clinical management regime that impacted patient care, management, length of hospital stay, and efficient use of hospital resources.

Stratifying risk of acute kidney injury in pre and post cardiac surgery patients using a novel biomarker-based algorithm and clinical risk score.

Acute kidney injury (AKI) following cardiac surgery significantly increases morbidity and mortality risks. Improving existing clinical methods of identifying patients at risk of perioperative AKI may advance management and treatment options. This study investigated whether a combination of biomarkers and clinical factors pre and post cardiac surgery could stratify patients at risk of developing AKI. Patients (n = 401) consecutively scheduled for elective cardiac surgery were prospectively studied. Clinical data was recorded and blood samples were tested for 31 biomarkers. Areas under receiver operating characteristic (AUROCs) were generated for biomarkers pre and postoperatively to stratify patients at risk of AKI. Preoperatively sTNFR1 had the highest predictive ability to identify risk of developing AKI postoperatively (AUROC 0.748). Postoperatively a combination of H-FABP, midkine and sTNFR2 had the highest predictive ability to identify AKI risk (AUROC 0.836). Preoperative clinical risk factors included patient age, body mass index and diabetes. Perioperative factors included cardio pulmonary bypass, cross-clamp and operation times, intra-aortic balloon pump, blood products and resternotomy. Combining biomarker risk score (BRS) with clinical risk score (CRS) enabled pre and postoperative assignment of patients to AKI risk categories. Combining BRS with CRS will allow better management of cardiac patients at risk of developing AKI.

Cytokine phenotype, genotype, and renal outcomes at cardiac surgery.

BACKGROUND: Cardiac surgery modulates pro- and anti-inflammatory cytokine balance involving plasma tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) together with urinary transforming growth factor beta-1 (TGFß1), interleukin-1 receptor antagonist (IL1ra) and tumour necrosis factor soluble receptor-2 (TNFsr2). Effects on post-operative renal function are unclear. We investigated if following cardiac surgery there is a relationship between cytokine (a) phenotype and renal outcome; (b) genotype and phenotype and (c) genotype and renal outcome. Since angiotensin-2 (AG2), modulates TGFß1 production, we determined whether angiotensin converting enzyme insertion/deletion (ACE I/D) genotype affects urinary TGFß1 phenotype as well as renal outcome. METHODS: In 408 elective cardiac surgery patients we measured pre- and 24 h post-operative urinary TGFß-1, IL1ra and TNFsr2 and pre- and 2 h post-operative plasma TNFα and IL-10. Post-operative responses were compared for each cytokine in patients grouped according to presence or absence of renal dysfunction defined as a drop from baseline eGFR of greater than 25% (as calculated by the method of modification of diet in renal disease (MDRD)) occurring (1) within the first 24 and (2) 48 postoperative hours (early renal dysfunction), (3) on the fifth postoperative day (late renal dysfunction) or (4) at any time throughout the 5 day postoperative period (early and late combined). Patient genotype was determined for TNF/G-308A, TGFß1-509 C/T, IL10/G-1082A and ACE I/D. RESULTS: Post-operative plasma IL-10 and urinary TGFß1 responses were significantly higher in patients who developed early renal dysfunction. IL1ra and TNFsr2 responses were significantly lower 24h post-operatively in patients who developed late renal dysfunction. Genotype did not alter cytokine phenotype or outcome. CONCLUSIONS/INFERENCES: Cytokine profiling may help predict early and late renal dysfunction. Genotypes studied did not alter phenotype or outcome.

The hemodynamic and respiratory effects of cuirass ventilation in healthy volunteers: Part 1.

OBJECTIVE: Negative-pressure ventilation (NPV) by external cuirass (RTX; Deminax Medical Instruments Limited, London, UK) in intubated patients after cardiac surgery improves hemodynamics measured by pulmonary artery catheter (PAC)-based methods, with an increased cardiac output (CO) and stroke volume (SV), without changing the heart rate (HR). The less-invasive pressure recording analytical method (PRAM) (Mostcare; Vytech Health srl, Padova, Italy) allows radial artery-based monitoring of the CO, SV, SV variation, and cardiac cycle efficiency (CCE). The authors investigated the hypothesis that NPV improves PRAM-based hemodynamics and arterial blood gas analysis in spontaneously breathing subjects. DESIGN: A clinical investigation. SETTING: A teaching hospital. PARTICIPANTS: Ten healthy volunteers. INTERVENTIONS: Subjects underwent 5 consecutive experimental ventilation modalities lasting 5 minutes: (1) baseline (no cuirass ventilation), (2) mode 1: cuirass ventilation with a continuous negative pressure of -20 cmH(2)O, (3) first rest period (no cuirass ventilation), (4) mode 2: cuirass ventilation in control mode of 12 breaths/min at -20 cmH(2)O, and (5) second rest period. MEASUREMENTS AND MAIN RESULTS: PRAM parameters were analyzed throughout the final minute of each experimental modality, which concluded with arterial blood gas sampling. Both NPV modes significantly reduced HR without changing CO or systemic vascular resistance. Mode 1 significantly increased CCE and decreased SVV. PO(2) decreased in both rest modes compared with baseline. This was prevented by NPV. In 5 smokers, PO(2) significantly increased in the control mode compared with first rest period. The control mode NPV improved oxygenation with a reduced PCO(2) and reciprocally increased pH. CONCLUSIONS: Five minutes of NPV improves hemodynamics and oxygenation in healthy subjects.

The hemodynamic and respiratory effects of continuous negative and control-mode cuirass ventilation in recently extubated cardiac surgery patients: Part 2.

OBJECTIVE: Negative-pressure ventilation (NPV) by external cuirass (RTX; Deminax Medical Instruments Limited, London, UK) in intubated patients after cardiac surgery improves hemodynamics measured by pulmonary artery catheter (PAC)-based methods with increased cardiac output (CO) and stroke volume (SV) without changing the heart rate (HR). The less-invasive pressure recording analytical method (PRAM) (MostCare; Vytech Health srl, Padova, Italy) allows radial artery monitoring of CO, SV, SV variation, and cardiac cycle efficiency (CCE). The authors investigated the hypothesis that NPV improves PRAM-based hemodynamics and arterial blood gas analysis in extubated cardiac surgery patients. DESIGN: A clinical investigation. SETTING: A teaching hospital. PARTICIPANTS: Twenty recently extubated cardiac surgery patients. INTERVENTIONS: Five consecutive experimental ventilation modalities lasted 5 minutes: (1) baseline (no cuirass ventilation), (2) mode 1 (cuirass ventilation with a continuous negative pressure of -20 cmH(2)O), (3) rest 1 (no cuirass ventilation), (4) mode 2 (cuirass ventilation in the control mode of 12 breaths/min at -20 cmH(2)O, and (5) rest 2. MEASUREMENTS AND MAIN RESULTS: PRAM parameters were analyzed throughout the final minute of each experimental modality, concluding with arterial blood gas sampling. NPV was well tolerated. HR was unchanged. Mode 2 SV was higher than baseline and rest 2. Mode 2 CO was higher than rest 2. Rest 2 systolic blood pressure was lower than rest 1 and mode 2. Increased CCE with NPV was not significant (p = 0.0696). Oxygenation and PCO(2) were unchanged although mode 2 pH increased. CONCLUSIONS: Extubated sedated cardiac surgery patients comfortably tolerated NPV with unchanged HR. SV and pH increased.

Cell salvage alters the systemic inflammatory response after off-pump coronary artery bypass grafting surgery.

BACKGROUND: Retransfused cardiotomy suction blood contains elevated inflammatory markers and is a bypass independent source of inflammatory mediators. We hypothesized that, during off-pump coronary artery bypass (OPCAB) grafting surgery, avoiding retransfusion of unwashed cardiotomy suction blood would beneficially alter both urinary and plasma cytokine concentrations and be renoprotective. METHODS: Thirty-seven OPCAB surgery patients were randomly allocated to control (retransfusion of unwashed shed blood) and treatment (retransfusion of washed shed blood or discarding of unwashed blood) groups. Over 72 hours we measured plasma (tumor necrosis factor-alpha [TNF-alpha], interleukin-8, interleukin-6, interleukin-10, TNF soluble receptor-2, and interleukin-1 receptor antagonist) and urinary TNF soluble receptor-2 and interleukin-1 receptor antagonist and markers of renal injury and dysfunction (N-acetyl beta D glucosaminidase and alpha1-microglobulin). RESULTS: We demonstrated elevated proinflammatory cytokines in cardiotomy suction blood, which were effectively eliminated by cell salvage. After retransfusion, in comparison with controls, the treatment group had reduced plasma TNF soluble receptor-2. As compared with controls, treatment group patients also demonstrated significantly reduced levels of the urinary anti-inflammatory cytokine TNF soluble receptor-2. There were no between group differences in markers of renal injury or dysfunction. CONCLUSIONS: We have demonstrated that the management of shed mediastinal blood alters perioperative, systemic, plasma and urinary cytokine homeostasis at OPCAB surgery but does not impact on subclinical renal injury or dysfunction in this low risk group of patients.

Methylprednisolone increases urinary nitrate concentrations and reduces subclinical renal injury during infrarenal aortic ischemia reperfusion.

OBJECTIVE: This study tests the hypothesis that methylprednisolone may influence eNOS activity in renal arterial and venous vascular beds and impede subclinical renal injury. SUMMARY BACKGROUND DATA: Acute renal failure is a major complication of cardiovascular surgery. Renal damage arises in part from excessive vasoconstriction mediated by an imbalance of vasoconstrictive ET-1 and vasodilatory NO produced by eNOS. While methylprednisolone may reduce subclinical renal injury as measured by urinary N-acetyl-beta-D-glucosaminidase (beta-NAG), its effects upon eNOS activity in renal arterial and venous vascular beds, reflected by urinary nitrate levels, is unclear. METHODS: A porcine model of normotensive, euvolemic infrarenal aortic ischaemia-reperfusion was used. Forty-two pigs underwent a 60-minute laparotomy followed by 150 minutes of infrarenal ischemia and 180 minutes of reperfusion. Animals were randomized to receive methylprednisolone 30 mg/kg or placebo after induction of general anesthesia. Urinary beta-NAG levels were assessed as an index of subclinical renal injury, whereas urinary nitrate was assessed as an indicator of eNOS activity in renal arterial and venous vascular beds. RESULTS: Methylprednisolone treatment did not influence mean arterial, central venous, or pulmonary artery wedge pressures but suppressed plasma IL-6 levels. After the ischemia-induced rise from preanaesthetic baseline levels, urinary beta-NAG levels declined to significantly lower values in the MP group, indicative of MP renal protection (P < 0.05). Conversely, urinary nitrate levels indicative of vascular e-NOS activity remained significantly and persistently higher in MP-treated animals (P < 0.05). CONCLUSION: This study, in a porcine model of renal ischaemia-reperfusion injury, shows the benefits of methylprednisolone pretreatment in enhancing urinary nitrate levels indicative of vascular eNOS activity and the reduction of urinary beta-NAG levels, which represent subclinical renal injury.

A clinical, renal and immunological assessment of surface modifying additive treated (SMART) cardiopulmonary bypass circuits.

Biocompatible cardiopulmonary bypass (CPB) circuits aim to reduce contact activation and its physiological consequences. We investigated the hypothesis that use of Surface Modifying Additive (SMA)-treated circuits (Sorin Group Ltd) compared with non-SMA circuits would be associated with preservation of blood pressure during CPB and modulation of perioperative subclinical renal function (urinary alpha-1-microglobulin (alpha-1-m)) and plasma and urinary cytokine changes. In a study of low-risk CABG patients (n=40), randomized to SMA (n=20) versus non-SMA circuits (n=20), we found better preserved blood pressure at CPB initiation in SMA patients (p <0.05), particularly in ACE-inhibited SMA patients (n =11) versus ACE-inhibited non-SMA patients (n =10) (p <0.05). Plasma anti-inflammatory IL-10, as well as urinary alpha-1-m, were elevated 48 hours postoperatively (p <0.05). SMA patients also had lower blood loss (p <0.05). SMA circuits have some clinical benefit, especially in ACE-inhibited patients.

Methylprednisolone favourably alters plasma and urinary cytokine homeostasis and subclinical renal injury at cardiac surgery.

UNLABELLED: Whilst elevated urinary transforming growth factor beta-1 (TGFbeta) is associated with chronic renal dysfunction its role in acute peri-operative renal dysfunction is unknown. In contrast, peri-operative increases in urinary IL-1 receptor antagonist (IL-1ra) and TNF soluble receptor-2 (TNFsr-2) mirror pro-inflammatory activity in the nephron and correlate with renal complications. Steroids modulate some plasma cytokines (decreasing TNFalpha, IL-8, IL-6 and increasing IL-10), whereas ability to reduce plasma and urinary TNFsr-2 and IL-1ra and peri-operative renal injury is unknown. Patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB) were randomised to receive methylprednisolone (n = 18) or placebo (n = 17) before induction of anaesthesia. Plasma and urinary pro- and anti-inflammatory cytokine balance was determined along with subclinical proximal tubular injury and dysfunction, measured by urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine and alpha-1-microglobulin/creatinine ratios, respectively. In the control group compared with baseline, plasma IL-8, TNFalpha, IL-10, IL-1ra and TNFsr-2 were significantly elevated along with urinary IL-1ra, TNFsr-2 and TGFbeta1. Urinary NAG/creatinine and alpha-1-microglobulin/creatinine ratios rose from completion of revascularisation until 6 h with recovery at 24 h with a further rise in NAG/creatinine ratio at 48 h. Compared to placebo, the methylprednisolone group showed significantly reduced plasma IL-8, TNFalpha, IL-1ra and TNFsr-2 whereas plasma IL-10 increased. Compared to placebo, the methylprednisolone group demonstrated significantly reduced urinary NAG/creatinine ratio, TNFsr-2 and TGFbeta1 at 24 h whereas urinary alpha-1-microglobulin/creatinine ratios increased. CONCLUSIONS: Methylprednisolone administration during cardiac surgery significantly reduces plasma and urinary TNFsr-2 and IL-1ra, urinary TGFbeta1 and subclinical renal injury but not dysfunction.

The effect of methylprednisolone on cytokine concentration and leukocyte adhesion molecule expression in an isolated cardiopulmonary bypass system.

This study examines the effect of methylprednisolone on cytokine balance and adhesion molecule expression within an isolated cardiopulmonary bypass (CPB) system. This isolated CPB system is an in vitro model which simulates the pro-inflammatory immune response. Whole blood from 10 volunteers was obtained in two equal amounts. Heparin and saline were added to the control group while heparin and methylprednisolone were added to the methylprednisolone group. The blood was added to two identical CPB circuits and bypass commenced by a trained perfusionist. Samples were taken at blood donation (Sample 0), 10 min after the addition of drugs (Sample 1) and after 30, 60 and 90 min of CPB (Samples 2, 3 and 4, respectively). Cytokines interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1ra) and tumour necrosis factor soluble receptor 2 (TNFsr2) and the leucocyte adhesion molecules L-selectin, HLA DR, CD18 and CD11b were determined. IL-8 increased in both groups. This increase was significantly less in the methylprednisolone group. Increases in granulocyte CD11b and CD18 expression were less in the methylprednisolone group than in the control group but did not reach statistical significance. These results indicate that methylprednisolone significantly reduces the production of IL-8 in an isolated CPB system. This effect occurs in the absence of IL-10.

Advances in cardiopulmonary bypass circuitry.

PURPOSE OF REVIEW: The purpose of this review is to present developments in cardiopulmonary bypass circuitry, and to give the authors' opinions on the causes of the potentially harmful processes that are initiated by cardiopulmonary bypass, and how they may be attenuated. RECENT FINDINGS: Much of the recently published work investigates the effect of various forms of biocompatible circuitry, either heparin bonded, or polymer coated. The increasing number of patients having off-pump coronary surgery allows comparison of such patients with those that have had surgery using the various forms of cardiopulmonary bypass circuitry. SUMMARY: Recent developments of biocompatible circuits are promising in terms of their potential for reducing the perioperative inflammatory response. The use of such circuitry, however, is likely to be of benefit only when included as part of an overall strategy to control triggers of the inflammatory response during and after cardiac surgery, particularly in the high-risk patient.