Non-invasive assessment of liver alterations in Senning and Mustard patients.

BACKGROUND: Adults with congenital heart disease and ventricular dysfunction are prone to liver congestion, leading to fibrosis or cirrhosis but little is known about the prevalence of liver disease in atrial switch patients. Liver impairment may develop due to increased systemic venous pressures. This prospective study aimed to assess non-invasively hepatic abnormalities in adults who underwent Senning or Mustard procedures. METHODS: Hepatic involvement was assessed non-invasively clinically by laboratory analysis, hepatic fibrotic markers, sonography, and liver stiffness measurements [transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)]. RESULTS: Overall, 24 adults who had undergone atrial switch operation (13 Senning, 11 Mustard; four female; median age 27.8 years; range 24-45 years) were enrolled. In liver stiffness measurements, only three patients had values within the normal reference. All other patients showed mild, moderate or severe liver fibrosis or cirrhosis, respectively. Using imaging and laboratory analysis, 71% of the subjects had signs of liver fibrosis (46%) or cirrhosis (25%). CONCLUSIONS: Non-invasive screening for liver congestion, fibrosis or cirrhosis could be meaningful in targeted screening for hepatic impairment in patients with TGA-ASO. As expert knowledge is essential, patients should be regularly controlled in highly specialised centres with cooperations between congenital cardiologists and hepatologists.

Neutrophil gelatinase-associated lipocalin reflects inflammation and is not a reliable renal biomarker in neonates and infants after cardiopulmonary bypass: a prospective case-control study.

Introduction Acute kidney injury is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Neutrophil gelatinase-associated lipocalin has been suggested to be a promising early biomarker of impending acute kidney injury. On the other hand, neutrophil gelatinase-associated lipocalin has been shown to be elevated in systemic inflammatory diseases without renal impairment. In this secondary analysis of data from our previous study on acute kidney injury after infant cardiac surgery, our hypothesis was that neutrophil gelatinase-associated lipocalin may be associated with surgery-related inflammation. METHODS: We prospectively enrolled 59 neonates and infants undergoing cardiopulmonary bypass surgery for CHD and measured neutrophil gelatinase-associated lipocalin in plasma and urine and interleukin-6 in the plasma. Values were correlated with postoperative acute kidney injury according to the paediatric Renal-Injury-Failure-Loss-Endstage classification. RESULTS: Overall, 48% (28/59) of patients developed acute kidney injury. Of these, 50% (14/28) were classified as injury and 11% (3/28) received renal replacement therapy. Both plasma and urinary neutrophil gelatinase-associated lipocalin values were not correlated with acute kidney injury occurrence. Plasma neutrophil gelatinase-associated lipocalin showed a strong correlation with interleukin-6. Urinary neutrophil gelatinase-associated lipocalin values correlated with cardiopulmonary bypass time. CONCLUSION: Our results suggest that plasma and urinary neutrophil gelatinase-associated lipocalin values are not reliable indicators of impending acute kidney injury in neonates and infants after cardiac surgery with cardiopulmonary bypass. Inflammation may have a major impact on plasma neutrophil gelatinase-associated lipocalin values in infant cardiac surgery. Urinary neutrophil gelatinase-associated lipocalin may add little prognostic value over cardiopulmonary bypass time.

Non-invasive assessment of liver changes in Eisenmenger patients.

BACKGROUND: Eisenmenger syndrome as a severe form of cyanotic congenital heart disease results in a complex multisystemic disorder. Due to increased systemic venous pressure and the inability to ensure systemic perfusion and metabolic requirements, the liver may develop congestion, fibrosis or cirrhosis. This study aimed to assess hepatic abnormalities in Eisenmenger patients non-invasively. METHODS AND RESULTS: 10 adults with Eisenmenger syndrome (six female; median age 44.2years; range 23-62years) were enrolled and hepatic involvement was assessed - using clinical assessment, laboratory analysis, hepatic fibrotic markers, abdominal sonography and liver stiffness measurements (transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)). Using imaging and laboratory analysis, 60% (6/10) of the Eisenmenger patients had signs of liver fibrosis (5/10) or cirrhosis (1/10). While TE, however, showed no relevant liver abnormalities in any Eisenmenger patient, ARFI detected liver fibrosis in 5/10 and cirrhosis and 1/10 patients. CONCLUSIONS: Adult Eisenmenger patients are at increased risk of hepatic impairment. Non-invasive screening could be helpful in detecting liver alterations. In our small series, however, TE could not detect fibrosis or cirrhosis in any affected patient, while ARFI was very reliable. Patients should be transferred to centres, where a multidisciplinary expert knowledge is available and a close collaboration between cardiologists and hepatologists exists.

Intraoperative renal near-infrared spectroscopy indicates developing acute kidney injury in infants undergoing cardiac surgery with cardiopulmonary bypass: a case-control study.

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.

Prediction of contrast-induced nephropathy in patients with serum creatinine levels in the upper normal range by cystatin C: a prospective study in 374 patients.

OBJECTIVE: Preexisting renal impairment is a risk factor for contrast-induced nephropathy (CIN). In patients with creatinine in the upper normal level, cystatin C might be a more sensitive predictor of CIN than creatinine. Therefore, in this study, we investigated the usefulness of cystatin C to predict CIN. SUBJECTS AND METHODS: In 400 consecutive patients with creatinine baseline levels between 0.8 and 1.3 mg/dL undergoing coronary angiography (n = 200) or CT (n = 200), baseline values of cystatin C, creatinine, blood urea nitrogen (BUN) and risk factors of CIN were determined. Creatinine was also assessed 24 and 48 hours after contrast administration. RESULTS: Creatinine significantly (p < 0.001) increased after 24 hours and 48 hours compared with baseline (1.06 ± 0.28 and 1.07 ± 0.28 vs 0.99 ± 0.18 mg/dL). Fifty-three of 373 evaluable patients (14.2%) had an increase in creatinine of ≥ 25% or ≥ 0.5 mg/dL within 48 hours. CIN according to this definition was significantly more frequent after intraarterial contrast administration (38/190, 20%) compared with IV contrast administration (15/183, 8.2%; p = 0.001). CIN was predicted by baseline cystatin C (area under the receiver operating characteristic [ROC] curve [AUC], 0.715; p < 0.001), whereas creatinine, creatinine clearance, and BUN were not predictive. The best predictive capabilities were provided by cystatin C/creatinine-ratio (AUC, 0.826; p < 0.001). Multivariate regression analysis showed that intraarterial contrast administration (p = 0.002) and higher baseline cystatin C (p < 0.001) combined with low creatinine (p = 0.044) were independently associated with higher increases in creatinine within 48 hours after contrast administration. CONCLUSION: CIN in patients with creatinine within the upper normal range is significantly more frequent after intraarterial than after IV contrast administration. In these patients, renal impairment after contrast administration is independently predicted by cystatin C and cystatin C/creatinine-ratio, whereas BUN and creatinine were not predictive.

Serum concentrations and pharmacokinetics of moxifloxacin in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass.

Although cephalosporins are recommended as primary agents, moxifloxacin may be a suitable second-line antibiotic in cardiac surgery, especially if additional Gram-negative coverage is warranted. Cardiopulmonary bypass (CPB) may alter the pharmacokinetics of drugs in numerous ways. Since no such data exist, the aim of this study was to assess the serum concentrations and pharmacokinetics of moxifloxacin in patients undergoing cardiac surgery with CPB. Fourteen coronary artery bypass graft surgery patients received an intravenous infusion of 400 mg moxifloxacin as peri-operative antibiotic prophylaxis. At 15 time points throughout a 24-h period, serum samples were obtained to measure moxifloxacin concentrations using high-performance liquid chromatography. In addition, a non-compartmental pharmacokinetic analysis, i.e. area under the concentration-time curve (AUC), volume of distribution at steady state (V(SS)), drug clearance (CL), elimination half-life (t(1/2)) and mean residence time (MRT), was performed in five patients. Apart from a slight transient decrease in moxifloxacin concentration at the onset, CPB did not affect the concentration-time curve. Mean ± standard deviation maximum drug concentration (C(max)) (5.12 ± 1.58 µg/mL), AUC (36.5 ± 5.40 µgh/mL), VSS (2.03 ± 0.30 L/kg), CL (11.2 ± 1.91 L/h), t(1/2) (9.47 ± 0.92 h) and MRT (12.9 ± 1.52 h) were comparable with historical data for healthy volunteers. We conclude that CPB does not alter the pharmacokinetics of moxifloxacin. No dose adjustments, especially with regard to the CPB circuit and its priming volume, are necessary in cardiac surgical patients.

Neither moxifloxacin nor cefuroxime produces significant attenuation of inflammatory mediator release in patients exposed to cardiopulmonary bypass: a randomized controlled trial.

OBJECTIVES: In vitro and experimental studies in animals have established the anti-inflammatory effects of moxifloxacin. Cardiopulmonary bypass (CPB) leads to an inflammatory response. The aim of this study was to assess whether the inflammatory cytokine response to CPB is reduced with a perioperative antibiotic prophylaxis, either moxifloxacin or cefuroxime (the standard prophylaxis). PATIENTS AND METHODS: Twenty-eight patients scheduled for elective coronary artery bypass grafting with CPB were randomly assigned to receive either moxifloxacin or cefuroxime as the perioperative antibiotic prophylaxis. Interleukin (IL)-6, -8, -10 and tumour necrosis factor-α (TNF-α) serum concentrations were determined at eight time points before and after CPB. RESULTS: In both groups, all cytokine concentrations significantly increased after the start of CPB. There were no statistically significant differences between the moxifloxacin and cefuroxime groups at any point; IL-6 concentrations [median (interquartile range)] 240 min after CPB, the primary endpoint, were 364 (192-598) and 465 (325-906) pg/mL (P = 0.323), respectively. CONCLUSIONS: Neither moxifloxacin nor cefuroxime produced significant attenuation of the inflammatory cytokine response to CPB. The reasons why moxifloxacin did not have significant anti-inflammatory effects in this unique clinical situation may be: (i) the inflammatory response to CPB may be different from that of infectious disease states that were used to establish the immunomodulatory effects of moxifloxacin; and (ii) a single intravenous dose, which was used in this investigation, may not lead to high enough plasma and intracellular concentrations.

Are the point-of-care diagnostics MULTIPLATE and ROTEM valid in the setting of high concentrations of heparin and its reversal with protamine?

OBJECTIVES: To evaluate the in vitro effects of high concentrations of heparin and its reversal with protamine on routine laboratory parameters as well as on modified thromboelastogram (ROTEM; TEM International, Munich, Germany) and impedance aggregometry (MULTIPLATE; Dynabyte, Munich, Germany). DESIGN: An observational, nonrandomized in vitro study. SETTING: A single-center, university hospital. PARTICIPANTS: Ten healthy volunteers. INTERVENTIONS: Heparinization of whole blood to levels of 2, 4, 6, and 8 IU/mL of heparin and reversal with protamine. For MULTIPLATE measurements, heparin levels up to 20 IU/mL were tested. MEASUREMENTS AND MAIN RESULTS: The present results show that the prothrombin time (PT) and fibrinogen measurements are altered significantly by heparin concentrations above 2 IU/mL. Protamine reversal also affected coagulation tests except for the fibrinogen. The INTEM test using the ROTEM system was influenced significantly by heparin concentrations of 2 IU/mL or higher, whereas EXTEM measurements remained stable up to 4 IU/mL. The findings for the FIBTEM test were stable up to 6 IU/mL but then declined to values less than 50% of baseline at 8 IU/mL. HEPTEM results remained valid under all concentrations of heparin tested. The effect of protamine on ROTEM was seen mainly in the INTEM and HEPTEM measurements. Heparin concentrations up to a level of 20 U/mL had no effect on MULTIPLATE measurements. Effects of protamine on MULTIPLATE became significant at heparin-to-protamine ratios below 1:1 and were more pronounced for adenosine diphosphate than for thrombin receptor-activated protein testing. CONCLUSIONS: Neither fibrinogen (Clauss) nor derived fibrinogen or FIBTEM testing is valid in the setting of high concentrations of heparin unless antagonized by heparinase. Reversal of heparin with protamine worsens platelet function at all ratios as detected by aggregometry (MULTIPLATE) and thromboelastography (ROTEM), starting at a 1:1 ratio. Therefore, appropriate coagulation testing under cardiopulmonary bypass conditions should be selected carefully according to heparin levels. In particular, fibrinogen values are falsely low at heparin levels of 2 IU/mL and above. Therefore, newer algorithms promoting the correction of fibrinogen levels on cardiopulmonary bypass should be based on appropriate testing.

Effects of G-CSF on systemic inflammation, coagulation and platelet activation in patients with acute myocardial infarction.

INTRODUCTION: In the prospective, randomised, double-blind, placebo-controlled Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL)-2 trial patients with acute myocardial infarction (AMI) and successful mechanical reperfusion received granulocyte-colony stimulating factor (G-CSF, 10 µg/kg KG s.c.) or placebo for 5 days. Aim of this substudy was to assess the impact of G-CSF on systemic inflammatory and procoagulant responses and platelet activation. METHODS AND RESULTS: Before and five days after G-CSF (n=56) or placebo (n=58) circulating cytokine concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12 and Tumor-Necrosis Factor-α (TNF-α were measured. Prothrombin fragment F1+2 and Tissue Factor activity served as a measure for activated coagulation. Platelet activation was characterized by cell surface expression of the activated fibrinogen receptor (PAC-1), P-selectin and CD40L by flow cytometry. Administration of G-CSF was associated with elevated TNF-α and CRP concentrations compared to the placebo group after 5 days. Other cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12) were comparable after treatment with G-SCF or placebo. Similarly, circulating prothrombin fragments F1+2, TF activity and platelet activation did not differ in both groups. CONCLUSION: Treatment with G-CSF in patients with AMI was associated with enhanced proinflammatory TNF-α and CRP levels but no activation of coagulation.

Plasma TF activity predicts cardiovascular mortality in patients with acute myocardial infarction.

OBJECTIVES AND BACKGROUND: Tissue factor (TF) contributes to thrombosis following plaque disruption in acute coronary syndromes (ACS). Aim of the study was to investigate the impact of plasma TF activity on prognosis in patients with ACS. METHODS AND RESULTS: One-hundred seventy-four patients with unstable Angina pectoris (uAP) and 112 patients with acute myocardial infarction (AMI) were included with a mean follow up time of 3.26 years. On admission, plasma TF activity was assessed. Patients were categorized into 2 groups: a high-TF activity group with TF >24 pmol/L and low TF activity group with TF ≤ 24 pmol/L. Fifteen cardiovascular deaths occurred in the uAP group and 16 in the AMI group. In AMI TF activity was 24,9 ± 2,78 pmol/l (mean ± SEM) in survivors and 40,9 ± 7,96 pmol/l in nonsurvivors (P = 0.024). In uAP no differences were observed (25.0 ± 8.04 pmol/L nonsurvivors vs. 25.7 ± 2.14 pmol/L survivors; P = 0.586). Kaplan-Meier estimates of survival at 3.26 years regarding TF activity in AMI were 81.3% and 92.2% with an hazard ratio of 3.02 (95% CI [1.05-8.79], P = 0.03). The Cox proportional hazards model adjusting for correlates of age and risk factors showed that plasma TF activity was an independent correlate of survival (hazard ratio 9.27, 95% CI [1.24-69.12], P = 0.03). In an additional group of patients with uAP and AMI, we identified circulating microparticles as the prevailing reservoir of plasma TF activity in acute coronary syndromes. CONCLUSION: Systemic TF activity in AMI has an unfavorable prognostic value and as a marker for dysregulated coagulation may add to predict the atherothrombotic risk.

Bivalirudin reduces platelet and monocyte activation after elective percutaneous coronary intervention.

Concomitant antithrombotic therapy is essential for the prevention of ischaemic events in percutaneous coronary intervention (PCI) and stenting. With new anticoagulant medications being developed and applied in PCI, this raises the question of possible interactions with platelet and leukocyte activation. We therefore sought to investigate the influence of bivalirudin and heparin in platelet and leukocyte activation in patients undergoing elective PCI. Forty-six patients were recruited consecutively in the setting of the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT)-3 trial and were randomly assigned to receive either unfactionated heparin or bivalirudin during elective PCI. Surface expression of CD62P (P-Selectin), CD42b (GPIbalpha), CD40L, PAC-1 on circulating platelets and CD11b, CD14 and CD15 on circulating leukocytes were evaluated by flow cytometry. Cytokine levels of IL-12p70, tumour necrosis factor (TNF), IL-8, IL-6, IL-1beta and IL-10 were determined by cytometric bead array. Platelet surface expression of PAC-1, P-Selectin and GPIbalpha was significantly reduced after PCI in patients receiving bivalirudin as compared to heparin. Similarly, CD11b expression on CD14+ monocytes was diminished after bivalirudin. However, no differences were observed in cytokine levels between the bivalirudin and the heparin group, before or after PCI. In conclusion, our data suggest that bivalirudin may reduce platelet and monocyte activation in patients undergoing elective PCI. Thereby, bivalirudin might reduce periinterventional thrombotic complications.