Hanne Berg Ravn

Failure of remote ischemic preconditioning to reduce the risk of postoperative acute kidney injury in children undergoing operation for complex congenital heart disease: A randomized single-center study

OBJECTIVEnThe objective of this study was to evaluate whether remote ischemic preconditioning can protect kidney function in children undergoing operation for complex congenital heart disease.nnnMETHODSnChildren (nxa0=xa0113) aged 0 to 15 years admitted for complex congenital heart disease were randomly allocated according to age to remote ischemic preconditioning and control groups. After exclusion of 8 patients, we conducted the analysis on 105 patients (remote ischemic preconditioning group, nxa0=xa054; control group, nxa0=xa051). Before surgery, remote ischemic preconditioning was performed as 4 cycles of 5 minutes of ischemia by inflating a cuff around a leg to 40 mm Hg above the systolic pressure. End points were development of acute kidney injury, initiation of dialysis, plasma creatinine, estimated glomerular filtration rate, plasma cystatin C, plasma and urinary neutrophil gelatinase-associated lipocalin, and urinary output. Secondary end points included postoperative blood pressure, inotropic score, and mortality, as well as morbidity reflected by reoperation and stays in the intensive care unit and hospital.nnnRESULTSnOverall, 57 of the children (54%) had acute kidney injury develop, with 27 (50%) in the remote ischemic preconditioning group and 30 (59%) in the control group (P > .2). Remote ischemic preconditioning was not associated with improvement in either any of the renal biomarkers or any of the secondary end points.nnnCONCLUSIONSnWe found no evidence that remote ischemic preconditioning provided protection of kidney function in children undergoing operation for complex congenital heart disease.

Neutrophil Gelatinase-Associated Lipocalin (NGAL): Validation of commercially available ELISA

Abstract Background. Neutrophil Gelatinase-Associated Lipocalin (NGAL) has been described as an excellent marker of acute kidney injury (AKI) using the enzyme-linked immunosorbent assay (ELISA) from BioPorto Diagnostics, DK. Validation of the ELISA kit and investigation of stability of the NGAL protein is a prerequisite before introducing NGAL as a marker for AKI in clinical research. Methods. Plasma and urine samples from a healthy adult and from 16 children undergoing surgery for congenital heart disease were used to validate the 036 NGAL ELISA kit from BioPorto Diagnostics and study stability of the NGAL protein. Results. Median intra-assay variation in plasma and urine from the healthy adult was <5% and median inter-assay variation was <10%. For children undergoing surgery for congenital heart disease intra-assay variation was <10%. ELISA kit batch-to-batch variation for plasma was 14.6%. We observed excellent results on analysis of linearity and spike-recovery and found no clinically important variation of NGAL measurements throughout the ELISA plate. Haemolysis significantly interfered with measurement of NGAL, whereas repeated thawing or 48 h of 4–5°C-storage before centrifugation and storage at −80°C did not influence NGAL measurements (ANOVA; n.s.). The NGAL protein is stable in plasma for at least 11 months at −80°C. Conclusion. 036 NGAL ELISA kit from BioPorto Diagnostics can be used with acceptable precision for plasma and urine. However, the presence of haemolysis in blood samples or the use of different batches of ELISA kits may seriously decrease the accuracy of measurements.

Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.

Ex-vivo response to blood products and haemostatic agents after paediatric cardiac surgery.

Bleeding complications after cardiac surgery are of particular importance in children because they are more prone to volume overload. To optimize haemostatic intervention, the coagulopathy has to be characterized, and knowledge about the effect of blood products and haemostatic agents is needed. The aims of the present study were to investigate changes in coagulation profiles after paediatric cardiac surgery and the effect after ex-vivo addition of blood products and haemostatic agents. Coagulation profiles were evaluated by thromboelastometry (ROTEM) in 54 children before and immediately after cardiac surgery. The haemostatic potential of various factor concentrates (fibrinogen concentrate, recombinant factor VIIa and factor XIII), fresh frozen plasma (FFP), pooled platelets and tranexamic acid was investigated. After surgery, the coagulation profiles revealed significantly prolonged clotting time (Pu200a=u200a0.008), and reduced clot propagation (Pu200a<u200a0.001) as well as reduced whole blood clot stability (Pu200a<u200a0.001). Ex-vivo addition of pooled platelets fully reversed the postoperative coagulopathy; this was also seen after addition of recombinant factor VIIa although less pronounced. Finally, addition of fibrinogen concentrate, FFP or tranexamic acid improved clot stability significantly. Whole blood coagulation was significantly impaired after cardiac surgery in children. Ex-vivo studies showed a total reversal of the coagulopathy after addition of pooled platelets and significantly improved clot stability after addition of fibrinogen concentrate, FFP and tranexamic acid, respectively.

Evaluation of different sized blood sampling tubes for thromboelastometry, platelet function, and platelet count

Abstract Background: To minimise the volume of blood used for diagnostic procedures, especially in children, we investigated whether the size of sample tubes affected whole blood coagulation analyses. Methods: We included 20 healthy individuals for rotational thromboelastometry (RoTEM®) analyses and compared three blood sampling tubes of different size: 1.8, 2.7, and 3.6 mL. All tubes were made of plastic and contained 3.2% sodium-citrate as anticoagulant. Platelet aggregation was investigated in 12 healthy individuals employing the Multiplate® Analyser comparing tubes of 3.6 mL and 1.8 mL. Platelet count was determined for each of the sampling tubes after 10, 60, and 120 min. Results: No significant differences were found in any of the RoTEM® measurements between the three sizes of tubes (p=0.07–0.53). Platelet aggregation was significantly lower when using smaller tubes (p=0.0004). The platelet count remained stable using a 3.6 mL tube during the entire observation period of 120 min (p=0.74), but decreased significantly after 60 min when using tubes smaller than 3.6 mL (p<0.0001). Conclusions: RoTEM® analyses were not affected by the size of blood sampling tubes. Therefore, 1.8 mL tubes should be preferred for RoTEM® analyses in order to minimise the volume of blood drawn. With regard to platelet aggregation analysed by impedance aggregometry tubes of different size cannot be used interchangeably. If platelet count is determined later than 10 min after blood sampling using tubes containing citrate as anticoagulant, a 3.6 mL tube should be preferred to avoid false low values.

Age-dependent effects of milrinone and levosimendan on ventricular function and haemodynamics in newborn and mature pigs.

Inodilators are used in the treatment of low cardiac output, mainly after cardiac surgery. At present, there is little knowledge of the effect of inodilators in the newborn heart. Immediately after birth and in the neonatal period, the metabolism and physiology of the heart undergo major changes. We hypothesised that effects of the inodilators milrinone and levosimendan on myocardial contractility and haemodynamics under normal physiological conditions were age dependent. Animal studies were conducted on 48 pigs using a closed-chest biventricular conductance catheter method. Pigs in two age groups, that is, 5-6 days and 5-6 weeks, were assigned to milrinone, levosimendan, or a control group. We observed that both milrinone - 19.2% with a p value of 0.05 - and levosimendan - 25.7% with a p value of 0.03 compared with the control group increased cardiac output, as well as myocardial contractility with a maximum pressure development over time: milrinone 28.2%, p = 0.01 and levosimendan 19.4%, p = 0.05. Milrinone improved diastolic performance (p < 0.05) in the left ventricle in the 5-6-week-old animals. In the newborn animals, neither of the inodilators increased ventricular contractility or cardiac output; however, we observed a significant decrease in the mean arterial pressure: milrinone 34.6%, p < 0.01 and levosimendan 30.1%, p = 0.02. Both inodilators demonstrated age-dependent haemodynamic effects, and it is noteworthy that neither milrinone nor levosimendan was able to increase cardiac output in the newborn heart.

Measures of right ventricular function after transcatheter versus surgical aortic valve replacement

ObjectivesnDescribe changes in measures of right ventricular (RV) function in patients treated for aortic stenosis using open-chest surgery (SAVR) or transcatheter treatment (TAVR).nnnMethodsnPatients in the Nordic Aortic Valve Intervention (NOTION) trial were randomized 1:1 to TAVR (n = 114) or SAVR (n = 106). Echocardiography was performed at baseline and 3 and 12 months post-procedure. Tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) were used as measures of longitudinal and transverse RV contraction. Left ventricular ejection fraction (LVEF) and LV atrioventricular plane displacement (AVPD) were recorded as measures of LV function. Association to NYHA class was examined.nnnResultsnThere were no differences in echocardiographic measurements between TAVR and SAVR at baseline. In the SAVR group, TAPSE was reduced after 3 months (2.4 ± 0.5 cm vs 1.6 ± 0.4 cm; P < 0.001), and 12 months (2.4 ± 0.5 cm vs 1.7 ± 0.4 cm; P < 0.001). RVFAC was reduced after 3 months (44% ± 11% vs 39% ± 10%; P = 0.001), but recovered at 12 months (43% ± 10%; P = 0.39). AVPD lateral increased during follow-up (1.4 ± 0.3 cm vs 1.6 ± 0.4 cm (P = 0.001) and 1.7 ± 0.4 cm, respectively; P < 0.001), whereas AVPD medial remained stable (baseline vs 3 months: P = 0.06 and baseline vs 12 months: P = 0.59). In the TAVR group, all echocardiographic measures remained unchanged from baseline to 12 months postoperatively. We found no association between echocardiographic changes and NYHA class.nnnConclusionsnTAPSE and AVPD lateral differed between TAVR and SAVR at 3 and 12 months follow-up, but these findings were not related to any changes in NYHA class. These observations indicate that following SAVR, echocardiographic changes may not reflect right ventricular function, but merely a change in the physiological conditions.nnnClinicaltrials.gov identifiernNCT01057173.

High-Target Versus Low-Target Blood Pressure Management During Cardiopulmonary Bypass to Prevent Cerebral Injury in Cardiac Surgery Patients: A Randomized Controlled Trial

Background: Cerebral injury is an important complication after cardiac surgery with the use of cardiopulmonary bypass. The rate of overt stroke after cardiac surgery is 1% to 2%, whereas silent strokes, detected by diffusion-weighted magnetic resonance imaging, are found in up to 50% of patients. It is unclear whether a higher versus a lower blood pressure during cardiopulmonary bypass reduces cerebral infarction in these patients. Methods: In a patient- and assessor-blinded randomized trial, we allocated patients to a higher (70–80 mmu2009Hg) or lower (40–50 mmu2009Hg) target for mean arterial pressure by the titration of norepinephrine during cardiopulmonary bypass. Pump flow was fixed at 2.4 L·min−1·m−2. The primary outcome was the total volume of new ischemic cerebral lesions (summed in millimeters cubed), expressed as the difference between diffusion-weighted imaging conducted preoperatively and again postoperatively between days 3 and 6. Secondary outcomes included diffusion-weighted imaging–evaluated total number of new ischemic lesions. Results: Among the 197 enrolled patients, mean (SD) age was 65.0 (10.7) years in the low-target group (n=99) and 69.4 (8.9) years in the high-target group (n=98). Procedural risk scores were comparable between groups. Overall, diffusion-weighted imaging revealed new cerebral lesions in 52.8% of patients in the low-target group versus 55.7% in the high-target group (P=0.76). The primary outcome of volume of new cerebral lesions was comparable between groups, 25 mm3 (interquartile range, 0–118 mm3; range, 0–25u2009261 mm3) in the low-target group versus 29 mm3 (interquartile range, 0–143 mm3; range, 0–22u2009116 mm3) in the high-target group (median difference estimate, 0; 95% confidence interval, −25 to 0.028; P=0.99), as was the secondary outcome of number of new lesions (1 [interquartile range, 0–2; range, 0–24] versus 1 [interquartile range, 0–2; range, 0–29] respectively; median difference estimate, 0; 95% confidence interval, 0–0; P=0.71). No significant difference was observed in frequency of severe adverse events. Conclusions: Among patients undergoing on-pump cardiac surgery, targeting a higher versus a lower mean arterial pressure during cardiopulmonary bypass did not seem to affect the volume or number of new cerebral infarcts. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02185885.

Does whole blood coagulation analysis reflect developmental haemostasis

&NA; Developmental haemostasis has been well documented over the last 3 decades and age-dependent reference ranges have been reported for a number of plasmatic coagulation parameters. With the increasing use of whole blood point-of-care tests like rotational thromboelastometry (ROTEM) and platelet function tests, an evaluation of age-dependent changes is warranted for these tests as well. We obtained blood samples from 149 children, aged 1 day to 5.9 years, and analysed conventional plasmatic coagulation tests, including activated partial prothrombin time, prothrombin time, and fibrinogen (functional). Whole blood samples were analysed using ROTEM to assess overall coagulation capacity and Multiplate analyzer to evaluate platelet aggregation. Age-dependent changes were analysed for all variables. We found age-dependent differences in all conventional coagulation tests (all P values < 0.05), but there was no sign of developmental changes in whole blood coagulation assessment when applying ROTEM, apart from clotting time in the EXTEM assay (Pu200a<u200a0.03). Despite marked differences in mean platelet aggregation between age groups, data did not reach statistical significance. Citrate-anticoagulated blood showed significantly reduced platelet aggregation compared with blood anticoagulated with heparin or hirudin (all P values < 0.003). We confirmed previous developmental changes in conventional plasmatic coagulation test. However, these age-dependent changes were not displayed in whole blood monitoring using ROTEM or Multiplate analyzer. Type of anticoagulant had a significant influence on platelet aggregation across all age groups.

Pulmonary artery perfusion versus no pulmonary perfusion during cardiopulmonary bypass in patients with COPD: a randomised clinical trial

Introduction Absence of pulmonary perfusion during cardiopulmonary bypass (CPB) may be associated with reduced postoperative oxygenation. Effects of active pulmonary artery perfusion were explored in patients with chronic obstructive pulmonary disease (COPD) undergoing cardiac surgery. Methods 90 patients were randomised to receive pulmonary artery perfusion during CPB with either oxygenated blood (n=30) or histidine-tryptophan-ketoglutarate (HTK) solution (n=29) compared with no pulmonary perfusion (n=31). The coprimary outcomes were the inverse oxygenation index compared at 21u2005hours after starting CPB and longitudinally in a mixed-effects model (MEM). Secondary outcomes were tracheal intubation time, serious adverse events, mortality, days alive outside the intensive care unit (ICU) and outside the hospital. Results 21u2005hours after starting CPB patients receiving pulmonary artery perfusion with normothermic oxygenated blood had a higher oxygenation index compared with no pulmonary perfusion (mean difference (MD) 0.94; 95% CI 0.05 to 1.83; p=0.04). The blood group had also a higher oxygenation index both longitudinally (MEM, p=0.009) and at 21u2005hours (MD 0.99; CI 0.29 to 1.69; p=0.007) compared with the HTK group. The latest result corresponds to a difference in the arterial partial pressure of oxygen of 23u2005mmu2005Hg with a median fraction of inspired oxygen of 0.32. Yet the blood or HTK groups did not demonstrate a longitudinally higher oxygenation index compared with no pulmonary perfusion (MEM, p=0.57 and 0.17). Similarly, at 21u2005hours there was no difference in the oxygenation index between the HTK group and those no pulmonary perfusion (MD 0.06; 95% CI −0.73 to 0.86; p=0.87). There were no statistical significant differences between the groups for the secondary outcomes. Discussion Pulmonary artery perfusion with normothermic oxygenated blood during cardiopulmonary bypass appears to improve postoperative oxygenation in patients with COPD undergoing cardiac surgery. Pulmonary artery perfusion with hypothermic HTK solution does not seem to improve postoperative oxygenation. Trial registration number NCT01614951; Pre-results.