Urinary Neutrophil Gelatinase-Associated Lipocalin/Hepcidin-25 Ratio for Early Identification of Patients at Risk for Renal Replacement Therapy After Cardiac Surgery: A Substudy of the BICARBONATE Trial.

BACKGROUND: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is strongly associated with mortality after cardiac surgery; however, options for early identification of patients at high risk for AKI-RRT are extremely limited. Early after cardiac surgery, the predictive ability for AKI-RRT even of one of the most extensively evaluated novel urinary biomarkers, neutrophil gelatinase-associated lipocalin (NGAL), appears to be only moderate. We aimed to determine whether the NGAL/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) early after surgery may compare favorably to NGAL for identification of high-risk patients after cardiac surgery. METHODS: This is a prospective substudy of the BICARBONATE trial, a multicenter parallel-randomized controlled trial comparing perioperative bicarbonate infusion for AKI prevention to usual patient care. At a tertiary referral center, 198 patients at increased kidney risk undergoing cardiac surgery with cardiopulmonary bypass were included into the present study. The primary outcome measure was defined as AKI-RRT. Secondary outcomes were in-hospital mortality and long-term mortality. We compared area under the curve of the receiver operating characteristic (AUC-ROC) of urinary NGAL with that of the urinary NGAL/hepcidin-25 ratio within 60 minutes after end of surgery. We compared adjusted AUC and performed cross-validated reclassification statistics of the (logarithmic) urinary NGAL/hepcidin-25 ratio adjusted to Cleveland risk score/EuroScore, cross-clamp time, age, volume of packed red blood cells, and (logarithmic) urinary NGAL concentration. The association of the NGAL/hepcidin-25 ratio with long-term patient survival was assessed using Cox proportional hazard regression analysis adjusting for EuroScore, aortic cross-clamp time, packed red blood cells and urinary NGAL. RESULTS: Patients with AKI-RRT (n = 13) had 13.7-times higher NGAL and 3.3-times lower hepcidin-25 concentrations resulting in 46.9-times higher NGAL/hepcidin-25 ratio early after surgery compared to patients without AKI-RRT. The NGAL/hepcidin-25 ratio had higher AUC-ROC compared with NGAL for risk of AKI-RRT and in-hospital mortality (unadjusted AUC-ROC difference 0.087, 95% confidence interval [CI], 0.036-0.138, P < .001; 0.082, 95% CI, 0.018-0.146, P = .012). For AKI-RRT, the NGAL/hepcidin-25 ratio increased adjusted category-free net reclassification improvement (cfNRI; 0.952, 95% CI, 0.437-1.468; P < .001) and integrated discrimination improvement (IDI; 0.040, 95% CI, 0.008-0.073; P = .016) but not AUC difference. For in-hospital mortality, the ratio improved AUC of the reference model (AUC difference 0.056, 95% CI, 0.003-0.108; P = .037) and cfNRI but not IDI. The urinary NGAL/hepcidin-25 ratio remained significantly associated with long-term mortality after adjusting for the model covariates. CONCLUSIONS: The urinary NGAL/hepcidin-25 ratio appears to early identify high-risk patients and outperform NGAL after cardiac surgery. Confirmation of our findings in other cardiac surgery centers is now needed.

Effect of iloprost inhalation on postoperative outcome in high-risk cardiac surgical patients: a prospective randomized-controlled multicentre trial (ILOCARD).

PURPOSE: Perioperative right ventricular (RV) failure due to pressure overload from pulmonary hypertension (PH) worsens postoperative outcomes after cardiac surgery. Inhaled iloprost is a potent pulmonary vasodilator improving RV performance, ameliorating myocardial and pulmonary ischemia-reperfusion injury and attenuating inflammation. We hypothesized that the prophylactic inhalation of iloprost would reduce postoperative ventilation times after cardiac surgery. METHODS: In this phase III, multicentre, randomized, double-blind, placebo-controlled trial, we randomly assigned 253 cardiac surgical patients at high risk of perioperative RV failure to the prophylactic inhalation of 20 µg iloprost or placebo before and during weaning from extracorporeal circulation. The primary endpoint was the duration of postoperative ventilation. Secondary endpoints included perioperative hemodynamics, intensive care unit and hospital length of stay, and 90-day mortality. Safety was assessed by the incidence of adverse events. RESULTS: Iloprost had no significant effect on the median [interquartile range] duration of postoperative ventilation compared with placebo (720 [470-1170] min vs 778 [541-1219] min, respectively; median decrease, 65 min; 95% confidence interval [CI], - 77 to 210; P = 0.37). While the nebulization of iloprost decreased RV afterload and improved cardiac index, major secondary endpoints were not significantly affected. Ninety-day mortality occurred in 14% of the iloprost patients compared with 14% of the placebo patients (hazard ratio, 0.97; 95% CI, 0.50 to 1.89; P = 0.93). The incidence of adverse events was comparable in both groups. CONCLUSIONS: The prophylactic inhalation of iloprost did not meaningfully improve the outcome in high-risk cardiac surgical patients. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00927654); registered 25 June, 2009.

RéSUMé: OBJECTIF: L'insuffisance cardiaque droite périopératoire due à une surcharge de pression provoquée par l'hypertension pulmonaire (HP) a un impact négatif sur le pronostic postopératoire après une chirurgie cardiaque. L'iloprost administré par inhalation est un vasodilatateur pulmonaire puissant qui améliore la performance du ventricule droit (VD), réduisant ainsi la lésion d'ischémie-reperfusion myocardique et pulmonaire et atténuant l'inflammation. Nous avons émis l'hypothèse qu'une inhalation prophylactique d'iloprost réduirait les temps de ventilation postopératoire après une chirurgie cardiaque. MéTHODE: Dans cette étude multicentrique de phase III, contrôlée par placebo, à double insu et randomisée, nous avons distribué aléatoirement 253 patients chirurgicaux courant un risque élevé d'insuffisance cardiaque droite périopératoire à une prophylaxie de 20 µg d'iloprost ou d'un placebo par inhalation avant et pendant le sevrage de la circulation extracorporelle. Le critère d'évaluation principal était la durée de ventilation postopératoire. Les critères d'évaluation secondaires étaient les données hémodynamiques périopératoires, la durée de séjour à l'unité de soins intensifs et à l'hôpital, et la mortalité à 90 jours. L'innocuité a été évaluée en fonction de l'incidence d'événements indésirables. RéSULTATS: L'iloprost n'a pas eu d'effet significatif sur la durée médiane [écart interquartile] de ventilation postopératoire par rapport au placebo (720 [470­1170] min vs 778 [541­1219] min, respectivement; réduction médiane, 65 min; intervalle de confiance [IC] 95 %, − 77 à 210; P = 0,37). Bien que la nébulisation d'iloprost ait réduit la post-charge du VD et amélioré l'index cardiaque, cette manœuvre n'a pas eu d'impact significatif sur les critères d'évaluation secondaires majeurs. Une mortalité à 90 jours a été observée chez 14 % des patients ayant reçu de l'iloprost, comparativement à 14 % des patients ayant reçu un placebo (rapport de risque, 0,97; IC 95 %, 0,50 à 1,89; P = 0,93). L'incidence d'événements indésirables était comparable dans les deux groupes. CONCLUSION: L'inhalation prophylactique d'iloprost n'a pas amélioré le pronostic des patients de chirurgie cardiaque à haut risque. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT00927654); enregistrée le 25 juin 2009.

Left Ventricular Systolic Dysfunction in Patients With Type-A Aortic Dissection Is Associated With 30-Day Mortality.

OBJECTIVE: The aim of this study was to analyze preoperative and postoperative echocardiographic parameters in patients with type-A acute aortic dissection (ATAAD) and to analyze whether impaired preoperative left ventricular function was associated with short- and long-term survival. To enable multivariable analysis, established risk factors of ATAAD were analyzed as well. DESIGN: Retrospective single-center study. SETTING: The German Heart Center Berlin. PARTICIPANTS: The retrospective data of 512 patients with ATAAD who were treated between 2006 and 2014 were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Preoperative versus postoperative left ventricular ejection fraction (LVEF), right ventricular ejection fraction, left ventricular end-diastolic diameter, and right ventricular end-diastolic diameter were not significantly different, and the mean values were within the reference ranges. Because of the surgical intervention, incidences and severities of aortic regurgitation and pericardial effusion decreased. In multivariable logistic analysis, the authors identified age (odds ratio [OR] 1.04, p < 0.001), preoperative LVEF ≤35% (OR 2.20, p = 0.003), any ischemia (Penn non-Aa) (OR 2.15, p < 0.001), and longer cardiopulmonary bypass time (OR 1.04, p < 0.001) as independent predictors of 30-day mortality. Cardiopulmonary resuscitation, tamponade, or shock, and pre-existing cardiac disease, were not predictors of death. CONCLUSION: After surgery, aortic insufficiency and pericardial effusion decreased, whereas cardiac functional parameters did not change. Severe LV dysfunction was identified as a new independent predictor of 30-day mortality.

Role of Transient Receptor Potential Vanilloid 4 in Neutrophil Activation and Acute Lung Injury.

The cation channel transient receptor potential vanilloid (TRPV) 4 is expressed in endothelial and immune cells; however, its role in acute lung injury (ALI) is unclear. The functional relevance of TRPV4 was assessed in vivo, in isolated murine lungs, and in isolated neutrophils. Genetic deficiency of TRPV4 attenuated the functional, histological, and inflammatory hallmarks of acid-induced ALI. Similar protection was obtained with prophylactic administration of the TRPV4 inhibitor, GSK2193874; however, therapeutic administration of the TRPV4 inhibitor, HC-067047, after ALI induction had no beneficial effect. In isolated lungs, platelet-activating factor (PAF) increased vascular permeability in lungs perfused with trpv4(+/+) more than with trpv4(-/-) blood, independent of lung genotype, suggesting a contribution of TRPV4 on blood cells to lung vascular barrier failure. In neutrophils, TRPV4 inhibition or deficiency attenuated the PAF-induced increase in intracellular calcium. PAF induced formation of epoxyeicosatrienoic acids by neutrophils, which, in turn, stimulated TRPV4-dependent Ca(2+) signaling, whereas inhibition of epoxyeicosatrienoic acid formation inhibited the Ca(2+) response to PAF. TRPV4 deficiency prevented neutrophil responses to proinflammatory stimuli, including the formation of reactive oxygen species, neutrophil adhesion, and chemotaxis, putatively due to reduced activation of Rac. In chimeric mice, however, the majority of protective effects in acid-induced ALI were attributable to genetic deficiency of TRPV4 in parenchymal tissue, whereas TRPV4 deficiency in circulating blood cells primarily reduced lung myeloperoxidase activity. Our findings identify TRPV4 as novel regulator of neutrophil activation and suggest contributions of both parenchymal and neutrophilic TRPV4 in the pathophysiology of ALI.

Monitoring depth of anesthesia utilizing a combination of electroencephalographic and standard measures.

BACKGROUND: For decades, monitoring depth of anesthesia was mainly based on unspecific effects of anesthetics, for example, blood pressure, heart rate, or drug concentrations. Today, electroencephalogram-based monitors promise a more specific assessment of the brain function. To date, most approaches were focused on a "head-to-head" comparison of either electroencephalogram- or standard parameter-based monitoring. In the current study, a multimodal indicator based on a combination of both electro encephalographic and standard anesthesia monitoring parameters is defined for quantification of "anesthesia depth." METHODS: Two hundred sixty-three adult patients from six European centers undergoing surgery with general anesthesia were assigned to 1 of 10 anesthetic combinations according to standards of the enrolling hospital. The anesthesia multimodal index of consciousness was developed using a data-driven approach, which maps standard monitoring and electroencephalographic parameters into an output indicator that separates different levels of anesthesia from awake to electroencephalographic burst suppression. Obtained results were compared with either a combination of standard monitoring parameters or the electroencephalogram-based bispectral index. RESULTS: The anesthesia multimodal index of consciousness showed prediction probability (P(K)) of 0.96 (95% CI, 0.95 to 0.97) to separate different levels of anesthesia (wakefulness to burst suppression), whereas the bispectral index had significantly lower PK of 0.80 (0.76 to 0.81) at corrected threshold P value of less than 0.05. At the transition between consciousness and unconsciousness, anesthesia multimodal index of consciousness yielded a PK of 0.88 (0.85 to 0.91). CONCLUSION: A multimodal integration of both standard monitoring and electroencephalographic parameters may more precisely reflect the level of anesthesia compared with monitoring based on one of these aspects alone.

Red blood cell storage duration is associated with various clinical outcomes in pediatric cardiac surgery.

BACKGROUND: Recommendations on the use of fresh red blood cells (RBCs) in pediatric patients undergoing cardiac surgery are based on limited information. Furthermore, the RBC storage time cut-off of fresh units remains unknown. METHODS: Data from 139 pediatric patients who underwent cardiac surgery and received RBCs from a single unit within 14 days of storage were analyzed. To identify the optimal cut-off storage time of RBCs for transfusion, multiple multivariate analyses aimed at different outcome parameters were performed. RESULTS: 26 patients received RBC units stored for ≤3 days, while 126 patients received RBCs that were stored for 4-14 days. The latter group required more RBC transfusions and fresh frozen plasma (FFP) than the former group (19 vs. 25 ml/kg, p = 0.003 and 73% vs. 35%, p = 0.0006, respectively). In addition, the odds for the administration of FFP increased with the transfusion of RBCs stored for more than 4 days. The optimal cut-off for post-operative morbidity was observed with a storage time of ≤6 days for length of ventilation (p = 0.02) and peak of C-reactive protein (CRP; p = 0.008). CONCLUSIONS: The obtained results indicate that the hazard of blood transfusion increased with increasing storage time of RBCs. The results of this study suggest that transfusion of fresh RBCs with a storage time of ≤2 or 4 days (concerning transfusion requirements) or ≤6 days (concerning postoperative morbidity) may be beneficial in pediatric patients undergoing cardiac surgery. However, further prospective randomized studies are required in order to draw any final conclusions.

Prophylactic perioperative sodium bicarbonate to prevent acute kidney injury following open heart surgery: a multicenter double-blinded randomized controlled trial.

BACKGROUND: Preliminary evidence suggests a nephroprotective effect of urinary alkalinization in patients at risk of acute kidney injury. In this study, we tested whether prophylactic bicarbonate-based infusion reduces the incidence of acute kidney injury and tubular damage in patients undergoing open heart surgery. METHODS AND FINDINGS: In a multicenter, double-blinded (patients, clinical and research personnel), randomized controlled trial we enrolled 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass. At induction of anesthesia, patients received either 24 hours of intravenous infusion of sodium bicarbonate (5.1 mmol/kg) or sodium chloride (5.1 mmol/kg). The primary endpoint was the proportion of patients developing acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early under recommendation of the Data Safety and Monitoring Committee because interim analysis suggested likely lack of efficacy and possible harm. Groups were non-significantly different at baseline except that a greater proportion of patients in the sodium bicarbonate group (66/174 [38%]) presented with preoperative chronic kidney disease compared to control (44/176 [25%]; p = 0.009). Sodium bicarbonate increased urinary pH (from 6.0 to 7.5, p<0.001). More patients receiving bicarbonate (83/174 [47.7%]) developed acute kidney injury compared with control patients (64/176 [36.4%], odds ratio [OR] 1.60 [95% CI 1.04-2.45]; unadjusted p = 0.032). After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint (OR 1.45 [0.90-2.33], p = 0.120]). A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control (11/174 [6.3%] versus 3/176 [1.7%], OR 3.89 [1.07-14.2], p = 0.031). CONCLUSIONS: Urinary alkalinization using sodium bicarbonate infusion was not found to reduce the incidence of acute kidney injury or attenuate tubular damage following open heart surgery; however, it was associated with a possible increase in mortality. On the basis of these findings we do not recommend the prophylactic use of sodium bicarbonate infusion to reduce the risk of acute kidney injury. Discontinuation of growing implementation of this therapy in this setting seems to be justified. TRIAL REGISTRATION: ClinicalTrials.gov NCT00672334 Please see later in the article for the Editors' Summary.

Lung endothelial dysfunction in congestive heart failure: role of impaired Ca2+ signaling and cytoskeletal reorganization.

RATIONALE: Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction. OBJECTIVE: We applied real-time fluorescence imaging to identify endothelial dysfunction and underlying molecular mechanisms in an experimental model of CHF induced by supracoronary aortic banding in rats. METHODS AND RESULTS: Endothelial dysfunction was evident in lungs of CHF rats as impaired endothelium-dependent vasodilation and lack of endothelial NO synthesis in response to mechanical stress, acetylcholine, or histamine. This effect was not attributable to downregulation of endothelial NO synthase. Imaging of the cytosolic Ca(2+) concentration ([Ca(2+)](i)) revealed a singular impairment of endothelial [Ca(2+)](i) homeostasis and signaling characterized by a lack of [Ca(2+)](i) oscillations and deficient or attenuated [Ca(2+)](i) responses to mechanical stress, histamine, acetylcholine, or thapsigargin. Reconstitution of a [Ca(2+)](i) signal by ionophore treatment restored endothelial NO production, but lack of endothelial responsiveness was not primarily attributable to downregulation of Ca(2+) influx channels in CHF. Rather, we identified a massive remodeling of the endothelial cytoskeleton in the form of an increased expression of beta-actin and F-actin formation which contributed critically to endothelial dysfunction in CHF because cytoskeletal disruption by cytochalasin D largely reconstituted endothelial [Ca(2+)](i) signaling and NO production. CONCLUSIONS: Our findings characterize a unique scenario of endothelial dysfunction in CHF that is caused by a singular impairment of [Ca(2+)](i) signaling, and identify cytoskeletal reorganization as a major regulator of endothelial signaling and function.

Urine hepcidin has additive value in ruling out cardiopulmonary bypass-associated acute kidney injury: an observational cohort study.

INTRODUCTION: Conventional markers of acute kidney injury (AKI) lack diagnostic accuracy and are expressed only late after cardiac surgery with cardiopulmonary bypass (CPB). Recently, interest has focused on hepcidin, a regulator of iron homeostasis, as a unique renal biomarker. METHODS: We studied 100 adult patients in the control arm of a randomized, controlled trial http://www.clinicaltrials.gov/NCT00672334 who were identified as being at increased risk of AKI after cardiac surgery with CPB. AKI was defined according to the Risk, Injury, Failure, Loss, End-stage renal disease classification of AKI classification stage. Samples of plasma and urine were obtained simultaneously (1) before CPB (2) six hours after the start of CPB and (3) twenty-four hours after CPB. Plasma and urine hepcidin 25-isoforms were quantified by competitive enzyme-linked immunoassay. RESULTS: In AKI-free patients (N = 91), urine hepcidin concentrations had largely increased at six and twenty-four hours after CPB, and they were three to seven times higher compared to patients with subsequent AKI (N = 9) in whom postoperative urine hepcidin remained at preoperative levels (P = 0.004, P = 0.002). Furthermore, higher urine hepcidin and, even more so, urine hepcidin adjusted to urine creatinine at six hours after CPB discriminated patients who did not develop AKI (area under the curve (AUC) receiver operating characteristic curve 0.80 [95% confidence interval (95% CI) 0.71 to 0.87] and 0.88 [95% CI 0.78 to 0.97]) or did not need renal replacement therapy initiation (AUC 0.81 [95% CI 0.72 to 0.88] 0.88 [95% CI 0.70 to 0.99]) from those who did. At six hours, urine hepcidin adjusted to urine creatinine was an independent predictor of ruling out AKI (P = 0.011). Plasma hepcidin did not predict no development of AKI. The study findings remained essentially unchanged after excluding patients with preoperative chronic kidney disease. CONCLUSIONS: Our findings suggest that urine hepcidin is an early predictive biomarker of ruling out AKI after CPB, thereby contributing to early patient risk stratification.

A transapical or transluminal approach to aortic valve implantation does not attenuate the inflammatory response.

BACKGROUND: Cardiopulmonary bypass (CPB) and cardiac surgery cause an inflammatory response, as measurable by an increase in the concentration of C-reactive protein (CRP), a nonspecific inflammation marker. Previous publications have demonstrated typical perioperative CRP concentration profiles in cases of uncomplicated aortic valve replacement (AVR) with CPB. A regression analysis for modifying factors showed that chronic disease (heart failure, diabetes, and pulmonary disease), along with obesity and sex, all tend to influence the CRP response. We analyzed the inflammatory response to aortic valve implantation (AVI) with interventional techniques, mainly transapical but also transfemoral and transaxillary approaches, in a retrospective case-control study design. METHODS: Sixty-eight patients who underwent AVI by the transapical (59 patients), transfemoral (7 patients), or transaxillary (2 patients) approach were matched by age, sex, body mass index (BMI), and chronic-disease state (absence or presence of diabetes, pulmonary disease, and renal impairment) with 68 patients who underwent conventional AVR with CPB. We compared the 2 groups with respect to perioperative CRP concentration, EuroSCORE, and outcome data (time to extubation and 30-day mortality). All data were collected prospectively and analyzed retrospectively. RESULTS: The 2 groups-the study population (interventional) and the control population (conventional)-were similar in age, sex distribution, BMI, and chronic-disease status. As expected, the study population had a significantly higher median EuroSCORE. The 2 groups had similar postoperative CRP profiles over time, but the interventional group had significantly higher peak concentrations on days 2, 3, and 4. The short-term outcomes, as assessed by ventilation time and 30-day mortality, were similar for the 2 groups. CONCLUSIONS: Using an interventional transcatheter approach to AVI (thereby eliminating CPB from the procedure and reducing surgical trauma) does not attenuate the patient's innate inflammatory response.

Urinary biomarkers to predict severe fluid overload after cardiac surgery: a pilot study.

Aim: To assess the predictive ability of urinary and plasma biomarkers and clinical routine parameters for subsequent severe fluid overload. Patients & methods: In a pilot study, we studied 100 adult patients after cardiac surgery. On intensive care unit admission, we measured biomarkers in urine (midkine, IL-6, neutrophil gelatinase-associated lipocalin [NGAL], hepcidin-25) and plasma (creatinine, urea, B-type natriuretic peptide, lactate, C-reactive protein, leukocytes, IL-6, NGAL, hepcidin-25) to predict postoperative severe fluid overload. Results: Urinary midkine, IL-6, NGAL and hepcidin-25 (all AUCs ≥0.79) predicted postoperative severe fluid overload (n = 5 patients). Urinary NGAL/hepcidin-25 ratio (AUC 0.867) predicted postoperative severe fluid overload after adjustment to EuroScore and need for norepinephrine on surgery day (odds ratio: 2.4). Conclusion: Urinary biomarkers on intensive care unit admission might be helpful to predict subsequent severe fluid overload after cardiac surgery.

Lay abstract Aim: To assess whether proteins in the urine or blood or clinical routine laboratory parameters can predict severe body fluid overload after cardiac surgery. Patients & methods: In a pilot study, we studied 100 adult patients after cardiac surgery. After surgery, we measured proteins in the urine (midkine, IL-6, neutrophil gelatinase-associated lipocalin [NGAL], hepcidin-25) and blood (creatinine, urea, B-type natriuretic peptide, lactate, C-reactive protein, leukocytes, IL-6, NGAL, hepcidin-25) to predict postoperative severe fluid overload. Results: Urinary midkine, IL-6, NGAL and hepcidin-25 predicted postoperative severe fluid overload (n = 5 patients). Urinary NGAL/hepcidin-25 ratio predicted postoperative severe fluid overload after adjustment to important covariates. Conclusion: Urinary biomarkers might be helpful to predict subsequent severe fluid overload after cardiac surgery.

Fast-track extubation after cardiac surgery in infants: Tug-of-war between performance and reimbursement?

OBJECTIVES: To compare the safety and resource-efficacy of the fast-track (FT) concept (extubation ≤8 hours after surgery) versus the conventional approach (non-FT, >8 hours postoperatively) in infants undergoing open-heart surgery. METHODS: Infants <7 kg operated on cardiopulmonary bypass between 2014 and 2018 were analyzed. Propensity score matching (1:1) was performed for group comparison (FT vs non-FT). Intensive care unit (ICU) personnel use and unit performance were evaluated. Postoperative outcome and reimbursement based on German diagnosis-related groups were compared. RESULTS: Of 717 infants (median age: 4 months, Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality score: 0.1-4), FT extubation was achieved in 182 infants (25%). After matching, 123 pairs (FT vs non-FT) were formed without significant differences in baseline characteristics. FT versus non-FT showed a significantly shorter ICU stay (in days): 1.8 (0.9-2.8) versus 4.2 (1.9-6.4), P < .01, and postoperative length of stay (in days): 7 (6-10) versus 10 (7-15.5), P < .01; significantly lower postoperative transfusion rates: 61.3% versus 77%, P < .01; and tendency toward lower early mortality: 0% versus 2.8%, P = .08. Reintubation rate did not differ between the groups (P = .7). Despite a decrease in personnel capacity (2014 vs 2018), the unit performance was maintained. The mean case-mix-index of FT versus non-FT was 8.56 ± 6.08 versus 11.77 ± 12.10 (P < .01), resulting in 27% less reimbursement in the FT group. CONCLUSIONS: FT concept can be performed safely and resource-effectively in infants undergoing open-heart surgery. Since German diagnosis-related group systems reimburse costs, not performance, there is little incentive to avoid prolonged mechanical ventilation. Greater ICU turnover rates and excellent postoperative outcomes are not rewarded adequately.

Negative-feedback loop attenuates hydrostatic lung edema via a cGMP-dependent regulation of transient receptor potential vanilloid 4.

Although the formation of hydrostatic lung edema is generally attributed to imbalanced Starling forces, recent data show that lung endothelial cells respond to increased vascular pressure and may thus regulate vascular permeability and edema formation. In combining real-time optical imaging of the endothelial Ca(2+) concentration ([Ca(2+)](i)) and NO production with filtration coefficient (K(f)) measurements in the isolated perfused lung, we identified a series of endothelial responses that constitute a negative-feedback loop to protect the microvascular barrier. Elevation of lung microvascular pressure was shown to increase endothelial [Ca(2+)](i) via activation of transient receptor potential vanilloid 4 (TRPV4) channels. The endothelial [Ca(2+)](i) transient increased K(f) via activation of myosin light-chain kinase and simultaneously stimulated NO synthesis. In TRPV4 deficient mice, pressure-induced increases in endothelial [Ca(2+)](i), NO synthesis, and lung wet/dry weight ratio were largely blocked. Endothelial NO formation limited the permeability increase by a cGMP-dependent attenuation of the pressure-induced [Ca(2+)](i) response. Inactivation of TRPV4 channels by cGMP was confirmed by whole-cell patch-clamp of pulmonary microvascular endothelial cells and intravital imaging of endothelial [Ca(2+)](i). Hence, pressure-induced endothelial Ca(2+) influx via TRPV4 channels increases lung vascular permeability yet concomitantly activates an NO-mediated negative-feedback loop that protects the vascular barrier by a cGMP-dependent attenuation of the endothelial [Ca(2+)](i) response. The identification of this novel regulatory pathway gives rise to new treatment strategies, as demonstrated in vivo in rats with acute myocardial infarction in which inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil reduced hydrostatic lung edema.

Inhaled nitric oxide versus aerosolized iloprost for the treatment of pulmonary hypertension with left heart disease.

OBJECTIVE: To determine the effects of inhaled nitric oxide (NO) and aerosolized iloprost on pulmonary hemodynamics and lung edema formation in a rat model of pulmonary hypertension due to congestive heart failure (CHF). DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory. SUBJECTS: One hundred sixty male Sprague-Dawley rats. INTERVENTIONS: CHF was induced by supracoronary aortic banding whereas sham-operated rats served as controls. CHF rats or controls inhaled NO, aerosolized iloprost, or 0.9% NaCl for 3 minutes each. Additional CHF groups received intravenous infusions of iloprost, sodium nitroprusside, or 0.9% NaCl. For prolonged drug administration over 150 minutes, NO was inhaled continuously whereas aerosolized iloprost was administered for 3 minutes each at 45-minute intervals. MEASUREMENTS AND MAIN RESULTS: Dose-response relations in rats with CHF showed a maximal pulmonary-selective reduction in blood pressure at 20 ppm NO and 2.5 microg/mL aerosolized iloprost, with iloprost therapy resulting in a greater decrease in pulmonary arterial pressure (PAP). At these doses, both vasodilators decreased pulmonary vascular resistance and increased venous oxygen saturation (Svo2) in the absence of systemic hemodynamic effects. No pulmonary or systemic effects were detected in rats with CHF inhaling 0.9% NaCl or in control rats inhaling NO or iloprost. Intravenous infusion of iloprost or sodium nitroprusside not only reduced pulmonary but also systemic vascular resistance. During prolonged inhalation, NO caused a stable reduction in PAP, whereas PAP decreased even further during repetitive iloprost inhalations. After 150 minutes, iloprost-treated rats had a higher Svo2 and lesser edema as compared with animals with CHF inhaling NO or untreated rats with CHF, although differences in wet/dry weight ratio did not reach statistical significance (p < 0.06). CONCLUSIONS: Inhaled vasodilators may offer an effective, safe, and pulmonary-selective strategy for the treatment of pulmonary hypertension in left heart disease, and inhaled iloprost may be superior to NO in this condition.

The feasibility of speckle tracking for intraoperative assessment of regional myocardial function by transesophageal echocardiography.

OBJECTIVES: The authors aimed to examine the feasibility of intraoperative transesophageal echocardiography (TEE) acquisition of a non-Doppler-based, speckle tracking-derived myocardial deformation parameter (strain) immediately before and after coronary artery bypass graft (CABG) surgery in patients with reduced left ventricular (LV) function. DESIGN: A clinical study. SETTING: The cardiac surgery operating room of a tertiary referral institution. PATIENTS: Ten patients with reduced LV function (ejection fraction lower than 35%) undergoing coronary revascularization were studied before and immediately after the procedure. INTERVENTIONS: Perioperative TEE. MEASUREMENTS AND RESULTS: A total of 120 myocardial segments were analyzed before and after CABG surgery. In visually obtained wall motion scoring (WMS), there were 29 normokinetic (N), 69 hypokinetic (H), 19 akinetic (A), and 3 dyskinetic (D) segments preoperatively and 26 N, 65 H, 21 A, and 8 D segments after CABG surgery. Preoperative radial strain correlated well with WMS (R = 0.82, p < 0.0001), whereas longitudinal strain showed only a weak correlation (R = 0.36, p < 0.0001). Postoperatively, correlations were similar. Interobserver variability as analyzed by kappa-statistics showed better agreement for radial (kappa = 0.82 +/- 0.05, p = 0.001) and longitudinal strain (kappa = 0.73 +/- 0.06, p = 0.004) than for WMS (kappa = 0.65 +/- 0.06). Preoperatively, strain was markedly greater in normally perfused segments than in ischemic segments, whereas the mean WMS revealed only minor differences. CONCLUSIONS: Strain calculation from TEE images is feasible during cardiac surgery and correlates well with WMS but has better interobserver agreement. Strain analysis, but not WMS, detected wall motion differences between normally perfused and ischemic segments. This simple method allows objective intraoperative quantification of myocardial segment function and may become an important monitoring tool in the future.

Intravital microscopy of the murine pulmonary microcirculation.

Intravital microscopy (IVM) is considered as the gold standard for in vivo investigations of dynamic microvascular regulation. The availability of transgenic and knockout animals has propelled the development of murine IVM models for various organs, but technical approaches to the pulmonary microcirculation are still scarce. In anesthetized and ventilated BALB/c mice, we established a microscopic access to the surface of the right upper lung lobe by surgical excision of a window of 7- to 10-mm diameter from the right thoracic wall. The window was covered by a transparent polyvinylidene membrane and sealed with alpha-cyanoacrylate. Removal of intrathoracic air via a trans-diaphragmal intrapleural catheter coupled the lung surface to the window membrane. IVM preparations were hemodynamically stable for at least 120 min, with mean arterial blood pressure above 70 mmHg, and mean arterial Po(2) and arterial Pco(2) in the range of 90-100 Torr and 30-40 Torr, respectively. Imaged lungs did not show any signs of acute lung injury or edema. Following infusion of FITC dextran, subpleural pulmonary arterioles and venules of up to 50-microm diameter and alveolar capillary networks could be visualized during successive expiratory plateau phases over a period of at least 2 h. Vasoconstrictive responses to hypoxia (11% O(2)) or infusion of the thromboxane analog U-46619 were prominent in medium-sized arterioles (30- to 50-microm diameter), minor in small arterioles <30 microm, and absent in venules. The presented IVM model may constitute a powerful new tool for investigations of pulmonary microvascular responses in mice.

Effect of modified ultrafiltration on bivalirudin elimination and postoperative blood loss after on-pump coronary artery bypass grafting: assessment of different filtration strategies.

OBJECTIVE: Bivalirudin has a short elimination half-life of approximately 25 to 30 minutes, but no antidote is available. We assessed the effect of four different strategies of modified ultrafiltration after cardiopulmonary bypass on the bivalirudin elimination and postoperative blood loss. METHODS: Five groups of seven patients undergoing elective "on-pump" coronary artery bypass grafting were enrolled in this controlled randomized investigation. The filtration strategies varied with regard to the filtration flow, the filtrate volume, the addition of vacuum suction to the filter system, and the performance of hemodiafiltration. Filtration was started after weaning from cardiopulmonary bypass (CPB). The cumulative postoperative blood drainage at 12 hours was recorded. RESULTS: Bivalirudin half-life in the control group was 0.6 +/- 0.11 hours, and the blood loss was 958 +/- 472 mL. Hemofiltration with a constant flow of 300 mL/m(2) body surface area/min and a filtrate volume of 3000 mL reduced the elimination half-life significantly to 0.47 +/- 0.11 hours. Adding the process of dialysis to hemofiltration resulted in a half-life of 0.52 +/- 0.04 hours and reduced the 12-hour postoperative blood loss significantly, compared to the control group, to 444 +/- 220 mL. The other strategies failed to augment the bivalirudin elimination and postoperative drainage effectively. CONCLUSION: Zero-balanced modified hemodiafiltration without addition of vacuum suction is effective in improving the elimination of bivalirudin after CPB and reducing the postoperative blood loss. Zero-balanced hemodiafiltration should be considered for the augmented elimination of bivalirudin in complex surgical procedures with a high risk of bleeding complications. However, larger investigations are warranted to confirm these results.

Health-related quality of life of patients after surgery for acute Type A aortic dissection.

OBJECTIVES: Acute Type A aortic dissection (ATAAD) and the ensuing surgical therapy may be experienced as a traumatic event by patients. This study aimed at analysing the prevalence of post-traumatic stress disorder (PTSD) and the physical and mental well-being of survivors of surgically treated ATAAD. METHODS: A total of 393 survivors were contacted and asked to fill in various health questionnaires. RESULTS: Two hundred and ten (53%) patients returned the questionnaires. The mean follow-up was 51 ± 27.8 months. The results showed that 67.6% had high blood pressure, 12.9% had pre-existing diseases of the aorta and 31.5% or 27% of these groups were at risk for PTSD according to the health questionnaires. Duration of intensive care unit or hospital stay had no effect on the risk for PTSD. According to the questionnaire, Short Form 12, physical and mental well-being was significantly reduced in the patients compared to a large German norm sample, even after adjustment for differences in age between the 2 cohorts. Physical activity prior to the event was associated with improved physical and mental well-being but did not reduce the risk for PTSD. CONCLUSIONS: Emergency surgery for ATAAD is associated with high risk for PTSD, which seems to negatively affect physical and mental well-being. More efforts should be directed at prevention and early diagnosis and therapy of PTSD. This study has evaluated 8-year trends in the presentation, diagnosis and outcomes such as physical and mental measures and prevalence rates of PTSD in patients who have undergone an emergency operation for ATAAD.

Urinary biomarkers may provide prognostic information for subclinical acute kidney injury after cardiac surgery.

OBJECTIVE: This study aimed to determine the biomarker-specific outcome patterns and short-and long-term prognosis of cardiac surgery-asoociated acute kidney injury (AKI) identified by standard criteria and/or urinary kidney biomarkers. METHODS: Patients enrolled (N = 200), originated a German multicenter study (NCT00672334). Standard risk injury, failure, loss, and end-stage renal disease classification (RIFLE) criteria (including serum creatinine and urine output) and urinary kidney biomarker test result (neutrophil gelatinase-associated lipocalin, midkine, interleukin 6, and proteinuria) were used for diagnosis of postoperative AKI. Primary end point was acute renal replacement therapy or in-hospital mortality. Long-term end points among others included 5-year mortality. Patients with single-biomarker-positive subclinical AKI (RIFLE negative) were identified. We controlled for systemic inflammation using C-reactive protein test. RESULTS: Urinary biomarkers (neutrophil gelatinase-associated lipocalin, midkine, and interleukin 6) were identified as independent predictors of the primary end point. Neutrophil gelatinase-associated lipocalin, midkine, or interleukin 6 positivity or de novo/worsening proteinuria identified 21.1%, 16.9%, 30.5%, and 48.0% more cases, respectively, with likely subclinical AKI (biomarker positive/RIFLE negative) additionally to cases with RIFLE positivity alone. Patients with likely subclinical AKI (neutrophil gelatinase-associated lipocalin or interleukin 6 positive) had increased risk of primary end point (adjusted hazard ratio, 7.18; 95% confidence interval, 1.52-33.93 [P = .013] and hazard ratio, 6.27; 95% confidence interval, 1.12-35.21 [P = .037]), respectively. Compared with biomarker-negative/RIFLE-positive patients, neutrophil gelatinase-associated lipocalin positive/RIFLE-positive or midkine-positive/RIFLE-positive patients had increased risk of primary end point (odds ratio, 9.6; 95% confidence interval, 1.4-67.3 [P = .033] and odds ratio, 14.7; 95% confidence interval, 2.0-109.2 [P = .011], respectively). Three percent to 11% of patients appear to be influenced by single-biomarker-positive subclinical AKI. During follow-up, kidney biomarker-defined short-term outcomes appeared to translate into long-term outcomes. CONCLUSIONS: Urinary kidney biomarkers identified RIFLE-negative patients with high-risk subclinical AKI as well as a higher risk subgroup of patients among RIFLE-AKI-positive patients. These findings support the concept that urinary biomarkers define subclinical AKI and higher risk subpopulations with worse long-term prognosis among standard patients with AKI.