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.

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.

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.

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.

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.

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.

The identification of three novel biomarkers of major adverse kidney events.

AIM: To describe the prognostic value of three novel biomarkers for acute adverse kidney events compared with routine biological markers. MATERIAL & METHODS: We used high-end MS to quantify biomarkers predictive of acute kidney injury (AKI) and major adverse kidney events (MAKE) in 100 adult patients after open heart surgery (n = 100). RESULTS: Early postoperatively measured LG3 (a C-terminal fragment of perlecan), LTBP2 (latent transforming growth factor binding protein-2), Cathepsin L as well as two other renal biomarkers (NGAL, Cystatin C) had greater predictive value for AKI (n = 23) and MAKE (n = 24) compared with creatinine, urea and urine output. CONCLUSIONS: LG3, LTBP2 and Cathepsin L deserve further exploration as biomarkers for the early identification of patients at risk of MAKE.

Pilot study of association of catechol-O-methyl transferase rs4680 genotypes with acute kidney injury and tubular stress after open heart surgery.

AIM: To assess the association of genetic variants of catecholamine-O-methyltransferase (COMT) genotypes with acute kidney injury (AKI) and tubular stress after open heart surgery. PATIENTS & METHODS: We genotyped 195 patients for the COMT-Val158Met polymorphism and measured creatinine, neutrophil gelatinase-associated lipocalin and midkine. We analyzed the association between such polymorphisms and these kidney-related variables. RESULTS: Nonsignificantly more COMT LL patients developed RIFLE-AKI compared with non-LL patients (p = 0.11). Compared with HL and HH patients, LL patients who developed AKI had lower increases in serum creatinine. COMT LL patients had less pronounced release of tubular stress biomarkers (neutrophil gelatinase-associated lipocalin: p = 0.045, midkine: p = 0.072). CONCLUSION: COMT genotype may associate with different patterns of renal functional changes and tubular stress biomarker release response after open heart surgery.

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.

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.

Vasodilatory effect of the stable vasoactive intestinal peptide analog RO 25-1553 in murine and rat lungs.

RATIONALE: Stable analogs of vasoactive intestinal peptide (VIP) have been proposed as novel line of therapy in chronic obstructive pulmonary disease (COPD) based on their bronchodilatory and anti-inflammatory effects. We speculated that VIP analogs may provide additional benefits in that they exert vasodilatory properties in the lung, and tested this hypothesis in both ex vivo and in vivo models. METHODS: In isolated perfused mouse lungs and in an in vivo rat model, pulmonary blood vessels were preconstricted by hypoxia and hemodynamic changes in response to systemic (ex vivo) or inhaled (in vivo) administration of the cyclic VIP analog RO 25-1553 were determined. RESULTS: In mouse lungs, RO 25-1553 reduced intrinsic vascular resistance at normoxia, and attenuated the increase in pulmonary artery pressure in response to acute hypoxia. Consistently, inhalation of RO 25-1553 (1 mg · mL(-1) for 3 min) caused an extensive and sustained (> 60 min) inhibition of the pulmonary arterial pressure increase in response to hypoxia in vivo that was comparable to the effects of inhaled sildenafil. This effect was not attributable to systemic cardiovascular effects of RO 25-1553, but to a lung specific reduction in pulmonary vascular resistance, while cardiac output and systemic arterial hemodynamics remained unaffected. No adverse effects of RO 25-1553 inhalation on pulmonary gas exchange, ventilation-perfusion matching, or lung fluid content were detected. CONCLUSION: Our findings demonstrate that inhaled delivery of the stable VIP analog RO 25-1553 induces a potent and sustained vasodilatory effect in the pulmonary circulation with no detectable adverse effects. Therapeutic inhalation of RO 25-1553 may provide vascular benefits in addition to its reported anti-inflammatory and bronchodilatory effects in COPD, yet caution is warranted given the overall poor results of vasodilator therapies for pulmonary hypertension secondary to COPD in a series of recent clinical trials.

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.

Low preoperative hepcidin concentration as a risk factor for mortality after cardiac surgery: a pilot study.

OBJECTIVE: Hepcidin regulates iron absorption and recycling and is central to host defense, protection from reactive iron species, and a biomarker of iron-related pathophysiology. We assessed the value of hepcidin measured preoperatively for the prediction of in-hospital mortality and renal outcomes. METHODS: We studied 100 adult patients undergoing cardiac surgery in the control arm of a randomized, controlled trial. Plasma and urine were sampled before induction of anesthesia, and hepcidin-25 was quantified by competitive enzyme-linked immunoassay. Renal outcomes were acute kidney injury defined by risk, injury, failure, loss of function, end-stage renal disease (RIFLE) classification and need for renal replacement therapy. Variables with the potential to influence hepcidin expression were investigated. RESULTS: Low preoperative hepcidin concentration in urine (median, 15.3 ng/mL; 25-75 percentiles, 0-129.1) and plasma (median, 49.2 ng/mL; 25th-75th percentile, 0-52.2) predicted mortality (area under the curve-receiver operating characteristic [AUC-ROC] for urine hepcidin, 0.89; 95% confidence interval, 0.73-0.99; cutoff, 130 ng/mL; sensitivity, 73%; specificity, 100%; and AUC-ROC for plasma hepcidin, 0.90; 95% confidence interval, 0.80-0.99; cutoff, 55 ng/mL; sensitivity, 83%; specificity, 100%). Survivors had median preoperative hepcidin concentrations of 325.3 ng/mL (25th-75th percentile, 120-770.1 ng/mL) in urine and 113.1 ng/mL (25th-75th percentile, 77.7-203.1 ng/mL) in plasma. Preoperative serum creatinine did not predict mortality (AUC-ROC, 0.50; 95% confidence interval, 0.10-0.94). Furthermore, preoperative urine, plasma hepcidin, and serum creatinine did not distinguish patients requiring postoperative renal replacement therapy from those without (urine: AUC-ROC, 0.62; 95% confidence interval, 0.38-0.86; plasma: AUC-ROC, 0.63; 95% confidence interval, 0.34-0.91; serum creatinine: AUC-ROC, 0.61; 95% confidence interval, 0.22-0.99). Preoperative renal function and hemoglobin did not correlate with hepcidin indices whereas plasma markers of inflammation did. CONCLUSIONS: Low preoperative hepcidin concentration might be a risk factor for in-hospital mortality. Findings should be validated in larger patient cohorts with a greater number of events.

Blood transfusion determines postoperative morbidity in pediatric cardiac surgery applying a comprehensive blood-sparing approach.

OBJECTIVE: Recently we suggested a comprehensive blood-sparing approach in pediatric cardiac surgery that resulted in no transfusion in 71 infants (25%), postoperative transfusion only in 68 (24%), and intraoperative transfusion in 149 (52%). We analyzed the effects of transfusion on postoperative morbidity and mortality in the same cohort of patients. METHODS: The effect of transfusion on the length of mechanical ventilation and intensive care unit stay was assessed using Kaplan-Meier curves. To assess whether transfusion independently determined the length of mechanical ventilation and length of intensive care unit stay, a multivariate model was applied. Additionally, in the subgroup of transfused infants, the effect of the applied volume of packed red blood cells was assessed. RESULTS: The median length of mechanical ventilation was 11 hours (interquartile range, 9-18 hours), 33 hours (interquartile range, 18-80 hours), and 93 hours (interquartile range, 34-161 hours) in the no transfusion, postoperative transfusion only, and intraoperative transfusion groups, respectively (P < .00001). The corresponding median lengths of intensive care unit stay were 1 day (interquartile range, 1-2 days), 3.5 days (interquartile range, 2-5 days), and 8 days (interquartile range, 3-9 days; P < .00001). The multivariate hazard ratio for early extubation was 0.24 (95% confidence interval, 0.16-0.35) and 0.37 (95% confidence interval, 0.25-0.55) for the intraoperative transfusion and postoperative transfusion only groups, respectively (P < .00001). In addition, the cardiopulmonary time, body weight, need for reoperation, and hemoglobin during cardiopulmonary bypass affected the length of mechanical ventilation. Similar results were obtained for the length of intensive care unit stay. In the subgroup of transfused infants, the volume of packed red blood cells also independently affected both the length of mechanical ventilation and the length of intensive care unit stay. CONCLUSIONS: The incidence and volume of blood transfusion markedly affects postoperative morbidity in pediatric cardiac surgery. These results, although obtained by retrospective analysis, might stimulate attending physicians to establish stringent blood-sparing approaches in their institutions.

Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction.

Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wild-type mice and in lungs from mice lacking Cx40 (Cx40-/-). In vivo, hypoxemia was more severe in Cx40-/- mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40-/-, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent α1G subtype Ca2+ channels, cytosolic phospholipase A2, and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner.

Impact of tricuspid valve annulus dilation on mid-term survival after implantation of a left ventricular assist device.

BACKGROUND: After left ventricular assist device (LVAD) implantation, right ventricular (RV) failure is a major cause of post-operative morbidity and mortality. Recently, in patients with similar hemodynamic challenge, but less severe RV impairment, who were undergoing surgery for mitral valve repair, concomitant tricuspid valve repair improved post-operative RV re-remodeling in patients with severely dilated tricuspid annuli without tricuspid regurgitation (TR). METHODS: Pre-operative transesophageal echocardiography and clinical data were prospectively collected from 122 patients without severe TR, who were selected for LVAD implantation. Patients were assigned to one of two groups according to pre-operative tricuspid annulus diameter <43 mm or >43 mm. Groups were compared for parameters that may impact survival after LVAD implantation. Kaplan-Meier survival curves were evaluated for the impact of tricuspid annulus size and right-to-left ventricular diameter ratio (R/L ratio) on 36-month survival. Multivariate analysis was used to identify the pre-operative parameters that independently affected survival. RESULTS: Patients with tricuspid annulus >43 mm presented with higher R/L ratio (0.73 ± 0.21 vs 0.56 ± 0.13; p < 0.00001) and higher proBNP plasma concentration (12,872 ± 13,084 vs 8,988 ± 13,018 pg/ml; p = 0.018). Both R/L ratio >0.72 and tricuspid annulus >43 mm adversely affected survival (p = 0.003 and 0.007, respectively). In the multivariate analysis only tricuspid annulus diameter >43 mm (hazard ratio 2.16, CI 1.21 to 3.84, p = 0.009) and age (hazard ratio 1.03, CI 1.00 to 1.06, p = 0.04) were independent predictors of survival after LVAD. CONCLUSIONS: Tricuspid dilation, even without severe regurgitation, adversely affects survival after LVAD implantation. Further studies are required to determine whether concomitant tricuspid valve repair may improve survival in these patients.