Albumin and Cardioprotection in On-Pump Cardiac Surgery-A Post Hoc Analysis of a Randomized Trial.

OBJECTIVES: To study the quantitative potency of plasma albumin on cardioprotection in terms of creatinine kinase-myocardial band mass (CK-MBm) in on-pump cardiac surgery. DESIGN: Post hoc analysis of a double-blinded randomized clinical trial. SETTING: Single-center study in the Helsinki University Hospital. PARTICIPANTS: A total of 1,386 adult on-pump cardiac surgical patients. INTERVENTION: Administration of 4% albumin (n = 693) or Ringers acetate (n = 693) for cardiopulmonary bypass priming and volume replacement intraoperatively and postoperatively during the first 24 hours. MEASUREMENTS AND MAIN RESULTS: Albumin concentration was measured preoperatively and intraoperatively (after protamine administration), and CK-MBm on the first postoperative morning. Multivariate linear regression analyses were measured in the whole cohort and the Ringer group. Plasma albumin concentration did not differ between the groups preoperatively (Ringer v albumin: 38.3 ± 5.0 g/L v 38.6 ± 4.5 g/L; p = 0.171) but differed intraoperatively (29.5 ± 5.2 g/L v 41.5 ± 6.0 g/L; p < 0.001). Creatinine kinase-myocardial band mass was higher in the Ringer (32.0 ± 34.8 µg/L) than in the albumin group (24.3 ± 33.0 µg/L) (p < 0.001). Aortic cross-clamping time associated with CK-MBm in the whole cohort (standardized ß = 0.376 [95% CI 0.315-0.437], p < 0.001) and the Ringer group (ß = 0.363 [0.273-0.452]; p < 0.001). Albumin administration in the whole cohort (ß = -0.156 [-0.201 to -0.111]; p < 0.001) and high intraoperative albumin concentration in the Ringer group (ß = -0.07 [-0.140 to -0.003]; p = 0.04) associated with reduced CK-MBm. Compared with ischemia-induced increase in CK-MBm, albumin's potency to reduce CK-MBm was 41% in the whole cohort (ß-value ratio of -0.156/0.376) and 19% in the Ringer group (ß-value ratio of -0.07/0.363). CONCLUSION: Both endogenous and exogenous albumin appear to be cardioprotective regarding CK-MBm release in on-pump cardiac surgery.

Albumin Infusion and Blood Loss After Cardiac Surgery.

BACKGROUND: In the recent ALBICS (ALBumin In Cardiac Surgery) trial, 4% albumin used for cardiopulmonary bypass priming and volume replacement increased perioperative bleeding compared with Ringer acetate. In the present exploratory study, albumin-related bleeding was further characterized. METHODS: Ringer acetate and 4% albumin were compared in a randomized, double-blinded fashion in 1386 on-pump adult cardiac surgery patients. The study end points for bleeding were the Universal Definition of Perioperative Bleeding (UDPB) class and its components. RESULTS: The UDPB bleeding grades were higher in the albumin group than the Ringer group: "insignificant" (albumin vs Ringer: 47.5% vs 62.9%), "mild" (12.7% vs 8.9%), "moderate" (28.7% vs 24.4%), "severe" (10.2% vs 3.2%), and "massive" (0.9% vs. 0.6%; P < .001). Patients in the albumin group received red blood cells (45.2% vs 31.5%; odds ratio [OR], 1.80; 95% CI, 1.44-2.24; P < .001), platelets (33.3% vs 21.8%; OR, 1.79; 95% CI, 1.41-2.28; P < .001), and fibrinogen (5.6% vs 2.6%; OR, 2.24; 95% CI, 1.27-3.95; P < .05), and underwent resternotomy (5.3% vs 1.9%; OR, 2.95; 95% CI, 1.55-5.60, P < .001) more often than patients in the Ringer group. The strongest predictors of bleeding were albumin group allocation (OR, 2.18; 95% CI, 1.74-2.74) and complex (OR, 2.61; 95% CI, 2.02-3.37) and urgent surgery (OR, 1.63; 95% CI, 1.26-2.13). In interaction analysis, the effect of albumin on the risk of bleeding was stronger in patients on preoperative acetylsalicylic acid. CONCLUSIONS: Perioperative administration of albumin, compared with Ringer's acetate, resulted in increased blood loss and higher UDBP class. The magnitude of this effect was similar to the complexity and urgency of the surgery.

A gamified mobile health intervention for children in day surgery care: Protocol for a randomized controlled trial.

AIMS: To describe a study protocol for a randomized controlled trial which will evaluate the effectiveness of a gamified mobile health intervention for children in whole day surgery care. DESIGN: A study protocol for a two-arm randomized controlled trial. METHODS: Participants will be randomly assigned to the intervention group (N = 62), in which patients receive routine care and play a mobile game designed for children or the control group (N = 62), in which patients receive routine care, including a mobile phone application that supports parents during the care path. The primary outcome is children's pre-operative anxiety, while the secondary outcome measures included fear and postoperative pain, along with parental satisfaction and anxiety. Data collection started in August 2020. RESULTS: The results of the ongoing randomized controlled trial will determine whether the developed gamified mobile health intervention can be recommended for hospital use, and whether it could be used to educate children about their surgical treatment to decrease anxiety.

Glucocorticoids, sodium transport mediators, and respiratory distress syndrome in preterm infants.

BACKGROUND: Antenatal glucocorticoids (GCs) reduce respiratory distress syndrome (RDS) in preterm infants and are associated with reduced lung liquid content. Our aim was to assess whether airway gene expression of mediators of pulmonary epithelial sodium and liquid absorption, and further, respiratory morbidity, associate with cord blood GC concentrations. METHODS: The study included 64 infants delivered <32 weeks gestation. Cortisol and betamethasone in umbilical cord blood were quantified with liquid chromatography-tandem mass spectrometry. The total GC concentration was calculated. Gene expression of the epithelial sodium channel (ENaC), Na,K-ATPase, and serum- and GC-inducible kinase 1 at <2 h and at 1 day postnatally in nasal epithelial cell samples was quantified with reverse transcription-polymerase chain reaction. The mean oxygen supplementation during the first 72 h was calculated. RESULTS: Concentrations of cord blood betamethasone and total GC were significantly lower in infants with RDS and correlated with mean oxygen supplementation. Expression of αENaC and α1- and ß1Na,K-ATPase at <2 h correlated with betamethasone and total GC concentrations. Expression of Na,K-ATPase was lower in infants with RDS. CONCLUSION: Enhancement of lung liquid absorption via increased expression of sodium transporters may contribute to the beneficial pulmonary effects of antenatal GCs. IMPACT: RDS is related to lower umbilical cord blood GC concentrations and lower airway expression of sodium transporters. In addition to the timing of antenatal GC treatment, resulting concentrations may be of importance in preventing RDS. Induction of sodium transport may be a factor contributing to the pulmonary response to antenatal GCs.

Parental Experiences of the Pediatric Day Surgery Pathway and the Needs for a Digital Gaming Solution: Qualitative Study.

BACKGROUND: The parents of hospitalized children are often dissatisfied with waiting times, fasting, discharge criteria, postoperative pain relief, and postoperative guidance. Parents' experiences help care providers to provide effective, family-centered care that responds to parents' needs throughout the day surgery pathway. OBJECTIVE: The objective of our study was to describe parental experiences of the pediatric day surgery pathway and the needs for a digital gaming solution in order to facilitate the digitalization of these pathways. METHODS: This was a descriptive qualitative study. The participants (N=31) were parents whose children were admitted to the hospital for the day surgical treatments or magnetic resonance imaging. The data were collected through an unstructured, open-ended questionnaire; an inductive content analysis was conducted to analyze the qualitative data. Reporting of the study findings adheres to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. RESULTS: Parental experiences of the children's day surgery pathway included 3 main categories: (1) needs for parental guidance, (2) needs for support, and (3) child involved in his or her own pathway (eg, consideration of an individual child and preparation of child for treatment). The needs for a digital gaming solution were identified as 1 main category-the digital gaming solution for children and families to support care. This main category included 3 upper categories: (1) preparing children and families for the day surgery via the solution, (2) gamification in the solution, and (3) connecting people through the solution. CONCLUSIONS: Parents need guidance and support for their children's day surgery care pathways. A digital gaming solution may be a relevant tool to support communication and to provide information on day surgeries. Families are ready for and are open to digital gaming solutions that provide support and guidance and engage children in the day surgery pathways.

Postnatal gene expression of airway epithelial sodium transporters associated with birth stress in humans.

INTRODUCTION: Lung fluid clearance is essential for successful postnatal pulmonary adaptation. The epithelial sodium channel (ENaC) and Na-K-ATPase, induced by serum- and glucocorticoid-inducible kinase 1 (SGK1) as well as aquaporins (AQP), represent key players in the switch from fetal lung fluid secretion to absorption and in early postnatal lung fluid balance. Birth stress, including a surge in catecholamines, promotes pulmonary adaptation, likely through the augmentation of epithelial sodium reabsorption. OBJECTIVES: We sought to determine the changes in the airway gene expression of molecules vital to epithelial sodium transport during early pulmonary adaptation, and the association with birth stress reflected in the norepinephrine concentration in the cord blood in humans. METHODS: We included 70 term newborns: 28 born via vaginal delivery and 42 via elective cesarean section. We determined the norepinephrine concentrations in the cord blood using tandem mass spectrometry and collected nasal epithelial cell samples at 2 min, 1 h, and 24 h postnatally to quantify ENaC, Na-K-ATPase, AQP5, and SGK1 mRNAs using RT-PCR. RESULTS: The molecular gene expression involved in airway epithelium sodium transport changed markedly within the first hour postnatally. Newborns born via elective cesarean section exhibited a lower expression of ENaC, Na-K-ATPase, and SGK1. Significant correlations existed between the expressions of ENaC, Na-K-ATPase, and SGK1, and the concentration of norepinephrine in the cord blood. CONCLUSIONS: The association of ENaC, Na-K-ATPase, and SGK1 expression with the cord blood norepinephrine concentration points to the importance of birth stress in promoting lung fluid clearance during early postnatal pulmonary adaptation.

Transient Tachypnea of the Newborn Is Associated With an Increased Risk of Hospitalization Due to Respiratory Syncytial Virus Bronchiolitis.

BACKGROUND: Transient tachypnea of the newborn (TTN) is a self-limiting respiratory disorder, resulting from a failure to clear the lungs of perinatal fluid. As similar pathophysiologic features are present in children with respiratory syncytial virus (RSV) bronchiolitis, we hypothesized that these two conditions may be connected. METHODS: This was a population-based cohort study that included all children born in term (≥37 weeks of gestation) without congenital malformations in Finland between 1996 and 2015. Children diagnosed with TTN (International Statistical Classification of Diseases and Related Health Problems, 10th Revision [ICD-10] code P22.1) after birth and children hospitalized because of RSV bronchiolitis (ICD-10 code J21.0) during first year of life were identified from the Medical Birth Register and National Hospital Discharge Register, respectively, and the data were linked. Logistic regression was used to analyze the association between these two conditions. RESULTS: Of the 1,042,045 children included in the study cohort, 16,327 (1.57%) were diagnosed with TTN at birth and 12,345 (1.18%) were hospitalized because of RSV bronchiolitis during the first year of life. The rate of RSV hospitalization was higher in children with a history of TTN compared with children without TTN diagnosis [260/16,327 (1.59%) vs. 12,085/1,025,718 (1.18%), respectively; P value <0.0001]. After adjusting for gestational age at birth, mode of delivery, gender, birth weight, multiple births, older siblings and maternal smoking, TTN was associated with increased risk for RSV hospitalization (odds ratio: 1.31, 95% confidence interval: 1.16-1.48). CONCLUSIONS: TTN diagnosis after birth was associated with increased risk for RSV hospitalization during the first year of life.

Public health response to large influx of asylum seekers: implementation and timing of infectious disease screening.

BACKGROUND: Infectious disease screening of migrants at increased risk is a feature of national infection prevention and control measures. Asylum seekers in Finland are offered screening of tuberculosis (TB), hepatitis B, human immunodeficiency virus infection (HIV) and syphilis based on individual risk assessment. We aimed to evaluate the public health response to a large influx of asylum seekers to Finland in 2015-2016 with respect to national guidelines on initial health services and infectious disease screening. METHODS: We used immigration and healthcare procurement data for all 38,134 asylum seekers to Finland during 2015-2016 to assess the implementation, timing and yields of infectious disease screening. RESULTS: The coverage of pulmonary TB screening was 71.6% [95% CI 71.1-72.0%] and that of hepatitis B, HIV or syphilis 60.6% [60.1-61.1%] among those eligible for screening. The estimated average delay from arrival to pulmonary TB screening was 74 days for adults and 43 days for children. Delay to hepatitis B, HIV and syphilis screening was 91 days for adults and 47 days for children. The seroprevalence of hepatitis B surface antigen positivity was 1.4% [95% CI 1.3-1.6%], HIV 0.3% [95% CI 0.1-0.4%] and Treponema pallidum specific antibodies 1.0% [95% CI 0.8-1.1%]. Data did not allow assessment of yields of pulmonary TB screening. CONCLUSIONS: Up to one third  of asylum seekers were not reached by screening and screenings were delayed from target timeframes. Children, as a vulnerable population, were screened earlier than adults. To ensure higher screening coverage, infectious disease risks should be reassessed and screening completed at contacts to healthcare during the post-asylum phase of integration. The large influx of asylum seekers to Finland in 2015-2016 tested the country's public health preparedness. After action reviews of the public health response to the large migrant influx such as screening implementation can be used for evidence-based improvement of public health preparedness and guidelines for initial health services and infectious disease screening.

Season, dietary factors, and physical activity modify 25-hydroxyvitamin D concentration during pregnancy.

PURPOSE: The objectives of this cross-sectional study were to define maternal and umbilical cord blood (UCB) 25-hydroxyvitamin D (25(OH)D) to characterize maternal factors modifying 25(OH)D during pregnancy and predict UCB 25(OH)D in two subgroups with Declined [Δ25(OH)D <0 nmol/l] and Increased [Δ25(OH)D >0 nmol/l] 25(OH)D concentration. METHODS: A complete dataset was available from 584 women. 25(OH)D was determined at gestational weeks 6-13 and in UCB. Baseline characteristics were collected retrospectively using questionnaires. Δ25(OH)D was calculated as UCB 25(OH)D-early pregnancy 25(OH)D. Dietary patterns were generated with principal component analysis. Multivariate regression models were applied. RESULTS: Vitamin D deficiency was scarce, since only 1% had 25(OH)D concentration <50 nmol/l both in early pregnancy and in UCB. Shared positive predictors of UCB 25(OH)D in the subgroups of Declined and Increased, were early pregnancy 25(OH)D (P < 0.001) and supplemental vitamin D intake (P < 0.04). For the Increased subgroup summer season at delivery (P = 0.001) and "sandwich and dairy" dietary pattern characterized with frequent consumption of vitamin D fortified margarine and milk products (P = 0.009) were positive predictors of UCB 25(OH)D. Physical activity (P = 0.041) and maternal education (P = 0.004) were additional positive predictors in the Declined group CONCLUSIONS: Maternal and newborn vitamin D status was sufficient, thus public health policies in Finland have been successful. The key modifiable maternal determinants for 25(OH)D during pregnancy, and of the newborn, were supplemental vitamin D intake, frequent consumption of vitamin D fortified foods, and physical activity.

Sex and Iron Modify Fibroblast Growth Factor 23 Concentration in 1-Year-Old Children.

Context: Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, but its regulation is inadequately characterized. Objective: To examine FGF23 regulators, especially sex and iron status, in early childhood. Design: A cross-sectional study involving 1-year-old children. Setting and Participants: Healthy term infants with a birth weight appropriate for gestational age were recruited to an ongoing vitamin D trial at Kätilöopisto Maternity Hospital, Helsinki, Finland. At 12-month follow-up visits, serum FGF23, 25-hydroxyvitamin D (25OHD), phosphate, ionized calcium, parathyroid hormone, and iron status were measured. All 721 children (51% girls) with complete data were included. Main Outcome Measures: Intact and C-terminal FGF23 concentrations and iron status at 1 year of age. Results: Intact FGF23 was greater in girls than in boys [median, 44.4 pg/mL; interquartile range (IQR), 36.8 to 51.9; median, 40.9 pg/mL; IQR, 34.5 to 49.0, respectively; P < 0.001]. C-terminal FGF23 was similar in boys and girls (median, 2.8 pmol/L; IQR, 2.1 to 3.7; median, 2.9 pmol/L; IQR, 2.2 to 3.7, respectively; P = 0.393). The iron concentration was positively associated with intact FGF23 and was the strongest modifier of intact FGF23 (regression coefficient, 0.498; 95% confidence interval, 0.333 to 0.663; P < 0.001) with ferritin, season, ionized calcium, 25OHD, and sex as other covariates. The association between iron and C-terminal FGF23 was inversely related (regression coefficient, -0.072; 95% confidence interval, -0.092 to -0.051; P < 0.001). Conclusions: At 1 year of age, FGF23 status was different in girls and boys, with intact FGF23 concentrations higher in girls. Iron modified FGF23 concentrations, with intact FGF23 higher and C-terminal lower, in those with greater iron concentrations.

Chronic Hypoxemia in Children With Congenital Heart Defect Impairs Airway Epithelial Sodium Transport.

OBJECTIVE: Ambient hypoxia impairs the airway epithelial Na transport, which is crucial in lung edema reabsorption. Whether chronic systemic hypoxemia affects airway Na transport has remained largely unknown. We have therefore investigated whether chronic systemic hypoxemia in children with congenital heart defect affects airway epithelial Na transport, Na transporter-gene expression, and short-term lung edema accumulation. DESIGN: Prospective, observational study. SETTING: Tertiary care medical center responsible for nationwide pediatric cardiac surgery. PATIENTS: Ninety-nine children with congenital heart defect or acquired heart disease (age range, 6 d to 14.8 yr) were divided into three groups based on their level of preoperative systemic hypoxemia: 1) normoxemic patients (SpO2% ≥ 95%; n = 44), 2) patients with cyanotic congenital heart defect and moderate hypoxemia (SpO2 86-94%; n = 16), and 3) patients with cyanotic congenital heart defect and profound systemic hypoxemia (SpO2 ≤ 85%; n = 39). MEASUREMENTS AND MAIN RESULTS: Nasal transepithelial potential difference served as a surrogate measure for epithelial Na transport of the respiratory tract. Profoundly hypoxemic patients had 29% lower basal nasal transepithelial potential difference (p = 0.02) and 55% lower amiloride-sensitive nasal transepithelial potential difference (p = 0.0003) than normoxemic patients. In profoundly hypoxemic patients, nasal epithelial messenger RNA expressions of two airway Na transporters (amiloride-sensitive epithelial Na channel and ß1- Na-K-ATPase) were not attenuated, but instead α1-Na-K-ATPase messenger RNA levels were higher (p = 0.03) than in the normoxemic patients, indicating that posttranscriptional factors may impair airway Na transport. The chest radiograph lung edema score increased after congenital cardiac surgery in profoundly hypoxemic patients (p = 0.0004) but not in patients with normoxemia or moderate hypoxemia. CONCLUSIONS: The impaired airway epithelial amiloride-sensitive Na transport activity in profoundly hypoxemic children with cyanotic congenital heart defect may hinder defense against lung edema after cardiac surgery.

Duration of gestation and mode of delivery affect the genes of transepithelial sodium transport in pulmonary adaptation.

BACKGROUND: Respiratory distress due to inadequate lung liquid clearance is a significant problem in infants delivered late preterm or early term, especially by elective cesarean delivery (CD). Lung liquid clearance depends on epithelial ion transport and in animals is induced by glucocorticoids. OBJECTIVES: In newborn late preterm and term infants to study airway epithelial gene expressions of epithelial sodium channel (ENaC), and the serum and glucocorticoid-inducible kinase 1 (SGK1), and their association with cortisol, mode of delivery, and gestational age (GA). METHODS: Infants were delivered at 35(0/7)-41(6/7) weeks. Cortisol in umbilical cord plasma was analyzed with liquid chromatography-tandem mass spectrometry. ENaC and SGK1 mRNAs in airway epithelial cells obtained within 3 h and at 1 day postnatally were quantified with real-time PCR. RESULTS: ENaC and SGK1 mRNAs were significantly lower in late preterm and early term infants than in those ≥ 39(0/7) weeks. Significant correlations existed between both ENaC and SGK1 and cord cortisol and GA. In term infants, SGK1 mRNA at 1.5 h was higher after vaginal delivery than elective CD. CONCLUSIONS: In late preterm and early term infants, low expression of ENaC and SGK1 may parallel insufficient lung liquid clearance predisposing to respiratory distress. Lower SGK1 expression after term CD could translate into insufficient sodium and lung liquid absorption. The findings demonstrate a central role for cortisol in regulation of ENaC and potentially perinatal sodium and lung liquid clearance.

Expression of airway epithelial sodium channel in the preterm infant is related to respiratory distress syndrome but unaffected by repeat antenatal beta-methasone.

BACKGROUND: The airway epithelial sodium channel (ENaC) is rate limiting for postnatal alveolar fluid clearance. Increased lung water content is a feature of respiratory distress syndrome (RDS), which is reduced by antenatal corticosteroid treatment in preterm infants. OBJECTIVES: Since corticosteroids also induce ENaC gene expression, we studied whether a repeat dose of antenatal beta-methasone affects postnatal expression of airway ENaC. METHODS: 17 pregnant women with imminent preterm birth were randomized to receive a single repeat dose of beta-methasone (12 mg) or placebo (repeat beta-methasone: 8 infants, gestational age (GA) 30.8 +/- 2.2 weeks; placebo: 14 infants, GA 30.4 +/- 2.7 weeks). Expression of alpha-, beta- and gammaENaC subunits in nasal epithelium 1-5 and 20-29 h postnatally was analyzed with reverse transcription-PCR. RESULTS: There were no differences between the study groups in RDS incidence or ENaC subunit expression (all p > 0.38). Regression coefficients for association of alphaENaC expression at 1-5 h with GA in infants with and without RDS differed significantly (p = 0.023). At 20-29 h, alphaENaC expression was lower in infants with RDS (p = 0.048). CONCLUSIONS: A single repeat dose of antenatal beta-methasone did not increase ENaC expression, which may in part explain the absence of reduction in RDS incidence.

G protein-coupled receptor for asthma susceptibility associates with respiratory distress syndrome.

BACKGROUND: Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) have some common features with asthma. AIM: To study whether G protein-coupled receptor for asthma susceptibility (GPRA) contributes to RDS or BPD. METHODS: A haplotype association study was performed in a case-control setting of 521 Finnish infants (including 176 preterm neonates with RDS and 37 with BPD). Immunoreactivity of GPRA isoforms A and B was determined in pulmonary samples of fetuses, term infants and preterm infants with RDS or BPD. GPRA mRNA expression was determined by quantitative real-time polymerase chain reaction (PCR) in samples from nasal respiratory epithelium of adults, term infants and preterm infants. RESULTS: In infants with RDS born at 32-35 weeks of gestation, GPRA haplotype H1 was significantly underrepresented in RDS, whereas haplotype H4/H5 was associated with an increased risk. As in asthma, GPRA B isoform was induced in bronchial smooth muscle cells in RDS and BPD. In nasal respiratory epithelium, relative GPRA mRNA expression was strong in adults, weak in preterm and slightly higher in term samples. CONCLUSIONS: The results suggest that near-term RDS and asthma share the same susceptibility and protective GPRA haplotypes. Altered GPRA expression may play a role in the pathogenesis of RDS and BPD in preterm infants.

Sodium transport in airway epithelium correlates with lung compliance in healthy newborn infants.

To study the relation between sodium transport in airway epithelium and postnatal pulmonary adaptation, we measured nasal potential difference at 1 to 4 hours and lung compliance at 21 to 48 hours after birth in 20 healthy infants. Sodium transport correlated with lung compliance ( r 2 = 0.40, P < .003). Airway sodium transport plays a role in postnatal pulmonary adaptation.