Ventilator-derived dynamic respiratory system compliance: Comparison with static compliance in children.

Measurement of dynamic lung compliance during breathing requires measurement of esophageal pressure, whereas static respiratory system compliance (Crs) method requires several airway occlusions. Despite their precision these compliance methods are cumbersome and not suitable for evaluation of pulmonary system in intensive care. The current ventilators display dynamic Crs, which, however, is seldom utilized in clinical practice. We studied the feasibility of ventilator-derived dynamic Crs measurement in pulmonary evaluation after congenital cardiac surgery in children. In 50 children static Crs was measured by double-occlusion technique, and compared with simultaneous ventilator-derived dynamic Crs values. The early postoperative dynamic and static Crs showed a correlation (r = 0.57, p < 0.0001), but static Crs was 48% higher than dynamic (p < 0.0001). Dynamic Crs measurement showed no correlation with radiographic lung edema findings, whereas the static Crs showed a negative correlation with radiographic lung edema scoring (r = -0.50, p = 0.0002). Thus ventilator-derived dynamic Crs seems less reliable in postoperative pulmonary evaluation than static Crs.

Assessment of extravascular lung water by ultrasound after congenital cardiac surgery.

BACKGROUND: Lung ultrasounds show vertical artifacts known as B-lines in the presence of increased extravascular lung water (EVLW). We aimed to investigate whether lung ultrasound could estimate EVLW after congenital cardiac surgery. METHODS: This prospective observational study comprised 61 children (age range 3 days to 7.4 years) undergoing congenital cardiac surgery. We compared postoperative B-line scores from lung ultrasounds, early postoperative ultrasound as our primary interest, with corresponding postoperative chest radiography (CXR) lung edema scores, with static lung compliance, and with short-term clinical outcome interpreted as time on mechanical ventilation and length of pediatric intensive care unit (PICU) stay. RESULTS: Our findings showed lung ultrasound B-line scores and CXR lung edema scores as correlating 1-6 hr postoperatively (r2 = 0.41, P < 0.0001), on the first postoperative day (r2 = 0.15, P = 0.004) and on the fourth postoperative day (r2 = 0.28, P = 0.008). The B-line score or CXR lung edema score showed no correlation with lung compliance. We found that in multivariable analyses, with length of perfusion and presence of postoperative complications as covariates, both lung ultrasound (P ≤ 0.02) and CXR (P ≤ 0.002) 1-6 hr postoperatively predicted the length of mechanical ventilation and PICU stay. The interobserver variability was less for lung ultrasound B-line score than for CXR lung edema score (P = 0.001). CONCLUSIONS: Our results show that lung ultrasound in assessment of postoperative EVLW predicted length of mechanical ventilation and stay in the PICU, and it had less interobserver variability than CXR. Accordingly, lung ultrasound may complement CXR in assessment of lung edema after surgery for congenital heart defect. Pediatr Pulmonol. 2017;52:345-352. © 2016 Wiley Periodicals, Inc.

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.

Long-term outcome after treatment of pulmonary atresia with ventricular septal defect: nationwide study of 109 patients born in 1970-2007.

OBJECTIVES: Treatment of pulmonary atresia with ventricular septal defect (PA + VSD) has evolved during recent decades, but it still remains challenging. This study evaluated 41-year experience of outcome, survival and treatment of PA + VSD patients. METHODS: Patient records and angiograms of 109 patients with PA + VSD born in Finland between 1970 and 2007, and treated at the Children's Hospital, Helsinki University Central Hospital, were retrospectively analysed in this nationwide study. RESULTS: Of the 109 patients, 66 (61%) had simple PA + VSD without major aortopulmonary collateral arteries (MAPCAs). Although we observed no difference in overall survival between those with or without MAPCAs, the patients without MAPCAs had better probability to achieve repair (64 vs 28%, P < 0.0003). Only 3 patients were treated by compassionate care. Overall survival was affected by the size of true central pulmonary arteries on the first angiogram (P = 0.001) and whether repair was achieved (P < 0.0001). After successful repair, the survival rate was 93% at 1 year, 91% from the second year, and functional capacity as assessed by New York Heart Association (NYHA) I-II remained in 85% of patients alive at the end of follow-up. Palliated patients at 1, 5, 10 and 20 years of age had Kaplan-Meier estimated survival rates of 55, 42, 34 and 20%, respectively. Patients who underwent repair attempts but were left palliated with right ventricle (RV)-pulmonary artery connection and septal fenestration had better survival than the rest of the palliated patients (P = 0.001). Further, the McGoon index improved after implementation of a systemic-pulmonary artery shunt in the overall PA + VSD population (P < 0.0001). CONCLUSIONS: These findings show that achievement of repair and initial size of true central pulmonary arteries affect survival of patients with PA + VSD. Although the overall survival of patients with MAPCAs showed no difference compared with simple PA + VSD patients, they had a higher risk of remaining palliated. However, palliative surgery may have a role in treatment of PA + VSD because the size of pulmonary arteries increased after placement of systemic-pulmonary artery shunt. In addition, subtotal repair by a RV-pulmonary artery connection and septal fenestration improved survival over extracardiac palliation.

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.

Need of transannular patch in tetralogy of Fallot surgery carries a higher risk of reoperation but has no impact on late survival: results of Fallot repair in Finland.

OBJECTIVES: Our study is a population-based evaluation of the long-term results after surgical repair for tetralogy of Fallot (TOF). All patients operated on in the country since the first procedure were identified via the Finnish research database of paediatric cardiac surgery and the Finnish population register. The follow-up was 99% completed due to comprehensive coverage of the registers. METHODS: The Finnish research database of paediatric cardiac surgery, surgical logs, diagnosis cards and computer files of the hospitals were used for data collection. The Finnish Population Register Center was used to obtain current patient status and dates of death and emigration. RESULTS: A total of 600 patients underwent surgical repair of TOF before the age of 15 years during the 46-year period from 1962 to 2007. The mean follow-up time was 23 ± 12.1 years; 513 (85%) patients were alive and living in Finland, 82 (14%) had died and 5 patients were lost to the follow-up (0.8%). A total of 40 patients (7%) died early (≤30 days) and 42 (7%) died late (>30 days) after the surgical correction. During the last two decades the early mortality rate was 1.5% and no early deaths were observed after the year 2000. A transannular patch (TAP) was used in the reconstruction of the right ventricular outflow tract in 191 (32%) of these patients and had no influence on late mortality but the event-free survival was significantly inferior in these patients. If a primary palliation was performed before the correction, the late survival was significantly inferior when compared with patients without initial palliation. Also reoperation was more common in patients with primary palliation. CONCLUSIONS: The long-term prognosis of surgically corrected TOF patients is good and has improved with each decade since the beginning of TOF surgery in Finland. Primary repair of tetralogy of Fallot predicts a lower mortality rate and longer freedom from reoperation when compared with two-stage repair. Need of a TAP in TOF surgery carries a higher risk of reoperation but has no impact on late survival.

Screening for congenital heart defects by transabdominal ultrasound - role of early gestational screening and importance of operator training.

The majority of congenital heart defects occur without identifiable risk factors. Detection rates are therefore highly dependent on the experience and expertise of the obstetrical screening operator. In the first trimester, the risk of congenital heart defects increases with increasing nuchal thickness (≥2.5 mm detects 44% of major congenital heart defects), but because of the number of false positives, the positive predictive value is only a few percent. The anatomy of major congenital heart defects may be delineated in less than half of the fetuses during early second trimester. The reported yield of congenital heart defects detection during the mid-gestational routine obstetrical screening has improved over time and detection rates up to 85% of major congenital heart defects have been reported when outflow tract and three-vessel views are included in conjunction with the four-chamber view. Improved detection rates have been achieved following screening operator training interventions combined with a low referral threshold to obtain a detailed fetal echocardiographic study.

Late gadolinium enhancement (LGE) progresses with right ventricle volume in children after repair of tetralogy of fallot.

BACKGROUND: Fibrosis after myocardial damage can be determined by cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE). We studied whether ventricular LGE is visible in the ventricles of pediatric and adolescent TOF (tetralogy of Fallot) patients by measuring LGE and investigating whether fibrosis correlated with right ventricular volume, pulmonary regurgitation, N-terminal pro-brain natriuretic peptide (NT-proBNP) or the aminoterminal propeptide of type III procollagen (PIIINP). We also studied if the patient's age, post-operative follow-up time or surgical history would affect LGE. METHODS: A total of 40 pediatric patients who had undergone TOF repair and 43 healthy age and gender matched controls underwent a CMR study, whereby LGE was scored in the right (RV) and the left ventricle. To exclude the possible iatrogenic scarring we calculated the LGE score by excluding the right ventricular outflow tract and VSD patch region. RESULTS: All patients had RV LGE and in 39 of 40 it was seen also outside the surgically affected areas. The amount of LGE correlated positively with the RV end-diastolic volume (r = 0.44, P = 0.0045), pulmonary regurgitation (r = 0.40, P = 0.013), and with NT-proBNP. The presence of LGE also depended on post-operative follow-up time (r = 0.53, P = 0.006). PIIINP levels of TOF patients were significantly higher than in the control subjects but it did not correlate with LGE or with any of the studied clinical markers. CONCLUSIONS: LGE is present globally in the right ventricular muscle in children and adolescents with TOF. The longer the follow-up time the more common was the LGE in the right ventricle.

Airway expression of the epithelial sodium channel α-subunit correlates with cortisol in term newborns.

BACKGROUND: Glucocorticoids have profound effects on lung maturation and function. In in vitro and animal models, they induce epithelial sodium channels (ENaCs) in the airway epithelium, a process that is important to perinatal lung fluid clearance. OBJECTIVE: The objective of this study was to determine whether, in newborn infants, airway ENaC expression is associated with cortisol concentrations. METHODS: Cord blood, saliva, and cells from nasal epithelium were obtained from 69 infants delivered at term. Epithelial and saliva sampling was repeated 3 times: <3, 22 to 29, and 40 to 54 hours postnatally. Cortisol, thyrotropin, and free triiodothyronine concentrations were measured with immunoassays, and expression of α-ENaC and ß-ENaC was quantified with real-time reverse-transcriptase polymerase chain reaction. RESULTS: Expression of α-ENaC <30 minutes postnatally correlated with cord plasma cortisol in infants delivered by elective cesarean delivery. In addition, in the total study population <2 hours postnatally, α-ENaC expression correlated with salivary cortisol concentrations. ß-ENaC expression, in contrast, showed no association with cortisol concentrations. A significant decrease in ß-ENaC expression during the first postnatal day was revealed, whereas timing of the peak in α-ENaC expression seemed to depend on mode of delivery. CONCLUSIONS: These results support a role in humans for endogenous glucocorticoids in the regulation of airway ion transport. This finding may be a physiologic mechanism mediating pulmonary adaptation in the newborn infant.

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.

Borderline left ventricles in prenatally diagnosed atrioventricular septal defect or double outlet right ventricle: echocardiographic predictors of biventricular repair.

BACKGROUND: Atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV) with normally related great arteries and normal ventricular sizes are associated with a good long-term prognosis after biventricular (BV) repair. The outcome of cases with a borderline small left ventricle (bLV) is unclear. The purpose of the study was to retrospectively determine echocardiographic predictors of successful BV repair in fetuses with AVSD or DORV with a bLV. METHODS AND RESULTS: From 1991 to 2004, 24 fetuses with AVSD plus bLV and 24 with DORV plus bLV were identified. Fetal echocardiographic parameters comparing BV repair versus single ventricle (SV) palliation were obtained, including the presence or absence of an apex-forming bLV was recorded. A bLV was defined as a right ventricular/left ventricular end-diastolic dimension ratio between 2 and 4 SDs for gestational age. The overall survival from fetal diagnosis was 21% (5/24) for AVSD/bLV and 13% (3/24) for DORV/bLV. Of 11 liveborns with AVSD/bLV and 8 liveborns with DORV/bLV, 6 underwent BV repair (5 survivors), 7 SV palliation (3 survivors), and 1 cardiac transplant. Five infants receiving compassionate care only were excluded from the analysis. Parameters such as ratio of valve annuli, ventricular end-diastolic dimensions, degree of valve regurgitation, and the presence of endocardial fibroelastosis were not too predictive of outcome. The presence of an apex-forming bLV was the only predictor of BV repair (6/6 BV repair vs 2/8 SV palliation, P < .05). CONCLUSIONS: Prenatally diagnosed AVSD or DORV with bLV has a very poor prognosis. An apex-forming bLV predicts successful BV repair and is an important prognostic indicator.

Improvement of lung compliance during postnatal adaptation correlates with airway sodium transport.

RATIONALE: Fetal lung liquid secretion is coupled with chloride transport into the lung lumen. The postnatal clearance of lung liquid is dependent on osmotic force generated by active sodium absorption. OBJECTIVE: To study the interaction between airway epithelial sodium transport and postnatal lung function. METHODS: We determined lung compliance and nasal transepithelial potential difference as a measure of airway ion transport and epithelial sodium channel gene expression in 41 healthy newborn infants during the first 50 h after birth. MEASUREMENTS AND MAIN RESULTS: Lung compliance improved significantly during the study period, whereas nasal potential difference remained constant. There was a significant decrease in the expressions of beta and gamma subunits of the epithelial sodium channel. A positive correlation existed between amiloride-sensitive nasal potential difference measured at 1-4 h of age and lung compliance at 21-27 h of age. We found no correlation between the molecular data and functional measurements. CONCLUSIONS: An important part of pulmonary adaptation takes place during the first hour after birth. The improvement of lung compliance continues over the first postnatal days and coincides with down-regulation of epithelial sodium channel beta and gamma subunit expression.

Low expression of human epithelial sodium channel in airway epithelium of preterm infants with respiratory distress.

OBJECTIVE: Active ion transport is critical to postnatal clearance of lung fluid. The importance of epithelial sodium channel (ENaC) in this clearance has been demonstrated in animal studies in which alpha-ENaC knockout mice died postnatally as a result of respiratory insufficiency. In animals, the expression of alpha-ENaC in respiratory epithelium is dependent on gestational age, but when assessed by in situ hybridization in the human (h), the mRNA is present from the earliest stages of pulmonary development. Therefore, the purpose of the present investigation was to quantify mRNA of the alpha-, beta-, and gamma-hENaC subunits of newborn preterm infants with respiratory distress and compare the gene expression data against those detected in healthy term infants. In addition, the effect of systemic dexamethasone therapy on the 3 hENaC subunits was studied in 4 preterm infants who received prolonged assisted ventilation. METHODS: The expression of subunits of hENaC was determined in samples taken from nasal respiratory epithelium of 7 healthy term infants (gestation age: 39.3 +/- 0.9 weeks [mean +/- standard deviation) and 5 preterm infants (gestational age: 27.2 +/- 0.9 weeks) with respiratory distress syndrome within 5 hours of birth. Betamethasone had been given to all mothers of preterm infants. In 4 additional preterm infants who still required assisted ventilation at 43 +/- 6 days postnatal age, the expression of alpha-hENaC was determined in samples taken before and during treatment with dexamethasone. RESULTS: Preterm infants with respiratory distress syndrome had low expression of all hENaC subunits relative to healthy term infants (alpha-hENaC: 5.38 +/- 2.01 [amol/fmol cytokeratin 18] vs 9.13 +/- 2.26; beta-hENaC: 2.44 +/- 1.43 vs 4.25 +/- 1.10; gamma-hENaC: 2.43 +/- 0.11 vs 6.81 +/- 3.24). Each of the 4 preterm infants who were treated with dexamethasone at approximately 1 month of age showed an increase in expression of alpha-hENaC and beta-hENaC subunit normalized to cytokeratin 18. CONCLUSION: All 3 subunits of the hENaC are low in preterm relative to full-term infants. alpha-hENaC mRNA in respiratory epithelium is increased by therapeutic doses of glucocorticosteroid. Low expression of alpha-hENaC in human respiratory epithelium may play a role in the pathogenesis of respiratory distress in preterm infants.

Attenuated lipid peroxidation in preterm infants during subsequent doses of intravenous lipids.

The aim of this study was to determine whether the administration of a lipid emulsion containing less polyunsaturated fatty acids but rich in monounsaturated fatty acids causes less in vivo lipid peroxidation in preterm infants. The prospective intervention study included 13 infants with birth weights and gestational ages ranging between 1,100 and 2,660 g and from 28.4 to 32.9 weeks. All were in a stable condition and randomly allocated for a 3-hour infusion (0.16 g/kg/h) of an olive oil-based and a soybean oil + medium chain fatty acid (MCT) emulsion on 2 consecutive days. Expired pentane and plasma triglycerides (TGs) were measured before, during, and after the 3-hour infusion. Basal exhaled pentane averaged 9.4 +/- 7.0 pmol/kg/min (mean +/- SD). During the olive oil-based emulsion, exhaled pentane increased to 95.2 +/- 56.7, and during soybean oil + MCT it increased to 110 +/- 93.9 pmol/kg/min (p < 0.05 both from basal, n.s. between preparations). One hour after discontinuation of the infusion, exhaled pentane returned to 21.1 +/- 12.6 pmol/kg/min (p < 0.05 vs. basal). Combined data on expired pentane measurements demonstrated that on day 1 pentane peaked at 124 +/- 87.0 pmol/kg/min which was significantly attenuated to 57.5 +/- 24.4 pmol/kg/min after an identical dose of lipid on day 2 (p < 0.05). No difference in peak TGs was detected between the two preparations or the study days. Infusion of a constant dose of intravenous lipids on 2 subsequent days to the newborn infants is associated with a reduction in lipid peroxidation. This finding may be dependent on normal postnatal maturation or may represent an appropriate adaptive response aiming at a reduction in oxidative stress. Peroxidation of soybean oil + MCT and olive oil-based lipid emulsions was similar in the newborn infants.