Establishment of a biobank for human lung tissues of congenital diaphragmatic hernia and congenital pulmonary airway malformation

BackgroundHuman tissue samples are an invaluable and little available source of information for translational studies of congenital lung diseases such as Congenital Diaphragmatic Hernia (CDH) or Congenital Pulmonary Airway Malformation (CPAM).PurposeWe aimed to establish a human lung tissue biobank of CDH and CPAM patients together with age-matched controls, coupled with a clinical database.MethodsPathology records from autopsies or surgical specimens for CDH and CPAM cases between 1980 and 2017 were reviewed. For surviving individuals, clinical patient data was obtained from corresponding pediatric surgery reports. Formalin-fixed, paraffin-embedded tissues of patients and age-matched controls were systematically stored for further translational studies. RNA integrity was determined on selected CDH blocks.ResultsA total of 16 CDH and 18 CPAM and age-matched control lung tissue blocks were included in our biobank. Ages ranged from 22 to 41 weeks of gestation (GA) in CDH (33.9 ± 6.35 weeks) and 26 weeks (GA) and 12 years in CPAM (2.3 ± 3.7 y). RNA isolation from CDH and control blocks yielded good RNA quality (OD 260/280 ratio: 2.01–2.09, OD 260/230 ratio: 2.04–2.09).ConclusionWe established a unique human biobank for CDH and CPAM tissues. The combination with clinical patient data will allow us to design future translational studies to improve our understanding of the disease pathogenesis of these congenital malformations.     

Prenatal diagnosis and assessment of congenital spinal anomalies: Review for prenatal counseling

The last two decades have seen continuous advances in prenatal ultrasonography and in utero magnetic resonance imaging. These technologies have increasingly enabled the identification of various spinal pathologies during early stages of gestation. The purpose of this paper is to review the range of fetal spine anomalies and their management, with the goal of improving the clinician's ability to counsel expectant parents prenatally.     

Impact of prenatal evaluation and protocol-based perinatal management on congenital diaphragmatic hernia outcomes

Background/Purpose

Although intuitive, the benefit of prenatal evaluation and multidisciplinary perinatal management for fetuses with congenital diaphragmatic hernia (CDH) is unproven. We compared the outcome of prenatally diagnosed patients with CDH whose perinatal management was by a predefined protocol with those who were diagnosed postnatally and managed by the same team. We hypothesized that patients with CDH undergoing prenatal evaluation with perinatal planning would demonstrate improved outcome.

Methods

Retrospective chart review of all patients with Bochdalek-type CDH at a single institution between 2004 and 2009 was performed. Patients were stratified by history of perinatal management, and data were analyzed by Fisher's Exact test and Student's t test.

Results

Of 116 patients, 71 fetuses presented in the prenatal period and delivered at our facility (PRE), whereas 45 infants were either outborn or postnatally diagnosed (POST). There were more high-risk patients in the PRE group compared with the POST group as indicated by higher rates of liver herniation (63% vs 36%, P = .03), need for patch repair (57% vs 27%, P = .004), and extracorporeal membrane oxygenation use (35% vs 18%, P = .05). Despite differences in risk, there was no difference in 6-month survival between groups (73% vs 73%).

Conclusions

Patients with CDH diagnosed prenatally are a higher risk group. Prenatal evaluation and multidisciplinary perinatal management allows for improved outcome in these patients.     

Diaphragmatic hernia in the fetus: prenatal diagnosis and outcome in 94 cases

Most babies born with congenital diaphragmatic hernia (CDH) die after birth. The natural course of CDH in the human fetus is not known. We found 94 cases of fetal CDH in the records of surgeons and obstetricians surveyed in the United States and Canada. We found the following: (1) prenatal diagnosis of CDH is accurate and current techniques can detect lethal nonpulmonary anomalies and prevent diagnostic errors; (2) despite optimal conventional therapy, most fetuses with detectable CDH will die in the neonatal period (80% mortality); (3) polyhydramnios is both a common prenatal marker for CDH (present in 76% of fetuses) and a predictor for poor clinical outcome (only 11% survived); (4) fetal CDH is a dynamic process--nonsurvivors have larger defects and may have more viscera displaced into the chest at an earlier stage of development. Surgical intervention before birth may be necessary to improve survival of the fetus with CDH and polyhydramnios.     

Prenatal pulmonary hypertension index: novel prenatal predictor of severe postnatal pulmonary artery hypertension in antenatally diagnosed congenital diaphragmatic hernia

Purpose

This study aim to assess the potential of prenatal predictors of postnatal severe pulmonary artery hypertension (PAH) in isolated left congenital diaphragmatic hernia (CDH) and to define a new prenatal pulmonary hypertension index (PPHI).

Methods

A retrospective chart review of CDH patients between May 2005 and October 2008 was conducted. Ten patients with systemic/suprasystemic and 9 patients with subsystemic pulmonary hypertension at 3 weeks of age were identified. Diameters of the right pulmonary artery, left pulmonary artery (LPA_d), aorta, and the length of vermis of the cerebellum were obtained from prenatal magnetic resonance imaging to calculate the PPHI [=(LPA_d/length of vermis of the cerebellum) × 10] and the modified McGoon index (MGI) [=(diameter of the right pulmonary artery + LPA_d)/diameter of aorta]. Prenatal pulmonary hypertension index and MGI were compared with lung-to-head ratio, percent predicted lung volume, and total lung volume for pulmonary hypertension and survival.

Results

The PPHI and MGI had a significant, negative correlation with pulmonary hypertension (r = −0.61, P = .005, and r = −0.72, P < .005, respectively). The PPHI and MGI are significantly lower in the systemic/suprasystemic PAH group compared with the subsystemic PAH group (1.11 ± 0.32 versus 1.63 ± 0.28, P = .004, and 0.71 ± 0.15 versus 1.05 ± 0.11, P < .001, respectively). There were no significant differences between the groups comparing the lung-to-head ratio, percent predicted lung volume, and total lung volume.

Conclusion

Both PPHI and MGI accurately predict the severity of postnatal PAH in isolated left CDH.     

An investigation on clinical differences between congenital pulmonary airway malformation and bronchial atresia

Background/Purpose

Differences in clinical features between congenital pulmonary airway malformation (CPAM) and bronchial atresia (BA) have not yet been clearly described.

Administration of prenatal betamethasone suppresses the adrenal-hypophyseal axis in newborns with congenital diaphragmatic hernia

Background

Congenital diaphragmatic hernia (CDH) is a condition that is characterized by pulmonary hypoplasia and pulmonary hypertension. Prenatal betamethasone often is administered to fetuses with CDH to improve pulmonary function. In this study, the authors investigate the possible role of the adrenal-hypophyseal axis in CDH in an animal model and subsequently in human infants with CDH.

Methods

Twin fetal sheep underwent creation of DH or a sham thoracotomy, and levels of plasma and lung ACTH and plasma cortisol were compared. For the human studies, plasma levels of ACTH, cortisol, and DHEA were measured in cord blood samples collected from 9 CDH (5 that received prenatal betamethasone) and compared with those of 14 normal newborns. In both studies, ACTH and cortisol levels were determined by radioimmunoassay (RIA). Human (DHEA) levels were determined by ELISA.

Results

Plasma ACTH and cortisol levels were elevated in fetal DH sheep compared with sham-operated controls; however, levels of ACTH in lung tissues were not different. Human newborns with CDH who have been exposed to prenatal steroids have significantly lower plasma ACTH, cortisol, and DHEA levels than normal newborns and CDH newborns not exposed to prenatal betamethasone.

Conclusions

In an ovine model of CDH, the adrenal-hypophyseal axis appears up-regulated in DH fetuses compared with sham-operated animals. Conversely, the adrenal-hypophyseal axis in human CDH newborns appears normal but is suppressed by the administration of prenatal betamethasone.     

Maternal medical and behavioral risk factors for congenital diaphragmatic hernia

Purpose

Maternal factors contributing to the etiology of congenital diaphragmatic hernia (CDH) remain unclear. We hypothesized that specific maternal medical conditions (pregestational diabetes, hypertension), and behaviors (alcohol, tobacco) would be associated with CDH.

Methods

We conducted a population-based case–control study using Washington State birth certificates linked to hospital discharge records (1987–2009). We identified all infants with CDH (n = 492). Controls were randomly selected among non-CDH infants. Maternal data were extracted from the birth record. Logistic regression was used to adjust for covariates.

Results

Cases and controls were generally similar regarding demographics, although CDH infants were more likely to be male than controls (58.5% vs. 52.5%). Isolated and complex (multiple-anomaly) CDH had similar characteristics. Each of the exposures of interest was more common among case mothers than among control mothers. In univariate analysis, alcohol use, hypertension, and pregestational diabetes were each significantly associated with the outcome. After multivariate adjustment, only alcohol use (OR = 3.65, p = 0.01) and pregestational diabetes (OR = 12.53, p = 0.003) maintained significance. Results were similar for both isolated and complex CDH.

Conclusions

Maternal pregestational diabetes and alcohol use are significantly associated with occurrence of CDH in infants. These are important modifiable risk factors to consider with regard to efforts seeking to impact the incidence of CDH.     

Neonatal minimally invasive surgery for congenital diaphragmatic hernias: a multicenter study using thoracoscopy or laparoscopy

Background  Minimally invasive surgery (MIS) for late-presenting congenital diaphragmatic hernia (CDH) has been described previously, but few neonatal cases of CDH have been reported. This study aimed to report the multicenter experience of these rare cases and to compare the laparoscopic and thoracoscopic approaches. Methods  Using MIS procedures, 30 patients (16 boys and 14 girls) from nine centers underwent surgery for CDH within the first month of life, 26 before day 5. Only one patient had associated malformations. There were 10 preterm patients (32–36 weeks of gestational age). Their weight at birth ranged from 1,800 to 3,800 g, with three patients weighing less than 2,600 g. Of the 30 patients, 18 were intubated at birth. Results  The MIS procedures were performed in 18 cases by a thoracoscopic approach and in 12 cases by a laparoscopic approach. No severe complication was observed. For 20 patients, reduction of the intrathoracic contents was achieved easily with 15 thoracoscopies and 5 laparoscopies. In six cases, the reduction was difficult, proving to be impossible for the four remaining patients: one treated with thoracoscopy and three with laparoscopy. The reasons for the inability to reduce the thoracic contents were difficulty of liver mobilization (1 left CDH and 2 right CDH) and the presence of a dilated stomach in the thorax. Reductions were easier for cases of wide diaphragmatic defects using thoracoscopy. There were 10 conversions (5 laparoscopies and 5 thoracoscopies). The reported reasons for conversion were inability to reduce (n = 4), need for a patch (n = 5), lack of adequate vision (n = 4), narrow working space (n = 1), associated bowel malrotation (n = 1), and an anesthetic problem (n = 1). Five defects were too large for direct closure and had to be closed with a patch. Four required conversion, with one performed through video-assisted thoracic surgery. The recurrences were detected after two primer thoracoscopic closures, one of which was managed by successful reoperation using thoracoscopy. Conclusions  In the neonatal period, CDH can be safely closed using MIS procedures. The overall success rate in this study was 67%. The indication for MIS is not related to weeks of gestational age, to weight at birth (if >2,600 g), or to the extent of the immediate neonatal care. Patients with no associated anomaly who are hemodynamically stabilized can benefit from MIS procedures. Reduction of the herniated organs is easier using thoracoscopy. Right CDH, liver lobe herniation, and the need for a patch closure are the most frequent reasons for conversion.     

Pulmonary vascular morphology in a fetal rabbit model for congenital diaphragmatic hernia

Background/Purpose

Although the pulmonary vascular abnormalities in congenital diaphragmatic hernia (CDH) are described from a morphologic point of view, the treatment of pulmonary hypertension (PH) remains one of the main unsolved problems in clinical daily practice. For this reason, detailed studies in well-validated animal models could still be of significance in our understanding of the pathogenesis of CDH.

Methods

In does of 23 days’ gestational age (GA), 39 fetuses underwent creation of diaphragmatic hernia (DH) and 15 fetuses a sham thoracotomy (SHAM). Thirty-nine nonoperated littermates served as internal controls (CTR). Fetuses were harvested by cesarean section on days 25, 27, 29, and 30 of gestation. Lung specimens were obtained and formalin fixed for further vascular morphometry studies.

Results

Lung vessels from DH fetuses started to show significantly smaller internal diameter (ID), external diameter (ED), larger arterial wall thickness (WT), and, in particular, a proportionally higher medial thickness (%MT) and adventitial thickness (%AT) from day 27 onward when compared with control fetuses. SHAM fetuses, which were harvested at term, showed no differences with CTR.

Conclusions

This is the first report documenting changes over time in the vascular system in a rabbit fetal model of surgically induced DH. These changes mimic pathologic findings observed in human fetuses and are also concordant with earlier observations in the surgical ovine model and the toxic nitrofen rat model.     

Neuraxial anesthesia in ex utero intrapartum therapy for parturients with fetal congenital diaphragmatic hernia: a prospective observational study

BackgroundCongenital diaphragmatic hernia (CDH) is characterized by defects in the fetal diaphragm and thoracic herniation of the abdominal viscera. The ex utero intrapartum treatment (EXIT) procedure is used to establish the fetal airway while on placental support. These EXIT procedures are commonly performed under general anesthesia, which increases maternal bleeding and the risk of insufficient placental perfusion subsequently. This study investigated the feasibility of performing neuraxial anesthesia for the EXIT procedure for fetal congenital diaphragmatic hernia to improve outcomes.MethodsParturients with fetal CDH who underwent an EXIT procedure between January 2019 and May 2021 in our institution were recruited. Variables evaluated included gestational age, surgical time, intra-operative blood loss, peri-operative hemoglobin, maternal complications, fetal lung-to-head ratio, time on placental bypass, and postnatal outcome.ResultsTwenty-two cases were included. All procedures were performed under neuraxial anesthesia. The median gestational age at the time of the EXIT procedure was 37 weeks. The median estimated blood loss was 200 mL. There was no report of an adverse maternal event. The placental bypass time was 142.9 ± 72.6 s, and access to the airway was successfully established within the bypass time. Twenty-one neonates reached an Apgar score of 9 at 5 min. In the first two hours after birth, the average pH of neonatal peripheral arterial blood was 7.35 ± 0.07 (n=19), and lactate level 1.85 ± 0.71 mmol/L (n=19).ConclusionsIn the EXIT procedure to establish an airway for fetal CDH, neuraxial anesthesia proved a feasible technique for maternal anesthesia.     

Prenatal risk stratification for isolated congenital diaphragmatic hernia: results of a Japanese multicenter study

Background/Purpose

The aim of this study was to establish a prenatal prognostic classification system for risk-stratified management in fetuses with isolated congenital diaphragmatic hernia (CDH).

Methods

A multi-institutional retrospective cohort study of isolated CDH, diagnosed prenatally in fetuses delivered during the 2002 to 2007 period at 5 participating institutions in Japan, was conducted. The risk stratification system was formulated based on the odds ratios of prenatal parameters for mortality at 90 days. The clinical severity in CDH infants were compared among the stratified risk groups.

Results

Patients were classified into the 3 risk groups: group A (n = 48) consisted of infants showing liver-down with contralateral lung-to-thorax transverse area ratio (L/T) ratio ≥0.08; group B of infants showing liver-down with L/T ratio <0.08 or liver-up with L/T ratio ≥0.08 (n = 35), and group C of infants showing liver-up with L/T ratio <0.08 (n = 20). The mortality at 90 days in groups A, B, and C were 0.0%, 20.0%, and 65.0%, respectively. The intact discharge rates were 95.8%, 60.0%, and 5.0%, respectively. This system also accurately reflected the clinical severity in CDH infants.

Conclusions

Our prenatal risk stratification system, which demonstrated a significant difference in postnatal status and final outcome, would allow for accurate estimation of the severity of disease in fetuses with isolated CDH, although it needs prospective validation in a different population.     

Consensus on resuscitative endovascular balloon occlusion of the Aorta: A first consensus paper using a Delphi method

BackgroundTo further strengthen the evidence base on the use of Resuscitative Endovascular Balloon occlusion of the Aorta (REBOA) we performed a Delphi consensus. The aim of this paper is to establish consensus on the indications and contraindications for the use of REBOA in trauma and non-trauma patients based on the existing evidence and expertise.Study DesignA literature review facilitated the design of a three-round Delphi questionnaire. Delphi panelists were identified by the investigators. Consensus was reached when at least 70% of the panelists responded to the survey and more than 70% of respondents reached agreement or disagreement.ResultsPanel members reached consensus on potential indications, contra-indications and settings for use of REBOA (excluding the pre hospital environment), physiological parameters for patient selection and indications for early femoral access. Panel members failed to reach consensus on the use of REBOA in patients in extremis (no pulse, no blood pressure) and the use of REBOA in patients with two major bleeding sites.ConclusionsConsensus was reached on indications, contra indications, physiological parameters for patient selection for REBOA and early femoral access. The panel did not reach consensus on the use of REBOA in patients in pre-hospital settings, patients in extremis (no pulse, no blood pressure) and in patients with 2 or more major bleeding sites. Further research should focus on the indications of REBOA in pre hospital settings, patients in near cardiac arrest and REBOA inflation times.     

Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia

Background

Lung and pulmonary vascular maldevelopment in congenital diaphragmatic hernia (CDH) results in significant morbidity and mortality. Retinoic acid (RA) and imatinib have been shown to improve pulmonary morphology following prenatal administration in the rat nitrofen-induced CDH model. It remains unclear if these changes translate into improved function. We evaluated the effect of prenatal RA and imatinib on postnatal lung function, structure, and pulmonary artery (PA) blood flow in the rat CDH model.

The pulmonary hemodynamic response to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia

The continuing high mortality in congenital diaphragmatic hernia led us to study the cardiopulmonary disturbances associated with this lesion. Since these infants infrequently have right-to-left shunting in the operating room, we adopted a treatment protocol of: continuing general anesthesia in the postoperative period using fentanyl and pancuronium; cardiac catheterization postoperatively, including placement of a pulmonary artery line and a pulmonary angiogram; rapid frequency ventilation; moderate fluid restriction; and avoidance of vasodilators until other means of management had clearly failed. Fourteen high-risk infants, presenting within 6 hours of birth, were studied and compared to 17 high-risk infants, who served as historical controls. As revealed by the physiologic data acquired in the catheterization laboratory, high-risk infants divided into "Responder" and "Nonresponder" groups. Seven of 10 "Responders" actually shunted left to right during the catheterization, demonstrating a low pulmonary vascular resistance. Seven of 10 subsequently demonstrated significant right-to-left shunting at the level of the ductus and the foramen ovale, indicating the hyperreactivity of the pulmonary vascular bed. All but one was managed successfully by ventilatory adjustments and deepening of the level of anesthesia. "Nonresponders" had a fixed right-to-left shunt unresponsive to any medical or ventilatory manipulation. All "Nonresponders" died. Pulmonary angiography suggested a smaller diameter of the affected pulmonary artery compared to the main pulmonary artery in the "Nonresponders." This implies true hypoplasia resulting in a vasculature too small to accept a full cardiac output. Survival in the treatment group "Responders" was eight of 10 (80%) v seven of 14 (50%) in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Optimal timing for elective resection of asymptomatic congenital pulmonary airway malformations

Purpose

We sought to determine optimal timing for CPAM resection within the first year of life.

Predicting perinatal outcome in isolated congenital diaphragmatic hernia using fetal pulmonary artery diameters

Objective

The aim of the study was to evaluate the potential of fetal pulmonary artery (PA) diameters to predict perinatal death and pulmonary arterial hypertension (PAH) in congenital diaphragmatic hernia (CDH).

Study Design

In this prospective observational study, observed PA (main, right, and left) diameters were measured at the level of the 3 vessels in 21 fetuses with isolated CDH and in 85 controls at 22 to 36 weeks. The observed/expected (o/e) diameters of the main, contralateral, and ipsilateral PAs were calculated by comparing these measurements with reference values obtained in our previous study and correlated with perinatal death and postnatal PAH.

Results

The o/e PA diameters were significantly reduced in fetuses with CDH compared to controls (P < .001) and in fetuses with CDH who died (P < .050). However, there was no significant association between PA diameters and PAH (P ≥ .050).

Conclusions

The PA diameters might be useful to predict perinatal death in isolated CDH but not postnatal PAH, suggesting that PA diameters are probably related to the severity of pulmonary hypoplasia.     

The lung to thorax transverse area ratio has a linear correlation with the observed to expected lung area to head circumference ratio in fetuses with congenital diaphragmatic hernias

Background/Purpose

The purpose of this study was to clarify the relationship between the lung to thorax transverse area ratio (L/T ratio) and the observed to expected lung area to head circumference ratio (O/E LHR), based on the results of a nationwide Japanese survey conducted in 2011, and to evaluate the compatibility of these prognostic predictors of fetal CDH.

Methods

Two hundred and forty-two prenatally diagnosed isolated CDH patients born between 2006 and 2010 were included in the present analysis. A regression analysis was conducted to investigate the relationship between the L/T ratio and the O/E LHR based on 191 simultaneous measurements of these parameters in 120 patients.

Results

The linear regression equation between the L/T ratio and the O/E LHR was: L/T ratio = 0.0233 + (0.00222 × O/E LHR), (R = 0.847, p < 0.0001). According to this equation, 25% of the O/E LHR, the cut-off value used in the fetal intervention for CDH, was equivalent to an L/T ratio of 0.08, a commonly accepted cut-off value for identifying the most severe cases of fetal CDH.

Conclusions

As there is a positive correlation between the L/T ratio and the O/E LHR, these two parameters proved to be used interchangeably according to the linear regression equation.     

Delphi法构建社区护士冠心病管理培训课程的研究

目的运用Delphi法对专家进行社区护士冠心病管理培训课程设置的函询,为社区护士冠心病管理继续教育提供研究支持。方法通过前期调查以及文献回顾,确定社区护士冠心病管理培训课程专家咨询表,运用Delphi法向26名专家对课程目标、学时数、课程内容、考核方式及参考书目等进行3轮咨询。结果专家3轮函询的积极系数分别为83.87%、96.15%、96.00%,权威系数为0.88,各指标的变异系数均0.25,专家意见的协调系数为0.181~0.359(P0.01)。最终确定社区护士冠心病管理培训课程内容,一级指标4个,二级指标18个,三级指标75个。结论专家的积极系数和权威系数均较高,专家意见的变异系数和协调系数均符合统计学要求,最终形成的结果具有一定的实际意义和参考价值。