Thomas Schaible

Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update

In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH.

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe

Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity. To date, there are no standardized protocols for the treatment of infants with this anomaly. However, protocols based on the literature and expert opinion might improve outcome. This paper is a consensus statement from the CDH EURO Consortium prepared with the aim of achieving standardized postnatal treatment in European countries. During a consensus meeting between high-volume centers with expertise in the treatment of CDH in Europe (CDH EURO Consortium), the most recent literature on CDH was discussed. Thereafter, 5 experts graded the studies according to the Scottish Intercollegiate Guidelines Network (SIGN) Criteria. Differences in opinion were discussed until full consensus was reached. The final consensus statement, therefore, represents the opinion of all consortium members. Multicenter randomized controlled trials on CDH are lacking. Use of a standardized protocol, however, may contribute to more valid comparisons of patient data in multicenter studies and identification of areas for further research.

Toxic epidermal necrolysis and Stevens-Johnson syndrome: A review*

Objectives: The aims of this review are to summarize the definitions, causes, and clinical course as well as the current understanding of the genetic background, mechanism of disease, and therapy of toxic epidermal necrolysis and Stevens-Johnson syndrome. Data Sources: PubMed was searched using the terms toxic epidermal necrolysis, Stevens-Johnson syndrome, drug toxicity, drug interaction, and skin diseases. Data Synthesis: Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute inflammatory skin reactions. The onset is usually triggered by infections of the upper respiratory tract or by preceding medication, among which nonsteroidal anti-inflammatory agents, antibiotics, and anticonvulsants are the most common triggers. Initially the diseases present with unspecific symptoms, followed by more or less extensive blistering and shedding of the skin. Complete death of the epidermis leads to sloughing similar to that seen in large burns. Toxic epidermal necrolysis is the most severe form of drug-induced skin reaction and includes denudation of >30% of total body surface area. Stevens-Johnson syndrome affects <10%, whereas involvement of 10%–30% of body surface area is called Stevens-Johnson syndrome/toxic epidermal necrolysis overlap. Besides the skin, mucous membranes such as oral, genital, anal, nasal, and conjunctival mucosa are frequently involved in toxic epidermal necrolysis and Stevens-Johnson syndrome. Toxic epidermal necrolysis is associated with a significant mortality of 30%–50% and long-term sequelae. Treatment includes early admission to a burn unit, where treatment with precise fluid, electrolyte, protein, and energy supplementation, moderate mechanical ventilation, and expert wound care can be provided. Specific treatment with immunosuppressive drugs or immunoglobulins did not show an improved outcome in most studies and remains controversial. The mechanism of disease is not completely understood, but immunologic mechanisms, cytotoxic reactions, and delayed hypersensitivity seem to be involved. Conclusion: Profound knowledge of exfoliative skin diseases is needed to improve therapy and outcome of these life-threatening illnesses.

Congenital Diaphragmatic Hernia: Predictive Value of MRI Relative Lung-to-Head Ratio Compared with MRI Fetal Lung Volume and Sonographic Lung-to-Head Ratio

OBJECTIVE The purpose of this study was to evaluate the prognostic accuracy of a new MRI-based relative lung-to-head ratio in regard to neonatal survival and need for extracorporeal membrane oxygenation (ECMO) in the care of fetuses with congenital diaphragmatic hernia (CDH) and to compare it with the previously described sonographic relative lung-to-head ratio and relative fetal lung volume assessed at antenatal MRI. MATERIALS AND METHODS Sonographic lung-to-head ratio and MRI fetal lung volume were measured in 90 fetuses (mean gestational age, 31.4+/-4.1 weeks) with CDH. Sonographic relative lung-to-head ratio and MRI relative fetal lung volume were assessed by expressing the observed sonographic lung-to-head ratio and MRI fetal lung volume as a percentage of the expected parameter value. The new MRI relative lung-to-head ratio was assessed as a percentage of the expected MRI lung-to-head ratio based on MRI fetal lung volume and MRI head circumference measurements. Measurements for survival and ECMO requirement were determined with the area under the curve (AUC). Data were analyzed for left-sided defects, right-sided defects, and associated liver herniation. RESULTS Among fetuses with left-sided CDH, all parameters were excellent in determining neonatal survival and need for ECMO therapy (p <or= 0.0027). Prognostic accuracy was best for the newly devised MRI relative lung-to-head ratio (AUC, 0.816 and 0.807) and lowest for sonographic relative lung-to-head ratio (AUC 0.783 and 0.703). Among fetuses with right-sided defects, the predictive value was lower for all parameters (AUC, 0.788-0.560). All neonates without liver herniation survived. CONCLUSION Among fetuses with left-sided CDH, assessment of pulmonary hypoplasia based on MRI relative fetal lung volume and MRI relative lung-to-head ratio is excellent in prediction of neonatal survival and ECMO requirement. The prognostic accuracy is slightly better than that of sonographic relative lung-to-head ratio. Among fetuses with right-sided CDH, the prognostic value of all parameters is lower than those among fetuses with left-sided defects.

MR Relative Fetal Lung Volume in Congenital Diaphragmatic Hernia: Survival and Need for Extracorporeal Membrane Oxygenation

PURPOSE To retrospectively evaluate the accuracy of the absolute fetal lung volume (FLV) measured at magnetic resonance (MR) imaging and seven formulas for calculating relative FLV to predict neonatal survival and the need for extracorporeal membrane oxygenation (ECMO) in fetuses with congenital diaphragmatic hernia (CDH). MATERIALS AND METHODS This retrospective study was approved by the research ethics committee, and informed consent was received from all mothers for previous prospective studies. In total, 68 fetuses with CDH were assessed by using MR image FLV measurement within 23-39 weeks gestation. The relative FLV was expressed as a percentage of the predicted lung volume calculated with biometric parameters according to seven formulas previously described in the literature. Applying the area under the curve (AUC), the various relative FLVs and the absolute FLV were investigated for their prognostic accuracy to predict neonatal survival and the need for ECMO therapy. RESULTS All relative FLVs and the absolute FLV revealed a significant difference in mean lung volume between neonates who survived and neonates who did not survive (P = .001 to P < .001) and measurement accuracy was excellent for each method (AUC, 0.800-0.900). For predicting neonatal ECMO requirement, differences in FLVs were smaller but still significant (P = .05 to <.009) and measurement accuracy was acceptable throughout (AUC, 0.653-0.739). CONCLUSION The various relative FLVs and the absolute FLV measured at MR planimetry are each highly valuable in predicting survival in fetuses with CDH. For predicting whether neonatal ECMO therapy is required, the accuracy of the absolute FLV (AUC, 0.68) and that of the relative FLVs (AUC, 0.653-0.739) was acceptable.

Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia

Background Congenital diaphragmatic hernia (CDH) is a life threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified. Objective To identify genomic alterations that contribute to the development of diaphragmatic defects. Methods A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations was screened for genomic alterations by array comparative genomic hybridisation or single nucleotide polymorphism based copy number analysis. Results Genomic alterations that were likely to have contributed to the development of CDH were identified in 8 patients. Inherited deletions of ZFPM2 were identified in 2 patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was identified in a patient with a partial pentalogy of Cantrell phenotype. Conclusions Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. These data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH related genes on chromosomes 16p11.2, 11q23-24 and 13q12, and suggest a possible role for FZD2 and Wnt signalling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.

Value of Myocardial Hypoxia Markers (Creatinine Kinase and Its MB-Fraction, Troponin-T, QT-Intervals) and Serum Creatinine for the Retrospective Diagnosis of Perinatal Asphyxia

Neonatal asphyxia is a major topic of neonatal research. However, no clear-cut physiologic parameters exist which enable an early identification of neonatal infants who are either at risk to develop brain damage or posthypoxic heart failure. Parameters indicating dysfunction of the heart and kidneys as creatinine and creatinine kinase have been evaluated. In our study, 47 asphyxiated infants (umbilical artery pH <7.18 and either a 1-min Apgar score <4 or a 5-min Apgar score <7) were compared to 27 nonasphyxiated controls regarding significant differences in creatinine, creatinine kinase, its MB fraction, and a newly introduced myocardial hypoxia indicator – troponin T – to establish the value of these parameters in the retrospective diagnosis of asphyxia. Further we evaluated two subsets of these 47 asphyxiated infants with either subsequent signs of encephalopathy (seizures) or heart failure. Creatinine, creatinine kinase and troponin T were significantly elevated in asphyxiated infants compared with controls; no differences were found in creatinine kinase and its MB fraction. In asphyxiated infants with heart failure, troponin T was significantly higher than in the other asphyxiated infants. However, none of the parameters studied was significantly different in patients with brain damage compared with asphyxiated infants without neurological sequelae. Troponin T has a high positive predictive value in the postnatal diagnosis of asphyxia. The diagnostic power of troponin T equals that of creatinine. However, troponin T is more sensitive in the identification of infants with asphyxia and cardiocirculatory failure than creatinine. Creatinine kinase and its MB fraction have no diagnostic value.

Congenital diaphragmatic hernia: a modern day approach.

Centralization of all complicated congenital diaphragmatic hernias (CDH) was organized in Germany from 1998, collecting 325 consecutive patients with striking increasing survival rates. This series report 244 patients from 2002 to 2007. Today, large defects are detected early in pregnancy by ultrasound and magnetic resonance imaging (MRI). In extracorporeal membrane oxygenation (ECMO) patients, prenatal lung head ratio (LHR) was 1.2 (median) at the 34th week of gestation or less than 25 ml lung tissue in MRI. This means that all patients below LHR of 1.4 should be transferred prenatally in a tertiary center. High risk group for survival was defined as LHR below 0.9, ie, 10 ml in MRI planimetry. Inborn patients show better results than outborns. In algorithm therapy, gentle ventilation plays an important role in preventing damage to the lung tissue and avoiding long term ventilation. When PaCO(2) was more than 75 mmHg, ventilation was changed to high frequency oscillatory ventilation (HFOV). Indication for ECMO was seen in preductal PaO(2) less than 50 mmHg over 2-4 h or less than 40 mmHg over 2 h. ECMO related risks included intracerebral bleeding (9%), intrapulmonary bleeding (14%), and convulsions (16%). Surgically, a longitudinal midline incision for exposure of the defect, the duodenal kinking, and probably for abdominal patching was perfect. A cone formed goretex patch provided more abdominal space and reduced abundant intrathoracical cavity. No drain was used. Postoperative complications were described. Overall survival in 244 consecutive patients was 86.5% for all patients born alive. All those who needed ECMO survived in 71%, underlining ECMO as a treatment of last choice. Follow-up for quality of life after CDH is described.

MR Lung Volume in Fetal Congenital Diaphragmatic Hernia : Logistic Regression Analysis Mortality and Extracorporeal Membrane Oxygenation

PURPOSE To prospectively assess the results of logistic regression analysis that were based on magnetic resonance (MR) image fetal lung volume (FLV) measurements to predict survival and the corresponding need for extracorporeal membrane oxygenation (ECMO) therapy in fetuses with congenital diaphragmatic hernia (CDH) before and after 30 weeks gestation. MATERIALS AND METHODS Written informed consent was obtained and the study was approved by the local research ethics committee. FLV was measured on MR images in 95 fetuses (52 female neonates, 43 male neonates) with CDH between 22 and 39 weeks gestation by using multiplanar T2-weighted half-Fourier acquired single-shot turbo spin-echo MR imaging. On the basis of logistic regression analysis results, mortality and the need for ECMO therapy were calculated for fetuses before and after 30 weeks gestation. RESULTS Overall, higher FLV was associated with improved survival (P < .001) and decreasing probability of need for ECMO therapy (P = .008). Survival at discharge was 29.2% in neonates with an FLV of 5 mL, compared with 99.7% in neonates with an FLV of 25 mL. The corresponding need for ECMO therapy was 56.1% in fetuses with an FLV of 5 mL and 8.7% in fetuses with an FLV of 40 mL. Prognostic power was considerably lower before 30 weeks gestation. CONCLUSION Beyond 30 weeks gestation, logistic regression analysis that is based on MR FLV measurements is useful to estimate neonatal survival rates and ECMO requirements. Prior to 30 weeks gestation, the method is not reliable and the FLV measurement should be repeated, particularly in fetuses with small lung volumes, before a decision is made about therapeutic options.

Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial).

Objectives:To determine the optimal initial ventilation mode in congenital diaphragmatic hernia. Background:Congenital diaphragmatic hernia is a life-threatening anomaly with significant mortality and morbidity. The maldeveloped lungs have a high susceptibility for oxygen and ventilation damage resulting in a high incidence of bronchopulmonary dysplasia (BPD) and chronic respiratory morbidity. Methods:An international, multicenter study (NTR 1310), the VICI-trial was performed in prenatally diagnosed congenital diaphragmatic hernia infants (n = 171) born between November 2008 and December 2013, who were randomized for initial ventilation strategy. Results:Ninety-one (53.2%) patients initially received conventional mechanical ventilation and 80 (46.8%) high-frequency oscillation. Forty-one patients (45.1%) randomized to conventional mechanical ventilation died/ had BPD compared with 43 patients (53.8%) in the high-frequency oscillation group. An odds ratio of 0.62 [95% confidence interval (95% CI) 0.25–1.55] (P = 0.31) for death/BPD for conventional mechanical ventilation vs high-frequency oscillation was demonstrated, after adjustment for center, head-lung ratio, side of the defect, and liver position. Patients initially ventilated by conventional mechanical ventilation were ventilated for fewer days (P = 0.03), less often needed extracorporeal membrane oxygenation support (P = 0.007), inhaled nitric oxide (P = 0.045), sildenafil (P = 0.004), had a shorter duration of vasoactive drugs (P = 0.02), and less often failed treatment (P = 0.01) as compared with infants initially ventilated by high-frequency oscillation. Conclusions:Our results show no statistically significant difference in the combined outcome of mortality or BPD between the 2 ventilation groups in prenatally diagnosed congenital diaphragmatic hernia infants. Other outcomes, including shorter ventilation time and lesser need of extracorporeal membrane oxygenation, favored conventional ventilation.