Congenital diaphragmatic hernia

doi:10.1016/S1526-0542(02)00262-2

Paediatric Respiratory Reviews

Volume 3, Issue 4, December 2002, Pages 339-348

https://doi.org/10.1016/S1526-0542(02)00262-2 Get rights and content

Abstract

Congenital diaphragmatic hernia (CDH) is a lethal human birth defect. Hypoplastic lung development is the leading contributor to its 30–50% mortality rate. Efforts to improve survival have focused on fetal surgery, advances in intensive care and elective delivery at specialist centres following in utero diagnosis.

The impact of abnormal lung development on affected infants has stimulated research into the developmental biology of CDH. Traditionally lung hypoplasia has been viewed as a secondary consequence of in utero compression of the fetal lung. Experimental evidence is emerging for a primary defect in lung development in CDH. Culture systems are providing research tools for the study of lung hypoplasia and the investigation of the role of growth factors and signalling pathways.

Similarities between the lungs of premature newborns and infants with CDH may indicate a role for antenatal corticosteroids. Further advances in postnatal therapy including permissive hypercapnia and liquid ventilation hold promise.

Improvements in our basic scientific understanding of lung development may hold the key to future developments in CDH care.

Section snippets

INTRODUCTION

Congenital diaphragmatic hernia (CDH) is an idiopathic birth malformation comprising the Bochdalek diaphragmatic defect, herniation of abdominal viscera into the thoracic cavity and pulmonary hypoplasia. An incidence of approximately 1:2500 births1., 2. results in a new case every 24–36 h in the UK. Despite current advances in neonatal care around 30–50% of affected infants die, largely due to respiratory insufficiency secondary to pulmonary hypoplasia.3., 4., 5. This review discusses

ANTENATAL DIAGNOSIS

Diagnosis of CDH is increasingly reported on antenatal ultrasound scans – either by routine anomaly scans at around 20 weeks gestation, or following clinical suspicion of maternal polyhydramnios. CDH is confirmed by visualising the stomach or loops of bowel within the thoracic cavity – ideally level with the “four-chamber” view of the fetal heart, along with mediastinal shift away from the side of the lesion. Antenatal diagnosis should prompt a careful search for cardiac and neural tube

PROGNOSTIC INDICATORS

One important aspect of counselling is the issue of prognosis. Should associated anomalies be found on the antenatal scan this will alter the projected outcome and each fetus should be considered individually. For isolated CDH defining accurate antenatal prognostic indicators has proved challenging. Features including early diagnosis (<25 weeks), polyhydramnios and the presence of an intrathoracic stomach bubble have all been suggested to equate with poor prognosis. None has been found to be

PLAN FOR DELIVERY

Antenatal counselling also provides an opportunity to formulate a plan for delivery. Ideally elective delivery should occur at an obstetric centre with easy access to paediatric surgical expertise to avoid long distances in the postnatal transfer of the infant. Caesarean section is usually reserved for obstetric indications.

POSTNATAL DIAGNOSIS

Should an antenatal diagnosis not be made, postnatal diagnosis most commonly occurs in the first few minutes of life. Signs of respiratory distress, a scaphoid abdomen and mediastinal shift away from the side of the lesion all suggest the diagnosis. X-ray appearances including an absent diaphragmatic outline, along with loops of bowel in the chest should confirm the diagnosis (Fig. 1). If necessary, the position of the tip of a nasogastric (NG) tube within the thorax, along with an upper

MANAGEMENT

At birth, or following diagnosis, the infant should be intubated and a large bore NG tube passed. Both interventions are designed to prevent any dilatation of the intrathoracic bowel, which would cause further respiratory embarrassment. Early postnatal management is aimed at providing adequate tissue oxygenation whilst avoiding high ventilatory pressures, that cause damage to the neonatal lungs through barotrauma. Traditionally this is achieved through routine use of sedation, with or without

INHALED NITRIC OXIDE

Initial attempts to treat pulmonary hypertension in the newborn involved the use of systemic vasodilators such as tolazoline or prostaglandins. However, significant side-effects, in particular systemic hypotension, made their use unacceptable.25., 26., 27. Inhaled nitric oxide presented an attractive alternative. Inhalational delivery and rapid metabolism mean that systemic side effects are minimised. Initial trials in infants with persistent pulmonary hypertension of the newborn were very

HIGH FREQUENCY OSCILLATORY VENTILATION

The use of high frequency oscillatory ventilation (HFOV) has been widely adopted. This follows the concept that altering the mode of ventilation by increasing the ventilator rate to 100–150 breaths/min with gas exchange occurring through bulk diffusion rather than mass flow may improve gas exchange whilst decreasing barotrauma. Despite the outcome of an early multicentre randomised trial in North America suggesting no benefits in preterm neonates with respiratory failure,³³ several anecdotal

EXTRACORPOREAL MEMBRANE OXYGENATION

ECMO, introduced in the late 1970s, involves placing the infant on cardiopulmonary support to allow a period of “lung rest” and reduction in pulmonary vascular resistance whilst providing the infant with oxygenated blood via an artificial circuit. ECMO is an accepted treatment modality for the management of respiratory failure in newborns. In the UK its use is restricted to designated paediatric ECMO centres.

Evidence to support the use of ECMO in CDH is conflicting. Early favourable reports

PERMISSIVE HYPERCAPNIA

An alternative approach, first suggested by Wung et al. in 1985 from New York is permissive hypercapnia.⁴⁵ This avoids the use of sedation, allowing the infant to breathe spontaneously on the ventilator. Peak inspiratory pressures are strictly limited, to avoid the effects of barotrauma on the hypoplastic lung, whilst PEEP is used to maximise alveolar recruitment. This technique permits arterial carbon dioxide levels to rise as necessary, whilst reserving sodium bicarbonate infusions to treat

EXOGENOUS SURFACTANT THERAPY

It is now widely accepted that the use of exogenous surfactant therapy to improve ventilation in premature infants is effective.49., 50. The benefits in CDH are less clear. Researchers have used a variety of methods to evaluate the surfactant status (measurements of phospholipid, phosphatidylcholine and surfactant proteins) in experimental CDH models. Lungs from the CDH lamb model have been shown to be deficient in phospholipid and phosphatidylcholine.51., 54. Similarly, lungs from the nitrofen

ANTENATAL STEROID THERAPY

Antenatal steroids improve lung maturation of pre-term infants.⁶² In CDH animal models, antenatal glucocorticoids have been shown to improve morphological maturity and reduce hypermuscularisation of the pulmonary vasculature.63., 64., 65., 66. Anecdotal benefits have been reported in a small number of cases (D. Tibboel, pers. comm.).67., 68. A multicentre trial (by the CDH Study Group) is currently evaluating antenatal glucocorticoid therapy in humans with prenatally diagnosed CDH.⁶⁷

LIQUID VENTILATION

Liquid ventilation using hyperbarically oxygenated fluid was briefly investigated for use in astronauts and divers during the 1950s. Theoretical advantages of liquid ventilation include the fact that, unlike gases, liquids spread uniformly in lung tissue, whilst decreasing the air–fluid interfaces and surface tension in alveoli. Initial efforts to use electrolyte solutions were unsuccessful due to poor gas solubility. However, the discovery of fluorocarbons has regenerated liquid ventilation as

LUNG TRANSPLANTATION

Lung transplantation is an established clinical treatment for paediatric patients with end-stage chronic respiratory insufficiency.⁷² Despite cumulative experience in the very young patient under the age of 1 year,⁷³ lung transplantation has only been performed in a single infant with CDH.⁷⁴ The concept of a temporary lung allograft, remaining in situ until the contralateral native lung has developed sufficiently to support postnatal life is an attractive proposition. The requirement for

SURGERY FOR CDH

Surgical repair of CDH has varied little in operative technique from the original reports. Operation is usually via a subcostal incision, although a thoracotomy may rarely be considered for right-sided lesions. Gentle reduction of abdominal viscera from the thorax is followed by identification and excision of any hernia sac (found in 10%).² Diaphragmatic closure is achieved by approximating freed native tissue with non-absorbable sutures. The anterior rim is frequently well formed, whilst the

LONG-TERM OUTCOME

Long-term follow up of survivors is required.⁹⁰ Apart from neurological sequelae resulting from chronic neonatal hypoxia, a high proportion of patients have chronic respiratory insufficiency secondary to pulmonary hypoplasia and the consequences of iatrogenic lung injury.91., 92. Gastro-oesophageal reflux and its attendant complications are perhaps related to diaphragmatic malfunction and may entail anti-reflux surgery.93., 94. Deformity of the spine and/or chest wall following CDH repair may

FETAL SURGERY FOR CDH

Failure of conventional postnatal therapies to significantly alter the prognosis of infants with CDH prompted paediatric surgeons to consider repair of the hernia antenatally. It was postulated that fetal diaphragmatic hernia repair would remove the compressive forces on the developing lung and permit lung growth to improve on the dismal survival of CDH. To address this hypothesis, surgeons created a surgical model of diaphragmatic hernia in fetal lambs and simulated antenatal closure of the

BASIC SCIENCE – LUNG DEVELOPMENT IN CDH

In recent years there has been an increased appreciation that CDH is more than just a “hole in the diaphragm”. The recognition of associated anomalies in 30–50% of CDH newborns implies that the key features of CDH may represent a global embryopathy.9., 111., 112., 113. This proposal suggests that lung hypoplasia arises during the embryonic period and before the fetal diaphragmatic hernia develops. Closure of the human diaphragm at 8 weeks gestation precludes any detailed investigation of lung

GROWTH FACTORS

Mammalian lung development requires the interaction of the fibroblast growth factor (FGF) family, cognate receptors (FGFRs) and heparan sulphate (HS) proteoglycans. This has been elucidated from studies in mice and the fruitfly, Drosophila melanogaster.¹²⁹ Branchless and breathless are Drosophila mutants lacking FGF and its receptor (FGFR), respectively.¹²⁹ Sugarless and sulphateless mutants lack HS. All these Drosophila mutants share abrogated airway branching.¹³⁰

Utilising this knowledge, we

VITAMIN A

Vitamin A is important in lung development. In 1953, Wilson and colleagues noted a high incidence of CDH in the pups of vitamin A deficient rats.¹³³ Interestingly it has been noted that human infants with CDH have significantly reduced levels of retinol and retinol-binding protein compared to age-matched controls.¹³⁴ A strain of transgenic mice in which both copies of the retinoic acid receptor (vitamin A binding receptor) gene have been deleted display CDH together with left lung agenesis and

TRANSGENIC MODELS

The ability to manipulate the expression of specific genes in transgenic mice has provided a powerful means of dissecting the genetic regulation of development and investigating the molecular events underpinning many malformations. Several mutant phenotypes have been described in which diaphragmatic hernia may feature. Whilst the inactivation of several genes may predispose to CDH, gene targeting typically does not ensure CDH in knockout offspring. This suggests a complex interaction of

FUTURE DIRECTIONS

What are the future therapeutic implications for clinicians treating CDH? Selection of patients for fetal surgery will require more accurate prognostic indicators of poor perinatal outcome. Fetal surgery at present may be “too little too late” to correct an established embryopathy in pulmonary development. Antenatal corticosteroid therapy is the subject of a multicentre trial. Fetoscopic delivery of targeted growth factors to enhance airway development in CDH will require careful appraisal. The

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Cited by (31)

Permissive hypercapnia in the management of congenital diaphragmatic hernia: Our institutional experience
2012, Journal of the American College of Surgeons
Congenital diaphragmatic hernia (CDH) is a potentially lethal anomaly associated with pulmonary hypoplasia and persistent pulmonary hypertension. Permissive hypercapnia is a strategy designed to reduce lung injury from mechanical ventilation in infants. It has been shown to be a potentially superior method of ventilator management for patients with CDH. In 2001, the Divisions of Neonatology and Pediatric Surgery at the University of Virginia Children's Hospital established permissive hypercapnia as the management strategy for treatment of CDH. We hypothesized that permissive hypercapnia would be associated with improved outcomes in this patient population.
This retrospective review compares outcomes of infants treated for CDH in the extracorporeal membrane oxygenation (ECMO) era before and after initiation of permissive hypercapnia at a single institution. Outcomes were compared using univariate statistical analysis.
Ninety-one patients were available for analysis and were divided into 2 groups: 42 (Group 1) treated before and 49 (Group 2) treated after implementation of permissive hypercapnia. Survival was higher in Group 2 (85.8% vs 54.8%; p = 0.001; relative risk [RR] 3.17). Morbidity was lower in Group 2 and approached statistical significance (65.3% vs 83.3%; p = 0.052). Patients in Group 2 were repaired later, had a lower rate of ECMO use, and were extubated earlier. There was no difference in hospital stay.
The use of permissive hypercapnia for infants with CDH was associated with decreased mortality, a longer period of ventilation before repair with a shorter period of ventilation after repair, a lower rate of ECMO use, and no lengthening of hospital stay. Permissive hypercapnia remains the standard of care for ventilation of infants with CDH at our institution.
Congenital diaphragmatic hernia -mechanisms of pulmonary hypoplasia
2011, Revue des Maladies Respiratoires
La hernie diaphragmatique congénitale (HDC) est une cause fréquente de détresse respiratoire néonatale. La mortalité et morbidité de cette affection sont en grande partie liée à l’hypoplasie pulmonaire et à l’existence d’une hypertension artérielle pulmonaire résistante au traitement. La pathogénie de la HDC et de ses malformations associées est en grande partie méconnue malgré des recherches importantes. Elle est basée sur la conception que la hernie des viscères abdominaux dans la cavité thoracique perturbe le développement du poumon. L’hypoplasie pulmonaire peut être également la conséquence d’un défaut d’expansion liée à la diminution des mouvements respiratoires. Nos connaissances sur la physiopathologie ont bénéficié de modèles animaux variés (chimiques ou génétiques). Ces études ont démontré que l’hypoplasie pulmonaire résultait de la perturbation de mécanismes moléculaires impliqués dans le développement embryonnaire du poumon. Des données récentes confèrent aux acides rétinoïques un rôle central dans les mécanismes de formation de la HDC. Bien que dans la plupart des cas, la HDC survient de façon sporadique, des résultats conséquents découlent de l’étude des syndromes génétiques et d’anomalies chromosomiques découvertes chez des patients. Des recherches sont encore nécessaires pour approfondir nos connaissances sur le développement pulmonaire normal et anormal dans la HDC. De telles études devraient permettre d’améliorer nos possibilités thérapeutiques et peut-être nos mesures préventives.
Congenital diaphragmatic hernia (CDH) is a common cause of severe neonatal respiratory distress. Mortality and morbidity are determined by the amount of pulmonary hypoplasia (PH) that occurs and by the development of therapy-resistant pulmonary hypertension. The pathogenesis and aetiology of CDH and its associated anomalies are still largely unknown despite all research efforts. The pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. PH, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Our understanding of CDH has also been aided by basic research with the use of dietary, teratogen-induced, and knockout models of CDH. These studies indicate that lung hypoplasia may involve disturbances of mitogenic signalling pathways fundamental to embryonic lung development. Recent data reveal the role of disruption of a retinoid-signalling pathway in the pathogenesis of CDH. Although multifactorial inheritance may best explain most cases of CDH in humans, much has been learned about the genetic factors that play a role in the development of CDH by studies of patients with CDH caused by specific genetic syndromes and chromosome anomalies. More research is warranted to improve our understanding of normal and abnormal lung development in relation to CDH. Such investigations will help in the design of new treatment strategies to improve the natural course or even to prevent this anomaly.
Absolute vs relative improvements in congenital diaphragmatic hernia survival: what happened to "hidden mortality"
2009, Journal of Pediatric Surgery
The aim of this study is to determine if there has been a true, absolute, or apparent relative increase in congenital diaphragmatic hernia (CDH) survival for the last 2 decades.
All neonatal Bochdalek CDH patients admitted to an Ontario pediatric surgical hospital during the period when significant improvements in CDH survival was reported (from January 1, 1992, to December 31, 1999) were analyzed. Patient characteristics were assessed for CDH population homogeneity and differences between institutional and vital statistics-based population survival outcomes. SAS 9.1 (SAS Institute, Cary, NC) was used for analysis.
Of 198 cohorts, demographic parameters including birth weight, gestational age, Apgar scores, sex, and associated congenital anomalies did not change significantly. Preoperative survival was 149 (75.2%) of 198, whereas postoperative survival was 133 (89.3%) of 149, and overall institutional survival was 133 (67.2%) of 198. Comparison of institution and population-based mortality (n = 65 vs 96) during the period yielded 32% of CDH deaths unaccounted for by institutions. Yearly analysis of hidden mortality consistently showed a significantly lower mortality in institution-based reporting than population.
A hidden mortality exists for institutionally reported CDH survival rates. Careful interpretation of research findings and more comprehensive population-based tools are needed for reliable counseling and evaluation of current and future treatments.
Diaphragm development and congenital diaphragmatic hernia
2007, Seminars in Pediatric Surgery
Citation Excerpt :
In all of these scenarios, the integrity of the diaphragm as a barrier between the abdomen and thoracic cavity is diminished, allowing the abdominal viscera to protrude into the thorax, forming a space-occupying lesion in this cavity and impairing fetal breathing movements, which together impedes lung development. Although this review focuses on the pathogenesis of the diaphragm defect in CDH, there is an extensive literature discussing lung abnormalities associated with CDH.17-22 In the 1970s, toxicological studies of the herbicide nitrofen (2,4-dichloro-phenyl-p-nitrophenyl ether) showed that, although relatively harmless to adult rodents, nitrofen induced developmental anomalies in the lungs, hearts, diaphragms, and skeletal tissues of fetuses exposed in utero.23,24
Advances in the understanding of normal diaphragm embryogenesis have provided the necessary foundation for novel insights into the pathogenesis of congenital diaphragmatic hernia (CDH). Although diaphragm formation is still not completely understood, we have identified key structures and periods of development that are clearly abnormal in animal models of CDH. The pleuroperitoneal fold (PPF) is a transient structure which is the target for the neuromuscular component of the diaphragm. The PPF has been shown to be abnormal in multiple animal models of Bochdalek CDH; specifically, a malformation of the nonmuscular component of this tissue is thought to underlie the later defect in the complete diaphragm. Based on data from animal models and the examination of human postmortem tissue, we hypothesize that abnormal PPF development underlies Bochdalek CDH. Further, the understanding of the pathogenesis of rarer subtypes of CDH will be advanced by the study of various new animal models discussed in this review.
Perinatal management of congenital diaphragmatic hernia
2006, Early Human Development
Congenital diaphragmatic hernia (CDH) retains high mortality due to lung hypoplasia and pulmonary hypertension. Efforts to improve survival and outcome have included fetal intervention, delivery at specialist centres, elective operation after stabilisation of labile physiology and minimising barotrauma. Permissive hypercapnea (‘gentle ventilation’) represents a significant advance in therapy gaining wider acceptance in centres worldwide. Human genetic studies are underway to identify candidate genes for the birth defect. Progress in the basic sciences may uncover critical aspects of developmental biology fundamental to CDH. Clinical trends in perinatal management of CDH are highlighted, which underpin the challenges of this lethal human anomaly.
Prevention of heart failure in the management of congenital diaphragmatic hernia by maintaining ductal patency. A case report
2006, Journal of Pediatric Surgery
Congenital diaphragmatic hernia is a rare entity in childhood carrying a high mortality rate of 30% to 50%. Ipsilateral pulmonary hypoplasia, increased pulmonary vascular resistance, and potential cardiac failure complicate early postnatal life. Surgical correction can either be performed on the first day of life or be deferred to a time after stabilization of the infant. Our patient presented with a left-sided Bochdalek's hernia containing large and small bowel. She required intubation and resuscitation on day 1 of life, and surgical repair had to be postponed. Further respiratory deterioration required commencement of inhaled nitric oxide and high-frequency ventilation. Pulmonary artery pressure rose to suprasystemic level. Closure of the ductus arteriosus on day 8 resulted in imminent right-sided heart failure. Commencement of alprostadil (prostaglandin E₁) reopened the ductus and stabilized the patient. Surgical repair was successful 3 days later. Alprostadil should be considered as an important component of therapy in severe cases of congenital diaphragmatic hernia, where deterioration of right-sided heart function occurs.

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SERIES: THORACIC SURGERYCongenital diaphragmatic hernia

Abstract

Section snippets

INTRODUCTION

ANTENATAL DIAGNOSIS

PROGNOSTIC INDICATORS

PLAN FOR DELIVERY

POSTNATAL DIAGNOSIS

MANAGEMENT

INHALED NITRIC OXIDE

HIGH FREQUENCY OSCILLATORY VENTILATION

EXTRACORPOREAL MEMBRANE OXYGENATION

PERMISSIVE HYPERCAPNIA

EXOGENOUS SURFACTANT THERAPY

ANTENATAL STEROID THERAPY

LIQUID VENTILATION

LUNG TRANSPLANTATION

SURGERY FOR CDH

LONG-TERM OUTCOME

FETAL SURGERY FOR CDH

BASIC SCIENCE – LUNG DEVELOPMENT IN CDH

GROWTH FACTORS

VITAMIN A

TRANSGENIC MODELS

FUTURE DIRECTIONS

J. Pediatr. Surg.

J. Pediatr. Surg.

Clin. Perinatol.

J. Pediatr. Surg.

J. Pediatr. Surg.

Clin. Perinatol.

Radiol. Clin. North Am.

J. Pediatr.

J. Pediatr. Surg.

J. Pediatr.

J. Pediatr.

Lancet

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

Transplant. Proc.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

J. Pediatr. Surg.

Clin. Perinatol.

Congenital diaphragmatic hernia: a retrospective autopsy study

Indian Pediatr.

Congenital diaphragmatic hernia

N Engl. J. Med.

Outcome of congenital diaphragmatic hernia

Pediatr. Pulmonol.

Drugs and congenital abnormalities

Lancet

Phenometrazine and fetal abnormalities

BMJ

Associated malformations and chromosomal anomalies in 42 cases of prenatally diagnosed diaphragmatic hernia

Am. J. Med. Genet.

Fetal diaphragmatic hernia: ultrasound diagnosis and clinical outcome in 28 cases

J. Pediatr. Surg.

Routine ultrasound for the prenatal diagnosis of congenital diaphragmatic hernia: the ‘isms’

Ultrasound Obstet. Gynecol.

SERIES: THORACIC SURGERY
Congenital diaphragmatic hernia