The last week (or two) have been devoted, at the neglect of all other aspects of normal life, to the study of congenital diaphragmatic hernia. For what purpose you may ask? Well, as many of you already know, I love learning about embryogenesis and development. LOVE. Also, it’s for marks…an essay to be exact. Since so much time and effort have recently been spent on this educational process, a blog-entry must be written in it’s honour (Note: to all you English students out there, this essay is not known for its grammar or style. Pure, ghetto science writing.)

Congenital Diaphragmatic Hernia – etiology, alterations in pulmonary function and current therapies.

Congenital diaphragmatic hernia (CDH), present in 1/2200 live births⁸, is characterized by pulmonary hypertension (= high blood pressure and resistance in the lungs), pulmonary hypoplasia (= teensy lungs) and a diaphragmatic defect (= a hole in the diaphragm, through which the gut and/or liver can enter the thoracic cavity). Survival rates range from 20 – 80%, depending on the anomalies associated with the patient and the method of treatment implemented. Bochdalek hernia is a posterolateral diaphragm defect that results in a left-sided hernia and accounts for 90% of CDH. Morgagni hernia occurs in approximately 10% of CDH patients and is characterized by a right-sided hernia that commonly involves the liver. Both animal models and clinical studies have helped researchers gain a greater understanding of the pathophysiology of CDH. Use of the herbicide nitrofen to induce diaphragmatic defects in rat pups is a well-established animal model. This treatment produces a defect in pleuroperitoneal fold (PPF) formation, yielding a pathophysiological condition similar to Bochdalek hernia, although the mechanisms mediating its toxicity are unknown^2,10. Advances in clinical care have increased survival⁴, however there is still significant morbidity and mortality associated with CDH.

How the heck…?

The exact mechanism causing CDH is unknown. A key point of contention is whether the pulmonary defect is primary, causing a secondary diaphragm defect; or vice versa.

The “classic” theory suggests that faulty migration of the primitive foregut into the abdomen interferes with normal diaphragm development, subsequently affecting pulmonary development⁵. Other theories propose pathophysiological mechanisms that include abnormal phrenic nerve development and delayed closure of the PPF.

Conversely, there are studies that support an initial pulmonary defect (= the lung is small to begin with). Within this framework, the hypoplastic lung leads to abnormal diaphragm development and allows herniation of the gut into the thoracic cavity. The nitrofen-induced experimental model supports this hypothesis, as defects in branching morphogenesis are observed to precede defects in diaphragmatic development^2,6,7. Still, other theories propose “two-hits”⁶ to the lung, in an attempt to unify the conflicting hypothesis about the causation of CDH. In this model, the first lung defect precedes (and may result in) the diaphragm defect. Subsequently, the erroneous presence of gut in the thoracic cavity would result in a secondary lung defect.

There are also hypotheses that specifically address factors related to the regulation of embryogenesis (= a problem in the regulation of development). The “smooth muscle hypothesis”⁶ proposes a feedback mechanism whereby airway luminal pressure is the result of a balance between branching morphogenesis and airway smooth muscle (ASM) contractility. According to this model, a “single-hit” to mesenchyme destined to become ASM can yield both pulmonary and diaphragmatic defects by disrupting the balance of this feedback loop. Another prominent theory emphasizes the role of retinoic acid (the active form of Vitamin A) in lung development, identifying deficiencies in the signaling of this molecule as a primary cause of CDH. Evidently, there are many potential causes of CDH⁵, which may be better characterized as a wide variety of heterogeneous pathologies that produce the same effect – pulmonary hypoplasia and hypertension associated with a diaphragmatic defect.

The good stuff – the affect on function

Many structural anomalies are associated with the presence of CDH, which may or may not be secondary to the pulmonary and diaphragmatic abnormalities. Commonly, live-born babies with CDH exhibit cardiac defects⁸. However, there are also many secondary defects. For the purpose of ultrasound imaging, some of these important changes include a mediastinal shift and therefore a shift in the normal axis of the heart, stomach or bowel present in the thoracic cavity and a low lung-to-head ratio⁸. Physiologically, the main issue in CDH is respiratory distress due to the hypoplastic nature of the lungs and pulmonary hypertension. There are significant changes in the structural composition of the lung in CDH. In addition to hypoplasia, development appears to be arrested at the canalicular stage of lung morphogenesis³, resulting in a decrease in the number of bronchi and alveoli, smaller airspaces and larger interstitium. Such changes affect gas-exchange by increasing dead space and decreasing the efficiency of the lungs. Both structure³ and growth factor expression⁵ lend support to the presence of pulmonary canalicular arrest in CDH.

In CDH there is a marked reduction in the size and composition of the pulmonary vasculature (= blood vessels of the lung, important in gas-exchange) with an increased thickness of the surrounding smooth muscle layer; contributing to the development of pulmonary hypertension. The transition from fetal to newborn circulation can also be affected in CDH. Maintenance of high pulmonary resistance (= high blood pressure in the lung) necessitates continued shunting across the ductus arteriosus, which remains patent (= open) in newborn life^1,3. As a result, venous return from the lungs is decreased and there is a decrease in saturated oxyhemoglobin concentration. Therefore, there are significant alterations in the cardio-pulmonary state of infants with CDH.

So…what happens now?

Recent advances have increased the number of cases that are diagnosed antenatally, consequently shifting the viable therapeutic interventions to include in-utero procedures as well.

In contrast to previous in-utero interventions that targeted the anatomical defect directly, current ideas in fetal surgery emphasize tracheal occlusion. Tracheal occlusion, also known as PLUG (“plug the lung until it grows”) results in the accumulation of fetal lung fluid^3,9, which is thought to promote growth of the lung by increasing cell division and airspace distension⁵. Despite positive results from animal studies⁹ there is evidence to suggest that tracheal occlusion leads to a decrease in type II pneumocytes, the critical surfactant-producing cell. Also, due to the functional integration of pulmonary epithelium and vasculature it is necessary to ensure that epithelial proliferation is accompanied by a corresponding increase in vasculature support. Lastly, there are ethical issues involved in undertaking in-utero fetal surgery, whereby the high rate of mortality demands that it is performed only on the most severely affected fetuses. Evidently there are core issues that still need to be addressed regarding PLUG as a method of treatment in CDH, however it is promising for the subset of severely affected fetuses.

Postnatally, there are many therapies used to stabilize and treat CDH depending on the severity of the condition. These include surgery, steroids, ventilation, exogenous surfactant^3,5 and vasodilator treatment. Typically, the infant is allowed to stabilize (in terms of oxygenation, blood pressure and acid/base status) before corrective surgery of the diaphragmatic defect³. Issues encountered include the amount of herniation, the size of the abdominal cavity and the resulting increase in intra-abdominal pressure (compared to thoracic pressure) post-surgery. Additional postnatal management is centered upon successful evasion of respiratory failure through mechanical ventilation or extra-corporeal membrane oxygenation (ECMO)^1,3,5,9. These therapies raise questions about the ideal ventilation or oxygenation strategy to minimize lung injury and subsequent morbidity. Lastly, inhaled nitric oxide (iNO) is used to manage the commonly seen persistent pulmonary hypertension.

The end

The clinical picture of congenital diaphragmatic hernia can vary with the size, location and type of herniation, the effect on pulmonary development, cardiac development and pulmonary vasculature, in brief. Advances in animal models have had some success in human trials, however there are still many issues regarding the appropriate pre and post natal therapies that should be implemented. Additional studies regarding the etiology of CDH are needed to elucidate the mechanism of pulmonary hypoplasia, in order to correctly repair the defect and minimize long-term morbidity seen in these patients.

References:

1. Bohn D. 2006. Paed Resp Rev,7S:S249-250.
2. Kluth, et al. 1993. J Pediat Surg 28(3):456-463.
3. Juretschke L. 2001. JOGNN, 30(3): 259-268.
4. Moya F. 2006. Semin Perinatol 29:67-68.
5. Rottier R, Tibboel D. Semin Perinatol 29:86-93.
6. Jesudason E. 2006. J Pediat Surg 41:431-435.
7. Robertson D, Harmon C, Goldberg S. 2006. J Pediat Surg 41:E9-E10.
8. Graham G, Devine PC. 2005. Semin Perinatol 29:69-76.
9. Cass D. 2006. Semin Perinatol 29:104-111.
10. Greer J. 2000. J Appl Physiol 89: 2123-2129.