Pulmonary hypertension in congenital diaphragmatic hernia

doi:10.1053/j.sempedsurg.2007.01.008

Seminars in Pediatric Surgery

Volume 16, Issue 2, May 2007, Pages 126-133

https://doi.org/10.1053/j.sempedsurg.2007.01.008 Get rights and content

Clinically significant pulmonary hypertension (PHTN) is a common finding in newborn infants with congenital diaphragmatic hernia (CDH) resulting in right to left shunting at pre- and postductal level, hypoxemia, and acute right heart failure in those most severely affected. Even in those without clinical manifestations of ductal shunting, cardiac echo studies would suggest that increased pulmonary vascular resistance and right ventricular pressures are almost a universal finding in this disease, and in some instances, may persist well into the postnatal period. The lung is small and structurally abnormal, and the pulmonary vascular bed is not only reduced in size, but responds abnormally to vasodilators. During the last 20 years, “gentle” ventilation, delayed surgery, and improved peri-operative care have made the greatest impact in decreasing mortality in this condition. Use of PGE1 should be considered early if there is hemodynamically significant PHTN, right ventricular dysfunction, and the patent ductus arteriosus (PDA) is becoming restrictive. In individual patients, inhaled nitric oxide (iNO) might be helpful, but the response to iNO should be confirmed using echocardiography. In patients who survive operation and leave the hospital, there are chronic causes of morbidity that need to be looked for and managed in a multi-disciplinary follow-up clinic.

Section snippets

Morphology of the lungs and pulmonary vasculature in CDH

The lung in CDH is architecturally, histologically, and functionally smaller and immature. It has a smaller number and generations of airways, thickened alveolar septa, and an abnormal architecture of the respiratory acinus.¹ The number and differentiation pattern of type II pneumocytes are also abnormal.²

The pulmonary arteries are decreased in density per unit lung volume, and the muscularization extends too far into the periphery, reaching the level of acinus. The media and adventitia of the

Pathogenesis of increased pulmonary vascular reactivity in CDH

Fetal pulmonary circulation is characterized by high vascular resistance. In the fetal lamb, <10% of ventricular output enters the lungs.¹¹ The underlying mechanisms likely involve physical factors such as the lack of ventilation and low oxygen tension. An imbalance between vasorelaxant and constrictor mediators is also likely to play a role.

Further insights into how this process evolves comes from recent work on molecular and biochemical pathogenesis of CDH as far as this relates to the

Predictors of outcome related to pulmonary vascular reactivity

Dillon and coworkers performed a retrospective chart review of all neonates with diagnosis of CDH from 1991 to 2002 at their institution, eliminating infants with complex congenital heart defect, prematurity, or limited treatment.²⁴ Forty-seven infants had 428 cardiac echo evaluations. Long-term survival rate was 74%. Forty-nine percent of patients had normal estimates of pulmonary artery pressure within the first 3 weeks of life; all of these survived. Seventeen percent had persistent systemic

The management of pulmonary vascular reactivity in CDH

The management of pulmonary hypertension in newborn infants until recently has been focused on reducing PVR by manipulations of pH and PaCO₂. This strategy was first outlined in a paper by Drummond²⁹ in 1981, where they described a reduction in ductal shunting in 6 neonates with PPHN by hyperventilation and increasing the pH to >7.5. Although this is frequently effective in increasing the postductal PaO₂, the degree of pulmonary barotrauma inflicted probably led to a significant number of

Outcome and the development of late PHTN

Iocono and coworkers⁸³ studied the course of pulmonary hypertension diagnosed by echocardiography in 51 infants with CDH who were treated in their institution between 1991 and 1997. Forty of these infants survived to discharge (78% survival). Of these 40 survivors, 7 infants (18%) had RV systolic pressure >½ systemic at discharge (classified as the “PPHN” group). Study group and control infants differed little in their population characteristics. There were significant differences with regard

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Increased Elastase and Matrix Metalloproteinase Levels in the Pulmonary Arteries of Infants With Congenital Diaphragmatic Hernia
2024, Journal of Pediatric Surgery
Pulmonary vascular disease (PVD) complicated with pulmonary hypertension (PH) is a leading cause of mortality in congenital diaphragmatic hernia (CDH). Unfortunately, CDH patients are often resistant to PH therapy. Using the nitrogen CDH rat model, we previously demonstrated that CDH-associated PVD involves an induction of elastase and matrix metalloproteinase (MMP) activities, increased osteopontin and epidermal growth factor (EGF) levels, and enhanced smooth muscle cell (SMC) proliferation. Here, we aimed to determine whether the levels of the key members of this proteinase-induced pathway are also elevated in the pulmonary arteries (PAs) of CDH patients.
Neutrophil elastase (NE), matrix metalloproteinase-2 (MMP-2), epidermal growth factor (EGF), tenascin-C, and osteopontin levels were assessed by immunohistochemistry in the PAs from the lungs of 11 CDH patients and 5 normal age-matched controls. Markers of proliferation (proliferating cell nuclear antigen (PCNA)) and apoptosis (cleaved (active) caspase-3) were also used.
While expressed by both control and CDH lungs, the levels of NE, MMP-2, EGF, as well as tenascin-C and osteopontin were significantly increased in the PAs from CDH patients. The percentage of PCNA-positive PA SMCs were also enhanced, while those positive for caspase-3 were slightly decreased.
These results suggest that increased elastase and MMPs, together with elevated tenascin-C and osteopontin levels in an EGF-rich environment may contribute to the PVD in CDH infants. The next step of this study is to expand our analysis to a larger cohort, and determine the potential of targeting this pathway for the treatment of CDH-associated PVD and PH.
Therapeutic.
LEVEL III.
Long term outcome of babies with pulmonary hypertension
2022, Seminars in Fetal and Neonatal Medicine
Citation Excerpt :
Neonatal pulmonary hypertension (PH) is associated with a broad range of potentially serious neonatal cardiorespiratory diseases with high morbidity and mortality [1]. Some manifest within hours of birth with acute hypoxemic respiratory failure such as persistent pulmonary hypertension of the newborn (PPHN) or meconium aspiration pneumonia, and others may evolve over hours or days following a brief “honeymoon” period as seen congenital diaphragmatic hernia (CDH) [2]. In conditions like bronchopulmonary dysplasia (BPD), where prematurity plays an important role, there may be considerable variation in presentation depending upon the degree of lung injury and other inflammatory triggers [3,4].
Neonatal pulmonary hypertension (PH) is associated with many severe congenital abnormalities (congenital diaphragmatic hernia) or acquired cardiorespiratory diseases such as pneumonia, meconium aspiration and bronchopulmonary dysplasia (BPD). If no cause is found it may be labelled idiopathic persistent pulmonary hypertension of the newborn. Although PH may result in life threatening hypoxia and circulatory failure, in the majority of cases, it resolves in the neonatal period following treatment of the underlying cause. However, in some cases, neonatal PH progresses into infancy and childhood where symptoms include failure to thrive and eventually right heart failure or death if left untreated. This chronic condition is termed pulmonary vascular hypertensive disease (PHVD). Although classification and diagnostic criteria have only recently been proposed for pediatric PHVD, little is known about the pathophysiology of chronic neonatal PH, or why pulmonary vascular resistance may remain elevated well beyond infancy. This review explores the many factors involved in chronic PH and what implications this may have on long term outcome when the disease progresses beyond the neonatal period.
Persistent pulmonary hypertension of newborn
2022, Seminars in Pediatric Surgery
Citation Excerpt :
Both the pulmonary airway and arterial branching are inhibited and developmentally abnormal while alveolarization is impaired70,71. The pulmonary vascular bed has a reduced cross-sectional area with thickened arteriolar media and adventitia along with pathophysiologic pulmonary vasoreactivity causing pulmonary hypertension with decreased blood flow to the lungs72,73,74,75. Long-term morbidity and mortality (20-30%) depends on the severity of lung hypoplasia and the associated PPHN, though outcomes continue to improve with ongoing standardization of clinical management.
Molecular Mechanisms Contributing to the Etiology of Congenital Diaphragmatic Hernia: A Review and Novel Cases
2022, Journal of Pediatrics
Congenital diaphragmatic hernia and associated omphalocele: a study from the CDHSG registry
2020, Journal of Pediatric Surgery
Congenital Diaphragmatic Hernia (CDH) associated with Omphalocele is a rare condition, and only a few case reports are available in the literature. Both conditions are associated with some degree of pulmonary hypoplasia. We hypothesize that the combination of CDH with Omphalocele might be associated with poorer outcomes.
The aim of this study was to describe the incidence of this association and postnatal outcomes from the largest database available for CDH.
Data from the multicenter, multinational database on infants with CDH (CDHSG Registry) born from 2007 to 2018 was analyzed.
A total of 5730 entries were made into the registry during the study period. The incidence of Omphalocele associated with CDH was 0.63% (36 out of 5730).
When comparing posterolateral Bochdalek hernias with Omphalocele (CDH + O) to CDH without Omphalocele (CDH-), CDH + O were born at significantly younger gestational ages. They were sicker directly after birth with significantly lower APGARs at all time points, but received ECMO significantly less often.
The distribution of left vs right side or the defect size did not differ but CDH + O required patch in a significantly larger extent. CDH + O had surgical repair significantly later and had significantly higher rates of non-repairs and significantly lower survival rates. The morbidity was significantly higher with longer hospital stays and higher requirements for O2 at 30 DOL.
CDH associated with Omphalocele is a rare but more severe condition with higher mortality and morbidity rates. Newborns with these combined conditions can be difficult to stabilize or might pose complicated management problems due to pulmonary hypertension and/or pulmonary hypoplasia.
Prognosis Study.
Level I.
Congenital diaphragmatic hernia-associated pulmonary hypertension
2020, Seminars in Perinatology
Congenital diaphragmatic hernia (CDH) is a neonatal pathology in which intrathoracic herniation of abdominal viscera via diaphragmatic defect results in aberrant pulmonary and cardiovascular development. Despite decades of study and many advances in the diagnosis and treatment of CDH, morbidity and mortality remain high, largely due to pulmonary hypertension (PH), along with pulmonary hypoplasia and cardiac dysfunction. In patients with CDH, hypoplastic pulmonary vasculature and alterations in multiple molecular pathways lead to pathophysiologic pulmonary vasculopathy and, for severe CDH, sustained, elevated pulmonary arterial pressures. This review addresses the multiple anatomic and physiologic changes that underlie CDH-associated PH (CDH-PH), along with the multimodal treatment strategies that exist currently and future therapies currently under investigation.

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Pulmonary hypertension in congenital diaphragmatic hernia

Section snippets

Morphology of the lungs and pulmonary vasculature in CDH

Pathogenesis of increased pulmonary vascular reactivity in CDH

Predictors of outcome related to pulmonary vascular reactivity

The management of pulmonary vascular reactivity in CDH

Outcome and the development of late PHTN

Semin Perinatol

J Pediatr Surg

Am J Obstet Gynecol

Am J Obstet Gynecol

Eur J Radiol

Paediatr Respir Rev

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Surg Res

J Pediatr Surg

Am J Obstet Gynecol

J Pediatr Surg

J Pediatr

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

J Pediatr

Arch Pediatr

J Thorac Cardiovasc Surg

J Pediatr Surg

J Pediatr

Pediatr Clin North Am

J Am Coll Cardiol

J Pediatr Surg

Ann Thorac Surg

J Card Fail

Chest

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

Am J Obstet Gynecol

J Pediatr Surg

Semin Perinatol

J Pediatr Surg

J Pediatr Surg

Semin Perinatol

J Pediatr Surg

J Pediatr Surg

J Pediatr Surg

Pulmonary growth and remodeling in infants with high-risk congenital diaphragmatic hernia

J Pediatr Surg

Early fetal development of lung vasculature

Am J Respir Cell Mol Biol

Morphometric analysis of preterm fetal pulmonary development in the sheep model of congenital diaphragmatic hernia

Pediatr Dev Pathol