Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019270 (hernia)
 15,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A newborn with right diaphragmatic hernia suffered myocardial stunning and suprasystemic pulmonary hypertension secondary to postpartal asphyxia. In addition to conventional therapy, norepinephrine, enoximone, and inhalational nitric oxide were successfully used. Norepinephrine improved myocardial perfusion pressure; the addition of enoximone, a phosphodiesterase-inhibitor, to beta-adrenergic agents increased cardiac performance. with decreasing concentrations of inhalational nitric oxide, severe pulmonary hypertension resolved after a few days, suggesting that transient endothelial dysfunction was partially responsible for pulmonary vasoconstriction in the newborn with congenital diaphragmatic hernia.
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PMID:Norepinephrine, enoximone, and nitric oxide for treatment of myocardial stunning and pulmonary hypertension in a newborn with diaphragmatic hernia. 766 10

Persistent pulmonary hypertension of the newborn (PPHN) is a potentially life-threatening condition characterized by a failure of pulmonary vascular resistance to decrease adequately during the transition to extrauterine life. Inhaled nitric oxide, a vasodilator that acts selectively on the pulmonary circulation, has revolutionized the treatment of this condition. However, inhaled nitric oxide has not proven effective in all patients, particularly those with congenital diaphragmatic hernias or meconium aspiration syndrome. Furthermore, large clinical trials of inhaled nitric oxide have failed to demonstrate significant differences in mortality between nitric oxide-treated and control infants with PPHN. Other therapeutic approaches to PPHN have been limited by a relative lack of specificity for the pulmonary circulation, and have received much less attention. Pharmacologic approaches, including pulmonary surfactants, prostacyclin, endothelin antagonists, Ca(2+)-channel blockers, magnesium sulfate, and tolazoline, have exhibited varying degrees of efficacy in lowering pulmonary vascular pressures in humans and/or animals. A number of these agents are also effective when used in combination. For example, phosphodiesterase inhibitors have been reported to act synergistically with inhaled nitric oxide. Surfactants also appear to be useful in PPHN, particularly in patients with congenital diaphragmatic hernia, when used in combination with other therapies. Surfactant lavage and other novel therapies may also be effective in combination therapy of meconium aspiration syndrome. Further studies should be directed at defining the optimal therapies in specific clinical settings. Validation of multiple therapeutic modalities for PPHN, including inhaled nitric oxide, will allow for rational, combined vasodilator strategies that are specific for the underlying pathophysiology in each patient.
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PMID:Pharmacologic therapy of persistent pulmonary hypertension of the newborn. 1131 14

A full-term neonate with a left-sided congenital diaphragmatic hernia (CDH) was ventilated mechanically by high-frequency oscillatory ventilation (HFOV). Despite inhaled nitric oxide (iNO) at a dose of 15 ppm, the neonate had severe respiratory acidosis and was placed on extracorporeal membrane oxygenation (ECMO) for 2 days. On day 7 of life, surgical repair of the CDH was performed. After the intervention, iNO (20 ppm) had to be restarted because of severe pulmonary hypertension (PHT). Ventilatory support and iNO then were weaned progressively. However, each daily attempt to discontinue iNO (from 2 ppm to 0 ppm), led to severe desaturation with significant right-to-left shunting. At the age of 33 days, dipyridamole (persantin) was administered intravenously at a dose of 0,4 mg/kg/min over 10 minutes and repeated every 12 hours for a total of 3 doses. After the second administration of dipyridamole, iNO could be stopped without rebound of PHT, and the neonate was extubated 1 week later. The authors report the use of dipyridamole for successful withdrawal of iNO. By inhibition of phosphodiesterase type 5, dipyridamole has the potential to increase the level of cyclic guanosine monophosphate in vascular smooth muscle cells, permitting vasodilation and restoration of endogenous NO. J Pediatr Surg 36:1864-1865.
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PMID:The use of dipyridamole to wean from inhaled nitric oxide in congenital diaphragmatic hernia. 1173 27

Nitric oxide (NO) plays a major role in the modulation of perinatal pulmonary vascular tone. Congenital diaphragmatic hernia (CDH), a major cause of severe persistent pulmonary hypertension of the newborn (PPHN), is often refractory to inhaled NO. Alterations in NO/cyclic guanosine 3',5' monophosphate (cGMP)-mediated pulmonary vasodilatation may contribute to PPHN in CDH. We assessed NO/cGMP-mediated pulmonary vasorelaxation in vitro in 140-d gestational lamb fetuses with surgically created left CDH (term = 147 d) to age-matched controls. Relaxation of fourth generation intralobar pulmonary artery rings in response to the endothelium-dependent vasodilator, acetylcholine (ACh), and to the specific inhibitor of cGMP-phosphodiesterase (PDE), zaprinast, did not differ between the two groups. By contrast, relaxation in response to the calcium ionophore A23187 was impaired in CDH as compared with control animals. Relaxation in response to the NO donor sodium nitroprusside (SNP) (a direct activator of soluble guanylyl cyclase [sGC]) was also impaired in CDH animals as compared with controls. Repeating the challenge increased vasorelaxation in response to SNP in CDH as compared with control animals. Immunohistochemistry revealed the presence of endothelial NO-synthase in the endothelium of pulmonary arteries from both control and CDH animals. We conclude that endothelium-dependent vasodilatation in response to ACh and A23187 was differently affected in the fetal surgical CDH-lamb model. Furthermore, activity of sGC but not that of PDE was impaired in CDH animals. PPHN and decreased inhaled NO responsiveness in CDH may involve decreased sGC activity.
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PMID:Altered guanylyl-cyclase activity in vitro of pulmonary arteries from fetal lambs with congenital diaphragmatic hernia. 1209 Dec 44

Pulmonary hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchopulmonary dysplasia, sepsis, or congenital heart disease. Because of the heterogeneous group of disorders, the therapeutic approach and response often depends on the underlying disease. In many of these conditions, there is evidence that cyclic nucleotide signaling and specifically phosphodiesterases (PDEs) are disrupted. PDE inhibitors represent an emerging class of pulmonary vasodilators in adults. Studies are now under way to evaluate the utility, efficacy, and safety of such therapies in infants with pulmonary hypertension.
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PMID:Phosphodiesterases: emerging therapeutic targets for neonatal pulmonary hypertension. 2169 44

Inhaled nitric oxide (iNO) is approved for use in persistent pulmonary hypertension of the newborn (PPHN) but does not lead to sustained improvement in oxygenation in one-third of patients with PPHN. Inhaled NO is less effective in the management of PPHN secondary to congenital diaphragmatic hernia (CDH), extreme prematurity, and bronchopulmonary dysplasia (BPD). Intravenous pulmonary vasodilators such as prostacyclin, alprostadil, sildenafil, and milrinone have been successfully used in PPHN resistant to iNO. Oral pulmonary vasodilators such as endothelin receptor antagonist bosentan and phosphodiesterase-5 inhibitors such as sildenafil and tadalafil are used both during acute and chronic phases of PPHN. In the absence of infection, glucocorticoids may also be effective in PPHN. Many of these pharmacologic agents are not approved for use in PPHN and our knowledge is based on case reports and small trials. Large multicenter randomized controlled trials with long-term follow-up are required to evaluate alternate pharmacologic strategies in PPHN.
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PMID:Pharmacologic strategies in neonatal pulmonary hypertension other than nitric oxide. 2677 36

Patients with congenital diaphragmatic hernia (CDH) suffer from severe pulmonary hypertension attributable to altered development of the pulmonary vasculature, which is often resistant to vasodilator therapy. Present treatment starts postnatally even though significant differences in the pulmonary vasculature are already present early during pregnancy. We examined the effects of prenatal treatment with the phosphodiesterase-5 inhibitor sildenafil on pulmonary vascular development in experimental CDH starting at a clinically relevant time. The well-established, nitrofen-induced CDH rodent model was treated daily with 100 mg/kg sildenafil from day 17.5 until day 20.5 of gestation (E17.5-20.5). Importantly, this timing perfectly corresponds to the developmental stage of the lung at 20 wk of human gestation, when CDH is detectable by 2D-ultrasonography and/or MRI. At E21.5 pups were delivered by caesarean section and euthanized by lethal injection of pentobarbital. The lungs were isolated and subsequently analyzed using immunostaining, real-time PCR, and volume measurements. Prenatal treatment with sildenafil improved lung morphology and attenuated vascular remodeling with reduced muscularization of the smaller vessels. Pulmonary vascular volume was not affected by sildenafil treatment. We show that prenatal treatment with sildenafil within a clinically relevant period improves pulmonary vascular development in an experimental CDH model. This may have important implications for the management of this disease and related pulmonary vascular diseases in human.
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PMID:Clinically relevant timing of antenatal sildenafil treatment reduces pulmonary vascular remodeling in congenital diaphragmatic hernia. 2752 24

Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the diaphragm, allowing abdominal viscera to herniate into the thoracic cavity and subsequently impair pulmonary and vascular development. Despite improving standardized postnatal management, there remains a population of severe CDH for whom postnatal care falls short. In these severe cases, antenatal surgical intervention (fetoscopic endoluminal tracheal occlusion [FETO]) may improve survival; however, FETO increases the risk of preterm delivery, is not widely offered, and still fails in half of cases. Antenatal medical therapies that stimulate antenatal pulmonary development are therefore interesting alternatives. By presenting the animal research underpinning novel antenatal medical therapies for CDH, and considering the applications of these therapies to clinical practice, this review will explore the future of antenatal CDH management with a focus on the phosphodiesterase-5 inhibitor sildenafil.
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PMID:Antenatal Medical Therapies to Improve Lung Development in Congenital Diaphragmatic Hernia. 2934 Oct 44

Patients with congenital diaphragmatic hernia (CDH) often suffer from severe pulmonary hypertension, and the choice of current vasodilator therapy is mostly based on trial and error. Because pulmonary vascular abnormalities are already present early during development, we performed a study to modulate these pulmonary vascular changes at an early stage during gestation. Pregnant Sprague-Dawley rats were treated with nitrofen at day 9.5 of gestation (E9.5) to induce CDH in the offspring, and subsequently, the phosphodiesterase-5 inhibitor sildenafil and/or the novel prostaglandin-I receptor agonist selexipag (active compound NS-304) were administered from E17.5 until E20.5. The clinical relevant start of the treatment corresponds to week 20 of gestation in humans, when CDH is usually detected by ultrasound. CDH pups showed increased density of air saccules that was reverted after the use of only sildenafil. The pulmonary vascular wall was thickened, and right ventricular hypertrophy was present in the CDH group and improved both after single treatment with sildenafil or selexipag, whereas the combination therapy with both compounds did not have additive value. In conclusion, antenatal treatment with sildenafil improved airway morphogenesis and pulmonary vascular development, whereas selexipag only acted positively on pulmonary vascular development. The combination of both compounds did not act synergistically, probably because of a decreased efficiency of both compounds caused by cytochrome- P450 3A4 interaction and induction. These new insights create important possibilities for future treatment of pulmonary vascular abnormalities in CDH patients already in the antenatal period of life.
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PMID:Treatment of rat congenital diaphragmatic hernia with sildenafil and NS-304, selexipag's active compound, at the pseudoglandular stage improves lung vasculature. 2974 54

Pulmonary arterial hypertension (PAH) is a rare disease in infants and children that is associated with significant morbidity and mortality. The disease is characterized by progressive pulmonary vascular functional and structural changes resulting in increased pulmonary vascular resistance and eventual right heart failure and death. In many pediatric patients, PAH is idiopathic or associated with congenital heart disease and rarely is associated with other conditions such as connective tissue or thromboembolic disease. PAH associated with developmental lung diseases such as bronchopulmonary dysplasia or congenital diaphragmatic hernia is increasingly more recognized in infants and children. Although treatment of the underlying disease and reversal of advanced structural changes have not yet been achieved with current therapy, quality of life and survival have improved significantly. Targeted pulmonary vasodilator therapies, including endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase type 5 inhibitors have resulted in hemodynamic and functional improvement in children. The management of pediatric PAH remains challenging as treatment decisions depend largely on results from evidence-based adult studies and the clinical experience of pediatric experts. This article reviews the current drug therapies and their use in the management of PAH in children.
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PMID:Drug Treatment of Pulmonary Hypertension in Children. 3196 Mar 61


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