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A proposal of new therapeutic strategy for antenatally diagnosed congenital diaphragmatic hernia.

PURPOSE: The prognosis of antenatally diagnosed congenital diaphragmatic hernia (ADCDH) is still very poor despite of innovation of various therapeutics. The authors reviewed their new therapeutic strategy of ADCDH from a viewpoint of cardiologic function. METHODS: The cardiac function in 19 cases of ADCDH was reviewed. The patients, at the age of 0 days, were divided into 2 groups, PG (+) and PG (-), according to the requirement of prostaglandin E1 (PGE1) to attenuate pulmonary hypertension. The left ventricular (LV) end-diastolic dimension (LV diastolic diameter index [LVDI]) and bilateral pulmonary arterial diameters (total pulmonary artery index [TPAI]) were measured on days 0 and 2. RESULT: Only 1 patient died of cardiac or respiratory failure, and the survivors' postoperative course was uneventful. Eleven patients needed inhalation of nitric oxide (NO), and in 9 of those, PGE1 was administered. The LVDI and TPAI of day 0 in PG (+) were significantly smaller than those in PG (-) and the controls. The LVDI increased from postnatal day 0 to day 2 in both PG (+) and PG (-). Although the LV was too small to output enough volume, the right ventricle successfully compensated for the low output through the ductus arteriosus, kept patent by NO and PGE1. CONCLUSION: For ADCDH with sever pulmonary hypertension, keeping patent ductus arteriosus with NO and PGE1 plays a critical role in obtaining excellent clinical outcome. Thus, the authors proposed a new therapeutic strategy for ADCDH based on a circulatory management.

Alprostadil↗

The histology of the lung in neonates with tricuspid valve disease and gross cardiomegaly due to severe regurgitation.

Lung autopsies from four neonates with Ebstein's anomaly or tricuspid valve dysplasia and gross cardiomegaly were examined. The mean cardiothoracic ratio was 92 +/- 0.5%. The degrees of pulmonary hypoplasia and pulmonary artery muscularization were assessed and were compared with those in lungs from four controls and four patients with diaphragmatic hernias. Lung and body weight ratios and radial alveolar counts, which reflect pulmonary hypoplasia and immaturity, were significantly decreased only in patients with diaphragmatic hernia. The thickness of the medical muscle layer in small pulmonary arteries was greater in patients with diaphragmatic hernia; however, in patients with tricuspid valve disease, it was relatively small. Abnormal vascular muscle extension was seen only in patients with diaphragmatic hernia. In the cases of tricuspid valve disease, although cardiomegaly and lung compression were severe, lung hypoplasia and immaturity were not, and neither abnormal medial thickening nor extension were found. Our results suggest that, at least in full-term infants with tricuspid valve disease, surgical relief of lung compression may improve respiratory function, even if the cardiomegaly is severe.

Birth Weight↗

A preparation for in vivo study of the diaphragmatic microcirculation in the rat.

A new preparation is described for the study of the microcirculation of the rat diaphragm by in vivo microscopy. After midline laparotomy, the abdominal site of the diaphragm muscle was exposed. The rat was mechanically ventilated and placed in the Trendelenburg position, thus allowing a microscope placed on a three-dimensional articulated system to be set up perpendicular to the diaphragm. The diaphragm was then transilluminated by inserting fiberoptic microprobes into the thorax cavity by thoracotomy in the fifth intercostal space. This preparation allowed us to describe the morphological characteristics of the arteriolar network in vivo. As regards the venular network, two parts were distinguished: one part collects the blood of the external half of the diaphragm, runs roughly parallel to the arterioles, and converges toward the internal mammary and intercostal veins; the other part collects the blood of the central half of the diaphragm and converges on the central venous arcade along its central tendon. Anastomotic channels between these two parts were observed, as well as spontaneous inversion of the direction of the blood flow, indicating the presence of unsteady pressure gradients in some branches of the venular network. Capillary density was also studied by measuring intercapillary distance, whose mean value was 21.43 +/- 0.67 microns. No differences in intercapillary distance were found between the external and central parts of the diaphragm. In conclusion, we describe a preparation which allowed us to study the diaphragmatic microcirculation for at least 2 hr under good hemodynamic conditions. The study of this specific microcirculation is important because the diaphragm's metabolism and functions are specific and because it is essential to life that its perfusion should be adapted to its specific metabolic requirements.

Animals↗

Esophageal manometry in the opossum.

The opossum esophagus is commonly used as an animal model of the human esophagus. We used esophageal manometry in normal animals to provide basal data about normal esophageal motor functions in vivo in this species. At rest, separate and distinct high pressure zones can be recorded at the level of the lower esophageal sphincter, diaphragmatic hiatus, aortic arch, and upper esophageal sphincter. Each zone demonstrates a characteristic pattern of pressures in the radii of the coronal section and a characteristic response to swallowing. The hiatal and aortic zones can be mistaken for the esophageal sphincters. Pressures in the sphincters fall with swallowing. Peristalsis is not bolus-dependent and occurs with 98% of swallows. Pressures generated by peristalsis are greater in the middle of the esophagus than at the ends. Values for resting lower esophageal sphincter pressure and the characteristics of peristalsis were reproducible between different studies in the same animals.

Animals↗

Adaptability of the hamster diaphragm to exercise and/or emphysema.

In vitro contractile properties of the diaphragm were measured in four groups of inbred adult hamsters (greater than 40wk), randomly divided into sedentary control (SC), exercise control (EC), sedentary emphysematous (SE), and exercise emphysematous (EE) groups. Emphysema was induced by a single endotracheal instillation of elastase. Exercise consisted of running 1 h/day, 7 days/wk for 20 wk. Functional residual capacity (FRC), measured by means of a pressure box, was approximately 2.5 times greater in both emphysematous groups compared with control groups. Small diaphragmatic bundles were then isolated and subjected to in vitro analysis of isometric contractile properties. No differences were observed among the four groups in time to peak tension, half-relaxation time, and shape of the force-frequency curve. The diaphragmatic length-tension curve of emphysematous animals was displaced toward the left; maximal tetanic tension was similar in all groups, while optimal length (Lo), defined as the length at which maximal twitch tension occurred, was significantly shorter in both emphysematous groups. The Lo was negatively correlated with the FRC. Exercise tended to increase the in vitro endurance of the diaphragm bundles in control animals only. Diaphragms from both emphysematous groups, however, did show the greatest resistance to fatigue. It is concluded that 1) daily running for 1 h does not influence the diaphragmatic contractile properties in the hamster, but fatigue was reduced; 2) the load of chronic emphysema decreased the hamster's diaphragm fatiguability; and 3) the diaphragms of emphysematous hamsters chronically adapt by decreasing diaphragmatic length in proportion to the degree of hyperinflation and thus probably continue to operate at an Lo.

Adaptation, Physiological↗

Radiofrequency (pacing and thermic effects) in the treatment of sleep-disordered breathing.

Radiofrequency, whether it is used for pacing or for its thermal liberation properties, has been investigated as a treatment for sleep-disordered breathing. Diaphragmatic pacing has a long history. The problems associated with pacing, which are related to patient selection, equipment failure, disturbances at the electrode/nerve interface, neuromuscular function failure, muscle fatigue, and the physiological consequences of stimulation, will have to be resolved with XIIth nerve stimulation. Radiofrequency thermal ablation has been applied on the tongue of an animal model. In man, turbinates, soft palate tissue and the base of tongue have been treated. These feasibility studies have demonstrated that obstructive sleep apnea syndrome and upper airway resistance syndrome can be completely controlled using radiofrequency thermal ablation in some subjects. These results can be obtained without complications related to speech, taste or swallowing. The treatment can be administered as an outpatient procedure, but many applications are needed, and treatment may span 6 months. Too high a level of radiofrequency will cause pain or otherwise avoidable complications. The determination of which patients will benefit most from these procedures will require further multi-center, placebo-controlled studies.

Ambulatory Care↗

Administration of prenatal betamethasone suppresses the adrenal-hypophyseal axis in newborns with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a condition that is characterized by pulmonary hypoplasia and pulmonary hypertension. Prenatal betamethasone often is administered to fetuses with CDH to improve pulmonary function. In this study, the authors investigate the possible role of the adrenal-hypophyseal axis in CDH in an animal model and subsequently in human infants with CDH. METHODS: Twin fetal sheep underwent creation of DH or a sham thoracotomy, and levels of plasma and lung ACTH and plasma cortisol were compared. For the human studies, plasma levels of ACTH, cortisol, and DHEA were measured in cord blood samples collected from 9 CDH (5 that received prenatal betamethasone) and compared with those of 14 normal newborns. In both studies, ACTH and cortisol levels were determined by radioimmunoassay (RIA). Human (DHEA) levels were determined by ELISA. RESULTS: Plasma ACTH and cortisol levels were elevated in fetal DH sheep compared with sham-operated controls; however, levels of ACTH in lung tissues were not different. Human newborns with CDH who have been exposed to prenatal steroids have significantly lower plasma ACTH, cortisol, and DHEA levels than normal newborns and CDH newborns not exposed to prenatal betamethasone. CONCLUSIONS: In an ovine model of CDH, the adrenal-hypophyseal axis appears up-regulated in DH fetuses compared with sham-operated animals. Conversely, the adrenal-hypophyseal axis in human CDH newborns appears normal but is suppressed by the administration of prenatal betamethasone.

Adrenocorticotropic Hormone↗

Peroxynitrite induces contractile dysfunction and lipid peroxidation in the diaphragm.

Peroxynitrite may be generated in and around muscles in several pathophysiological conditions (e.g., sepsis) and may induce muscle dysfunction in these disease states. The effect of peroxynitrite on muscle force generation has not been directly assessed. The purpose of the present study was to assess the effects of peroxynitrite administration on diaphragmatic force-generating capacity in 1) intact diaphragm muscle fiber bundles (to model the effects produced by exposure of muscles to extracellular peroxynitrite) and 2) single skinned diaphragm muscle fibers (to model the effects of intracellular peroxynitrite on contractile protein function) by examining the effects of both peroxynitrite and a peroxynitrite-generating solution, 3-morpholinosydnonimine, on force vs. pCa characteristics. In intact diaphragm preparations, peroxynitrite reduced diaphragm force generation and increased muscle levels of 4-hydroxynonenal (an index of lipid peroxidation). In skinned fibers, both peroxynitrite and 3-morpholinosydnonimine reduced maximum calcium-activated force. These data indicate that peroxynitrite is capable of producing significant diaphragmatic contractile dysfunction. We speculate that peroxynitrite-mediated alterations may be responsible for much of the muscle dysfunction seen in pathophysiological conditions such as sepsis.

Aldehydes↗

Terbutaline and diaphragm function in chronic obstructive pulmonary disease: a double-blind randomized clinical trial.

We conducted a double-blind, randomized crossover trial to evaluate whether oral terbutaline (2.5 mg orally three times daily for a week) increased the force of diaphragmatic contraction in normocapnic patients with chronic obstructive pulmonary disease. Ten patients with moderate to severe airway obstruction completed the trail. Compared with placebo, terbutaline produced a mean increase of 5.8 cmH2O in peak inspiratory mouth pressure and a mean increase of 5.0 cmH2O in transdiaphragmatic pressure during a maximal inspiratory manoeuvre. These small changes with terbutaline failed to achieve statistical significance. Also, terbutaline failed to alter flow rates (FEV1, Vmax50) or patients' dyspnoea ratings using two separate clinical scales (Pneumoconiosis Research Unit Score and the Modified Dyspnoea Index). Because all observed changes in respiratory muscle strength were small and because the trial had power to detect small changes in inspiratory mouth pressures, we suggest that oral terbutaline at the dose administered in this study has little noteworthy effect on respiratory muscle strength in normocapnic patients with chronic obstructive pulmonary disease.

Aged↗

[Manometry, effect of pentagastrin and appearance of reflux in experimentally created hiatal hernia (author's transl)].

The importance of morphological and hormonal factors in the gastro-oesophageal junction can be evaluated, since a hiatal hernia comparable to the axial sliding hernia could be created in animal experiments. A new adequate procedure of manometry enables intraluminal pressures to be measured as a functional analysis. In 10 dogs a hiatal hernia with roentgenological reflux was performed. Pentagastrin administered intravenously could not prevent the gastro-oesophageal reflux. Pentagastrin intensified the muscle tension for only 5 minutes, but could not maintain the closing mechanism because of the altered morphological structure. After having restored the longitudinal tension of the organ by gastropexia, the terminal oesophagus has regained its closing function.

Animals↗

Upregulated tumor necrosis factor-alpha gene expression in the hypoplastic lung in patients with congenital diaphragmatic hernia.

Recent studies using animal models of congenital diaphragmatic hernia (CDH) have reported a reduction in both surfactant (SF) phospholipids and proteins in CDH lungs compared to controls, resulting in biophysical and physiologic impairment of SF function in the hypoplastic CDH lung. Furthermore, SF replacement has been shown to improve physiological function in CDH lungs. Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide whose overproduction has been implicated in the pathogenesis of a number of pathological conditions, such as neonatal and adult respiratory distress syndrome. TNF-alpha has been shown to selectively inhibit the de-novo synthesis of SF phospholipid components in type II pneumocytes. It has been demonstrated that TNF-alpha is synthesized locally in lung and functions in an autocrine/paracrine mode. The aim of this study was to investigate TNF-alpha messenger RNA (mRNA) expression in hypoplastic CDH lung using in-situ hybridization histochemistry, to determine the molecular basis of the SF deficiency in the hypoplastic CDH lung. Lung-tissue samples were obtained at autopsy from 7 full-term newborns (age range: 1-21 days) with CDH and 4 stillborns with CDH. Normal lung tissue from eight infants with sudden infant death syndrome (age range: 5-30 days) acted as controls. In-situ hybridization was performed using TNF-alpha specific and digoxigenin-labeled oligonucleotide probe and visualized by nitroblue tetrazolium staining. In control lung tissue, mRNA expression of TNF-alpha was absent or weak in type II pneumocytes and alveolar macrophages. In contrast, mRNA expression of TNF-alpha was markedly increased in both type II pneumocytes and alveolar macrophages in hypoplastic CDH lung. Our findings of up-regulated TNF-alpha gene expression in CDH lung suggest that the SF deficiency observed in hypoplastic CDH lung may be the result of increased local production of TNF-alpha.

Case-Control Studies↗

The diaphragm in emphysema.

Because of hyperinflation, the diaphragm of emphysematous patients operates at a disadvantageous position which affects its mechanical arrangement, modifies the configuration of its zone of apposition, increases its radius of curvature, and decreases its muscle fiber length below optimal configuration. The diaphragm in emphysema therefore displays a suboptimal configuration limiting its ability to function properly but shows no inherent structural insufficiency, unless its contractility is impaired by significant arterial blood gas anomalies or severe malnutrition. The demand imposed on the diaphragm in emphysema is increased by both hyperinflation and air-flow obstruction. With altered performance of the diaphragm and increased demand, force reserve is diminished and diaphragmatic fatigue may occur; this imbalance is targeted in some treatment modalities of emphysema such as pulmonary rehabilitation programs and lung volume reduction surgery.

Biomechanical Phenomena↗

Functional comparison of unilateral versus bilateral lung volume reduction surgery.

BACKGROUND: Lung volume reduction surgery (LVRS) has shown early promise as a palliative therapy in severe emphysema. A number of patients, however, are not candidates for a bilateral operation, or exhibit a predominantly unilateral disease distribution. METHODS: Over 20 months, we performed LVRS in 92 patients selected on the basis of severe hyperinflation with air trapping, diaphragmatic dysfunction, and disease heterogeneity. Twenty-eight patients underwent unilateral LVRS on the basis of asymmetric disease distribution, prior thoracic operation, or concomitant tumor resection. RESULTS: Unilateral LVRS resulted in comparable improvements in exercise capacity and dyspnea as the bilateral procedure, with a similar perioperative mortality and actuarial survival to 24 months. Improvements in spirometric indices of pulmonary function, however, were less in patients undergoing unilateral than bilateral LVRS. CONCLUSIONS: In properly selected patients, unilateral LVRS provides functional and subjective benefits of comparable magnitude to those associated with a bilateral operation. Unilateral LVRS is therefore an option in the therapy of end-stage emphysema in patients with asymmetric disease distribution, a prior thoracic operation, or contraindications to sternotomy, and may have a role as a bridge to transplantation in selected cases.

Aged↗