Treating pulmonary hypertension in pediatrics.

INTRODUCTION: Pulmonary hypertension is a hemodynamic condition occurring rarely in pediatrics. Nevertheless, it is associated with significant morbidity and mortality. When characterized by progressive pulmonary vascular structural changes, the disease is called pulmonary arterial hypertension (PAH). It results in increased pulmonary vascular resistance and eventual right ventricular failure. In the vast majority of cases, pediatric PAH is idiopathic or associated with congenital heart disease, and, contrary to adult PAH, is rarely associated with connective tissue, portal hypertension, HIV infection or thromboembolic disease. AREAS COVERED: This article reviews the current drug therapies available for the management of pediatric PAH. These treatments target the recognized pathophysiological pathways of PAH with endothelin-1 receptor antagonists, prostacyclin analogs and PDE type 5 inhibitors. New treatments and explored pathways are briefly discussed. EXPERT OPINION: Although there is still no cure for PAH, quality of life and survival have been improved significantly with specific drug therapies. Nevertheless, management of pediatric PAH remains challenging, and depends mainly on results from adult clinical trials and pediatric experts. Further research on PAH-specific treatments in the pediatric population and data from international registries are needed to identify optimal therapeutic strategies and treatment goals in the pediatric population.

Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension.

BACKGROUND: The impact of osmotic therapies on brain oxygen has not been extensively studied in humans. We examined the effects on brain tissue oxygen tension (PbtO(2)) of mannitol and hypertonic saline (HTS) in patients with severe traumatic brain injury (TBI) and refractory intracranial hypertension. METHODS: 12 consecutive patients with severe TBI who underwent intracranial pressure (ICP) and PbtO(2) monitoring were studied. Patients were treated with mannitol (25%, 0.75 g/kg) for episodes of elevated ICP (>20 mm Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with mannitol. PbtO(2), ICP, mean arterial pressure, cerebral perfusion pressure (CPP), central venous pressure and cardiac output were monitored continuously. RESULTS: 42 episodes of intracranial hypertension, treated with mannitol (n = 28 boluses) or HTS (n = 14 boluses), were analysed. HTS treatment was associated with an increase in PbtO(2) (from baseline 28.3 (13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min; all p<0.01) while mannitol did not affect PbtO(2) (baseline 30.4 (11.4) vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all p>0.1). Compared with mannitol, HTS was associated with lower ICP and higher CPP and cardiac output. CONCLUSIONS: In patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administered as second tier therapy is associated with a significant increase in brain oxygenation, and improved cerebral and systemic haemodynamics.

Trends in self-reported prevalence and management of hypertension, dyslipidaemia and diabetes in adults in Switzerland, 1992-2007

Purpose: to assess the trends of self-reported prevalence of cardiovascular risk factors (CV RFs: hypertension, dyslipidaemia, diabetes) and their management for period 1992 to 2007 in the Swiss population. Methods: four National health interview surveys conducted between 1992 and 2007 in representative samples of the Swiss population (63,782 subjects overall). Self-reported CV RFs prevalence, treatment and controllevels were computed after weighting. Weights were calculated by raking ratio such that the marginal distribution of the weighted totals conforms to the marginal distribution of the targeted population. Multivariate analysis adjusted on age, sex, education, nationality and SMI was conducted using logistic regression. Results: prevalence of ail CV RFs increased between 1992 and 2007, see table. Although the self-reported prevalence of treatment among subjects with CV RFs increased, and this was confirmed by multivariate analysis: OR for hypocholesterolaemic treatment relative to 1992: 0.64 [0.52-0.78]; 1.39 [1.18-1.65] and 2.00 [1.69-2.36] for 1997, 2002 and 2007, respectively. Still, in 2007, circa 40% of hypertensive, 60% of dyslipidaemic and 50% of diabetic subjects weren't treated. Conversely, an adequate control of CV RFs was reported by treated subjects, with an increase during the study period. This increase was confirmed by multivariate analysis (not shown). Conclusion: the self-reported prevalence of hypertension, dyslipidaemia and diabetes increased between 1992 and 2007 in the Swiss population. Despite a good control of treated subjects, still a significant percentage of subjects with CV RFs are not treated.

Hypertension artérielle réfractaire au traitement due au syndrome d'apnées du sommeil et à la prise de médicaments [Obstructive sleep apnea and drugs as causes of treatment-resistant hypertension].

Treatment-resistant hypertension is still common despite the availability of several types of antihypertensive agents acting by different mechanisms. The existence of refractory hypertension should lead to rule out "white-coat hypertension", poor adherence to prescribed drugs as well as classical causes of secondary hypertension such as renal artery stenosis, primary aldosteronism, pheochromocytoma and renal disease. It is also important to consider the possible existence of obstructive sleep apnea or the regular intake of vasopressive drugs or substances.

Alpha1-adrenoceptor-dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension.

Excessive proliferation of vascular wall cells underlies the development of elevated vascular resistance in hypoxic pulmonary hypertension (PH), but the responsible mechanisms remain unclear. Growth-promoting effects of catecholamines may contribute. Hypoxemia causes sympathoexcitation, and prolonged stimulation of alpha(1)-adrenoceptors (alpha(1)-ARs) induces hypertrophy and hyperplasia of arterial smooth muscle cells and adventitial fibroblasts. Catecholamine trophic actions in arteries are enhanced when other conditions favoring growth or remodeling are present, e.g., injury or altered shear stress, in isolated pulmonary arteries from rats with hypoxic PH. The present study examined the hypothesis that catecholamines contribute to pulmonary vascular remodeling in vivo in hypoxic PH. Mice genetically deficient in norepinephrine and epinephrine production [dopamine beta-hydroxylase(-/-) (DBH(-/-))] or alpha(1)-ARs were examined for alterations in PH, cardiac hypertrophy, and vascular remodeling after 21 days exposure to normobaric 0.1 inspired oxygen fraction (Fi(O(2))). A decrease in the lumen area and an increase in the wall thickness of arteries were strongly inhibited in knockout mice (order of extent of inhibition: DBH(-/-) = alpha(1D)-AR(-/-) > alpha(1B)-AR(-/-)). Distal muscularization of small arterioles was also reduced (DBH(-/-) > alpha(1D)-AR(-/-) > alpha(1B)-AR(-/-) mice). Despite these reductions, increases in right ventricular pressure and hypertrophy were not attenuated in DBH(-/-) and alpha(1B)-AR(-/-) mice. However, hematocrit increased more in these mice, possibly as a consequence of impaired cardiovascular activation that occurs during reduction of Fi(O(2)). In contrast, in alpha(1D)-AR(-/-) mice, where hematocrit increased the same as in wild-type mice, right ventricular pressure was reduced. These data suggest that catecholamine stimulation of alpha(1B)- and alpha(1D)-ARs contributes significantly to vascular remodeling in hypoxic PH.

Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients.

INTRODUCTION: Mutations in the TMEM70 are the most common cause of nuclear ATP synthase deficiency resulting in a distinctive phenotype characterized by severe neonatal hypotonia, hypertrophic cardiomyopathy (HCMP), facial dysmorphism, severe lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria (3-MGA). METHODS AND RESULTS: We collected 9 patients with genetically confirmed TMEM70 defect from 8 different families. Six were homozygous for the c.317-2A>G mutation, 2 were compound heterozygous for mutations c.317-2A>G and c.628A>C and 1 was homozygous for the novel c.701A>C mutation. Generalized hypotonia, lactic acidosis, hyperammonemia and 3-MGA were present in all since birth. Five patients presented acute respiratory distress at birth requiring intubation and ventilatory support. HCMP was detected in 5 newborns and appeared a few months later in 3 additional children. Five patients showed a severe and persistent neonatal pulmonary hypertension (PPHN) requiring Nitric Oxide (NO) and/or sildenafil administration combined in 2 cases with high-frequency oscillatory (HFO) ventilation. In 3 of these patients, echocardiography detected signs of HCMP at birth. CONCLUSIONS: PPHN is a life-threatening poorly understood condition with bad prognosis if untreated. Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient. This report further expands the clinical and genetic spectrum of the syndrome indicating PPHN as a frequent and life-threatening complication regardless of the type of mutation. Moreover, in these children PPHN appears even in the absence of an overt cardiomyopathy, thus representing an early sign and a clue for diagnosis.

NEDD4-2 and salt-sensitive hypertension.

PURPOSE OF REVIEW: NEDD4-2 is an ubiquitin-protein ligase that was originally identified as an interactor of the epithelial Na+ channel (ENaC); this interaction is defective in Liddle's syndrome, causing elevated ENaC activity and salt-sensitive hypertension. In this review we aim to highlight progress achieved in recent years demonstrating that NEDD4-2 is involved in the control of Na+ transporters that are different from ENaC, but which also play a role in salt-sensitive hypertension. RECENT FINDINGS: It has been shown that NEDD4-2 interacts with ubiquitylates and negatively regulates the thiazide-sensitive NCC (Na+,Cl- -cotransporter), both in vitro and in vivo in inducible, nephron-specific Nedd4-2 knockout mice. Moreover, evidence has been provided that NEDD4-2 is also involved in the regulation of human NHE3 (Na+,H+-exchanger 3) and NKCC2 (Na+,K+,2Cl- -cotransporter 2). SUMMARY: The emerging role of NEDD4-2 in the regulation of different Na+ transporters along the nephron and the identification of human polymorphisms in the NEDD4-2 gene (Nedd4L) related to salt-sensitive hypertension makes this ubiquitin-protein ligase an interesting target for the development of antihypertensive drugs.

La prise en charge de l'hypertension artérielle par des médecins en formation suit-elle les recommandations actuelles?

Résumé De nombreuses recommandations nationales et internationales sont publiées régulièrement qui définissent la manière dont les patients hypertendus devraient être pris en charge. Ces recommandations sont-elles suivies et applicables ? Dans cette étude transverse effectuée à la PMU à Lausanne, nous avons évalué la qualité de la prise en charge de 225 patients hypertendus suivis par des assistants en formation de médecine de premier recours. Ces 225 patients ont été retenus après une sélection de 1044 dossiers de la consultation générale de la PMU. Les résultats montrent que la moyenne des 3 dernières pressions artérielles était contrôlée dans 32,4% des cas à moins de 140/90 mmHg (TA systolique contrôlée à 42% et TA diastolique à 58%). 60% des patients ont eu une mesure de pression à chacune des 3 dernières consultations. 79% des mesures se terminaient par 0 ou par 5(théoriquement 20%). Le contrôle de la pression artérielle n'était pas statistiquement différent quelles que soient les comorbidités connues (diabète, insuffisance rénale ou insuffisance cardiaque). En conclusion, la qualité de la mesure et de la prise en charge de la TA par les médecins de premier recours en formation est comparable à celle retrouvée en pratique ambulatoire et pourrait être améliorée. Les recommandations basées sur la stratification des FRCV se heurtent à des problèmes dans leur application pratique. Le contrôle de la TA n'est pas meilleur chez les patients à haut risque cardio-vasculaire.

Hypertension pulmonaire d'origine indéterminée chez un homme de 56 ans.. [Pulmonary hypertension of undertermined origine in a man aged 56...]

The case of a patient with severe pulmonary hypertension whose etiology has remained unknown until an autopsy was performed is discussed in a symposium of pathological anatomy. This case helped to address the diagnostic and therapeutic management of pulmonary hypertension. The broad differential diagnosis of this disease requires a diagnostic strategy to be developped. Clinical reasoning leading to a probable diagnosis based on clinical biological and radiological information is not only a difficult task for the speaker but also a rich source of learning opportunities for our medical community.

Ocular biocompatibility of a poly(ortho ester) characterized by autocatalyzed degradation.

The biocompatibility of autocatalyzed poly(ortho ester) (POE(70)LA(30)), a viscous, hydrophobic, bioerodible polymer, was investigated. POE(70)LA(30) was synthesized, sterilized by gamma irradiation, and injected in rabbit eyes at adequate volumes through subconjunctival, intracameral, intravitreal, and suprachoroidal routes. Clinical examinations were performed postoperatively at regular time points for 6 mo, and histopathologic analysis was carried out to confirm tissular biocompatibility. After subconjunctival injection, the polymer was well tolerated and persisted in the subconjunctival space for about 5 weeks. In the case of intracameral injections, polymer biocompatibility was good; the POE(70)LA(30) bubble was still present in the anterior chamber for up to 6 mo after injection. No major histopathologic anomalies were detected, with the exception of a localized Descemet membrane thickening. After intravitreal administration, POE(70)LA(30) biocompatibility was excellent, and no inflammatory reaction could be detected during the observation period. The polymer was degraded in approximately 3 mo. Suprachoroidal injections of POE(70)LA(30) were reproducible and well tolerated. POE(70)LA(30) triggered a slight elevation of the retina and choroid upon clinical observation. The polymer was detectable in the suprachoroidal space for about 6 mo. No inflammatory reaction and no major retinal anomalies could be detected by histology. In conclusion, POE(70)LA(30) appears to be a promising biomaterial for intraocular application, potentially providing sustained drug delivery over an extended period of time, with a good tolerance.

The management of the type 2 diabetic patient with hypertension - too late and too little: suggested improvements

Patients with comorbid hypertension and type 2 diabetes are common, have a greatly increased risk of premature cardiovascular and renal morbidity and mortality, and are likely to increase substantially in number over the next 10-15 years. We suggest the need for more aggressive management strategies for these patients, regardless of their baseline blood pressure, including the early use of combination therapy with blockers of the renin-angiotensin system.

Hypertension artérielle: macrocirculation et microcirculation [Arterial hypertension: macrocirculation and microcirculation]

The aim of the present report is to outline, in concise from, the changes in vascular structure which accompany hypertension. Consideration will be given to their potential contribution to hypertensive end organ damage. In so doing, it is important to consider both the macrovascular and microvascular levels, because interactions between them are presently believed to be critically important. The links between hypertension and the pathogenesis of arteriosclerosis fall outside the scope of this short review.

Hypertension artérielle réfractaire au traitement due au syndrome d'apnées du sommeil et à la prise de médicaments [Obstructive sleep apnea and drugs as causes of treatment-resistant hypertension].

Treatment-resistant hypertension is still common despite the availability of several types of antihypertensive agents acting by different mechanisms. The existence of refractory hypertension should lead to rule out "white-coat hypertension", poor adherence to prescribed drugs as well as classical causes of secondary hypertension such as renal artery stenosis, primary aldosteronism, pheochromocytoma and renal disease. It is also important to consider the possible existence of obstructive sleep apnea or the regular intake of vasopressive drugs or substances.