Current and future strategies in the treatment of childhood pulmonary hypertension

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Abstract

Strategies for treating pulmonary hypertension in children vary with the severity and acuity of the disorder. Treatment of acute life threatening pulmonary hypertension is focused on principles of perioperative and critical care. These entail exclusion of anatomic and correctable causes of pulmonary hypertension, selective use of intracardiac right to left shunting, sedation, moderate hyperventilation and alkalosis, supplemental oxygen, normalization of lung volumes, judicious use of inotropic support and use of vasodilators. Newer vasodilators target excess or deficient endothelial cell production; prostacyclin and endothelin receptor blockers may be particularly useful after interventions such as cardiopulmonary bypass that render the pulmonary vascular endothelium transiently dysfunctional. Inhaled vasodilators, including aerosolized prostacyclin and inhaled nitric oxide, offer more selectivity and may improve intrapulmonary shunting in patients with pulmonary hypertension and concomitant lung disease. The underpinning for new treatments of chronic (including primary) pulmonary hypertension emphasizes discoveries in genetics and vascular biology which may permit new vessel growth, repair or remodeling, and even normalization of pathologic vessels in the lung. Traditional therapy for primary pulmonary hypertension involves supplemental oxygen, digoxin, diuretics, warfarin for older patients and calcium channel blockers for responders to acute testing. Recent trials have shown reduction in mortality and improvement in symptoms as well as the hemodynamic profile of patients treated with continuous prostacyclin infusions. Indeed, reversal of presumed progressive, fatal disease has been reported with prostacyclin, as well as with chronic inhaled nitric oxide. This is further inspired by exciting animal studies using elastase inhibitors, endothelin receptor blockers, type V phosphodiesterase inhibitors and gene transfer therapy to induce over expression of vasodilator genes, notably endothelial nitric oxide synthase and prostaglandin I synthase. These therapies alone or in combination offer promise for the future and hope of reversibility of even advanced forms of pulmonary hypertension.

Introduction

Treatment strategies for pulmonary hypertension in children will vary with the acuity or chronicity of the hypertensive disorder. The underlying cause of pulmonary hypertension may be idiopathic (primary) or it may arise secondary to a wide variety of childhood disorders, particularly congenital heart disease or interventions associated with repair or palliation of structural heart disease. Treatment of acute life threatening pulmonary hypertension is focused on principles of perioperative and critical care, while the underpinning for new treatments of chronic (including primary) pulmonary hypertension emphasizes discoveries in genetics and vascular biology which may permit new vessel growth, repair or remodeling, even normalization of abnormal vessels in the lung. The following discussion addresses first the critical care strategies aimed at treating pulmonary hypertension, primarily among children with congenital heart disease. Much of the discussion relates to the comparative effects of inhaled nitric oxide among these patients. This is followed by a review of (outpatient) treatment options for patients with chronic pulmonary hypertension, predominantly those with primary pulmonary hypertension. Here the clinical discussion centers on the recent findings and hopeful promise of prostacyclin and innovative applications of new findings in vascular biology.

Section snippets

Diversity in diagnoses

Pulmonary hypertension frequently confronts the critical care practitioner. It is present in the neonatal period as a life threatening pathologic entity associated with persistent pulmonary hypertension of the newborn and other forms of acute hypoxemic respiratory failure. Later, infants with lung hypoplasia and reduced microvascular cross-sectional area in the lungs invariably have difficulty with pulmonary hypertension if they survive the neonatal period; they face further exacerbations of

Secondary pulmonary hypertension

Rare forms of chronic pulmonary hypertension in children are diverse and therapy should be tailored to the underlying disease when known [218]. Avoidance of circumstances that are known to incite or aggravate pulmonary hypertension (high altitude, extreme exercise, pregnancy, birth control pills, etc.) is sound and obvious advice.

Adequate repair (not palliation) of congenital heart disease very early in life is the best solution to preventing the development of progressive pulmonary vascular

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