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Pulmonary vasodilation: a therapeutic objective for respiratory therapists.

Pulmonary vasoconstriction, specifically the reversal or modulation of the pulmonary vasculature related to pulmonary hypertension and persistent fetal circulation among other causes, is getting a lot of attention in the learning circles of neonatal -pediatric respiratory therapists. I thought I would provide a brief overview of new research and applied science in this critical therapeutic objective. Traditionally, respiratory therapists have been on the front lines, employing technical and pharmacologic measures to open the pulmonary vessels to increased blood flow from the right heart. It is important to note that children who are 'responders' to any of these therapy options may manifest only with pulmonary vasoconstriction, and those labeled as 'nonresponders' to pulmonary vasodilating agents should be closely evaluated for cardiac abnormalities or congenital heart diseases. Purohit and coworkers listed traditional methods to treat pulmonary hypertension to include hyperoxemia, as oxygen dilates pulmonary vessels and decreases pulmonary vascular resistance, hyperventilation as a standard, effective therapy for persistent fetal circulation with high pulmonary vascular resistance, and the use of tolazoline (Priscoline, an alpha adrenergic blocker) given IV with fluid and volume expanders. When tolazoline was cautiously administered to responders, it relieved pulmonary vasoconstriction without hypotension. Nuntnarumit's research team did a retrospective chart review on case series of infants weighing <750 g at birth who received tolazoline during a severe hypoxemic episode while receiving maximal ventilator support for respiratory distress syndrome. A slow bolus infusion of low dose tolazoline (0.5 mg-2 mg/kg) mixed with plasmanate or normal saline (10 mL/kg) was administered. Outcome measures evaluated included an increase in PaO2 <20 mm Hg from pre-treatment value and an increase in oxygen saturation to <90%. They found that forty-three infants with a mean gestational age and birth weight of 24 weeks and 581 g, respectively, received tolazoline. All infants were mechanically ventilated and required a fraction of inspired oxygen of 1.0. Oxygenation improved in 72% (31/43) of infants. The authors concluded that in all responders, oxygen saturation increased to < 90% within 30 minutes of tolazoline administration, and improvement in pH, pCO2, oxygenation index, and mean airway pressure were also noted.

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Newer pharmacologic treatments have been used to treat neonatal or pediatric pulmonary hypertension that meets the World Health Organization (WHO) classifications: 1.1 Idiopathic PAH (IPAH). This refers to PAH which occurs at random, without an apparent cause. IPAH can also be referred to as "primary pulmonary hypertension" or PPH, and some older information will still use this term. 1.2 Heritable PAH The heritable category, formerly called familial, includes two types of PAH. 1.3 Drug-and toxin-induced PAH, caused by certain drugs and toxins including aminorex, fenfluramine, dexfenfluramine, and toxic rapeseed oil have been associated with the development of PAH. 1.4 PAH associated with other diseases and conditions. This category includes PAH associated with connective tissue and collagen vascular disease. This section includes diseases such as scleroderma, lupus crest syndrome, HIV infection, portal hypertension, and congenital heart diseases (CHD).

The most common treatment in neonates and pediatric patients of late has been nitric oxide, or NO. It is important to note that physiologic NO is a gaseous signaling molecule, playing a role in biological processes. Ignarro and coworkers showed that physiologic NO is elevated in populations living at high altitudes, allowing them to avoid hypoxia by vasodilating the pulmonary vasculature. Ashutosh found exhaled physiologic NO elevated in uncontrolled moderate and severe persistent asthma. The inner lining of blood vessels use nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing pulmonary blood flow. Gardenhire slated that therapeutic nitric oxide was a potent pulmonary vasodilator, with the closely monitored prescribed doses of 10-80 ppm of NO. Risks of inhaled NO included methemoglobinemia, NO2 production / toxicity.

In another area undergoing scrutiny, endothelin receptor antagonists (ETA) have been used to treat pulmonary hypertension. In a well done article by Ergul, the author noted that endothelin-1 is a potent modulator of vasoconstriction, trigger of smooth-muscle cell division, cell proliferation, and vascular hypertrophy, which plays an important pathogenic role in the development and progression of pulmonary hypertension. Plasma and pulmonary tissue endothelin-1 are elevated in patients with pulmonary hypertension and correlate with disease severity. Activation of ETB receptors on endothelial cells leads to release of nitric oxide (NO), which causes smooth muscle vasodilatation. Plasma and pulmonary tissue endothelin-1 are elevated in patients with pulmonary hypertension and correlate with disease severity. Two distinct types of endothelin receptor have been identified in the pulmonary vasculature: Endothelin type A receptors, found in pulmonary vascular smooth muscle cells, and endothelin type B receptors, located primarily in pulmonary vascular endothelial cells, and to a lesser extent in pulmonary vascular smooth-muscle cells.

Bosentan (Tracleer, PO tablets) dual endothelin (Type A & B) receptor antagonist can be taken by children PO as a tablet. 62.5 to 125 mg, 2 times/day, although some of the literature suggests that the child should be < 12 years of age. Selective endothelin antagonist receptor blocker include ambrisentan an oral, selective ETA receptor blocker, given orally at a dose of 5 - 10 mg / day. Sitaxsentan (now in clinical trials in US, but approved for use in Canada and EU as Thelin) and Ambrisentan are both selective endothelin antagonists. Calcium channel blockers have been used in pediatric pulmonary hypertension and work by literally restricting calcium molecules access to smooth muscle receptor sites, as more calcium generally results in more constriction. Calcium channel blockers for pulmonary hypertension could include nifedipine, amlodipine, and diltiazem. Barst found that oral calcium channel blockers generally sufficed as therapy for children who responded to short term vasodilation therapy. Siobal's excellent review of pulmonary vasodilators found that long-term use of calcium channel blockers (diltiazem and nifedipine) reduced pulmonary arterial pressure and improved survival over a 5-year period, but cautioned that oral calcium channel blockers use was limited by their dose-related systemic vasodilator effects, a potential for hypotension, worsening right-ventricular function, increased intrapulmonary shunt, and hypoxemia. Siobal further stated that while experiments with inhaled calcium channel blockers were ongoing for other indications, their use as inhaled pulmonary vasodilators has not been evaluated.

An emerging option for the treatment of pediatric pulmonary hypertension is phosphodiesterase 5 inhibitors (PDE), especially sildenafil in the form of Revatio, oral 20mg three times per day. This highly soluble powder allowed Nahata and workers to compound sildenafil elixir for pediatric patients. Several toxicologic studies and cases have reported minimal side effects when sildenafil was accidentally ingested by a child in adult dosages.

Prostacyclin analogues have been available since 1987, and enable the vessels in the lung to dilate, thus filling the pulmonary vascular reservoir needed for cardiac output. Prostaglandins and prostacyclins work by cAMP-mediated 2nd messenger smooth muscle relaxation. Drug administration and dosages may include Flolan or epoprostenol, via continuous IV infusion via central venous catheter using an ambulatory infusion pump 1 to 20 ng/kg/min, treprostinil (Remodulin), continuous subcutaneous infusion 0.625 to 1.25 ng/kg/min, and iloprost (Ventavis) via inhalation, nebulizer (using one of two approved drug delivery devices) 2.5 to 5 meg, 6-9 times/day. Rashid and Ivy suggest an outstanding algorithm for decision making in pediatric pulmonary hypertension, and several authors recommended that after care of these patients may include a thorough workup, monitoring, and possible anticoagulation, correction of hypovolemia, use of diuretics, digoxin, intravenous inotropes, low dose dobutamine / dopamine in severe right heart failure with hypoperfusion. The therapeutic objective of pulmonary vasodilation is exciting in that it allows respiratory therapists to evaluate the correction of both the V (alveolar ventilation) and the Q (the flow of blood from the heart through the pulmonary circulation) in the V/Q equation and expand and improve the care we provide for our neonatal and pediatric patients.

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Douglas Masini is the Department Head/Chair of the Respiratory Therapy Program at Armstrong Atlantic State University in Savannah, CA. He can be reached at douglas.masini@armstrong.edu.

by Douglas Masini, EdD, RPFT, RRT-NPS, AE-C, FAARC
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Title Annotation:PEDIATRIC/NEONATAL RESPIRATORY CARE
Author:Masini, Douglas
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Date:Jul 1, 2010
Words:1351
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