Jesse D. Roberts

Inhaled nitric oxide in persistent pulmonary hypertension of the newborn

Nitric oxide (NO) has vasodilatory effects on the pulmonary vasculature in adults and animals. We examined the effects on systemic oxygenation and blood pressure of inhaling up to 80 parts per million by volume of NO at FiO2 0.9 for up to 30 minutes by 6 infants with persistent pulmonary hypertension of the newborn (PPHN). In all infants this treatment rapidly and significantly increased preductal oxygen saturation (SpO2); in 5 infants postductal SpO2 and oxygen tensions also increased. Inhalation of NO did not cause systemic hypotension or raise methaemoglobin. These data suggest that low levels of inhaled NO have an important role in the reversal of hypoxaemia due to PPHN.

INHALED NITRIC OXIDE AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Background Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. Methods In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. Results Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. Conclusions Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Inhaled nitric oxide in congenital heart disease.

BackgroundCongenital heart lesions may be complicated by pulmonary arterial smooth muscle hyperplasia, hypertrophy, and hypertension. We assessed whether inhaling low levels of nitric oxide (NO), an endothelium-derived relaxing factor, would produce selective pulmonary vasodilation in pediatric patients with congenital heart disease and pulmonary hypertension. We also compared the pulmonary vasodilator potencies of inhaled NO and oxygen in these patients. Methods and ResultsIn 10 sequentially presenting, spontaneously breathing patients, we determined whether inhaling 20-80 ppm by volume of NO at inspired oxygen concentrations (FIO2) of 0.21-0.3 and 0.9 would reduce the pulmonary vascular resistance index (Rp). We then compared breathing oxygen with inhaling NO. Inhaling 80 ppm NO at F102 0.21-0.3 reduced mean pulmonary artery pressure from 48 ± 19 to 40+14 mm Hg and Rp from 658±421 to 491±417 dyne sec cm-5 m-2 (mean±SD, both p<0.05). Increasing the F102 to 0.9 without adding NO did not reduce mean pulmonary artery pressure but reduced Rp and increased the ratio of pulmonary to systemic blood flow (Qp/Qs), primarily by increasing Qp (p<0.05). Breathing 80 ppm NO at F1O2 0.9 reduced mean pulmonary artery pressure and Rp to the lowest levels and increased Qp and Qp/Qs (all p<0.05). While breathing at F102 0.9, inhalation of 40 ppm NO reduced Rp (p<0.05); the maximum reduction of Rp occurred while breathing 80 ppm NO. Inhaling 80 ppm NO at F102 0.21-0.9 did not alter mean aortic pressure or systemic vascular resistance. Methemoglobin levels were unchanged by breathing up to 80 ppm NO for 30 minutes. ConclusionInhaled NO is a potent and selective pulmonary vasodilator in pediatric patients with congenital heart disease complicated by pulmonary artery hypertension. Inhaling low levels of NO may provide an important and safe means for evaluating the pulmonary vasodilatory capacity of patients with congenital heart disease without producing systemic vasodilation.

Inhaled Nitric Oxide A Selective Pulmonary Vasodilator: Current Uses and Therapeutic Potential

Since the recognition of nitric oxide (NO) as a key endothelial-derived vasodilator molecule in 1987, the field of NO research has expanded to encompass many areas of biomedical research. It is now well established that NO is an important signaling molecule throughout the body. The therapeutic potential of inhaled NO as a selective pulmonary vasodilator was suggested in a lamb model of pulmonary hypertension and in patients with pulmonary hypertension in 1991.1,2 Because NO is scavenged by hemoglobin (Hb) on diffusing into the blood and is thereby rapidly inactivated, the vasodilatory effect of inhaled NO is limited largely to the lung. This is in contrast to intravenously infused vasodilators that can cause systemic vasodilation and severe systemic arterial hypotension. Recent data indicate that inhaled NO can be applied in various diseases. For example, studies suggest that inhaled NO is a safe and effective agent to determine the vasodilatory capacity of the pulmonary vascular bed. This article summarizes the pharmacology and physiology of inhaled NO and reviews the current uses of inhaled NO for the treatment, evaluation, and prevention of cardiovascular and respiratory diseases. ### Chemistry of NO Gas NO is a colorless, odorless gas that is only slightly soluble in water.3 NO and its oxidative byproducts (eg, NO2 and N2O4) are produced by the partial oxidation of atmospheric nitrogen in internal combustion engines, in the burning cinder cones of cigarettes, and in lightning storms. Medical-grade NO gas is produced under carefully controlled conditions, diluted with pure nitrogen, and stored in the absence of oxygen. The recent article by Williams4 provides a review of the chemistry of NO. ### Therapeutic Versus Endogenous NO Concentrations in the Airway Although early studies of inhaled NO in the treatment of pulmonary hypertension used concentrations of 5 to 80 ppm, it has since been realized that concentrations >20 ppm provide little additional …

Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. Effects on pulmonary hemodynamics and oxygenation.

Background:Nitric oxide (NO) inhalation selectively decreases pulmonary artery hypertension and improves arterial oxygenation in patients with the adult respiratory distress syndrome (ARDS). In this study of patients with severe ARDS, we sought to determine the effect of inhaled NO dose and time on pulmonary artery pressure and oxygen exchange and to determine which patients with ARDS are most likely to show this response. Methods:Thirteen patients with severe ARDS (hospital mortality 67%) inhaled 0-40 parts per million (ppm) NO. Seven of these patients continued to breathe 2-20 ppm NO for 2-27 days. Results:Inhaling 5-40 ppm NO decreased mean pulmonary artery pressure in a dose-related fashion (from 34 ± 7 to 30 ± 7 mmHg at 20 ppm NO). Systemic arterial pressure did not change. The ratio of arterial oxygen tension to inspired oxygen fraction increased (from 126 ± 36 to 149 ± 38 mmHg) and the venous admixture decreased (from 31.2 ± 5.5 to 28.2 ± 5.2%) without a clear dose-response effect. During prolonged NO inhalation, 2-20 ppm NO effectively reduced mean pulmonary artery pressure (38 ± 7 vs. 31 ± 6 mmHg) and increased arterial oxygen tension (79 ± 10 vs. 114 ± 27 mmHg) without evidence of tachyphylaxis. The decrease of pulmonary vascular resistance during NO inhalation correlated with the level of pulmonary vascular resistance without NO (r=-0.72). The reduction of venous admixture correlated with the level of venous admixture without NO (r=-0.78). Conclusions:Long-term NO inhalation at low concentrations selectively decreases mean pulmonary artery pressure and improves arterial oxygen tension in patients with ARDS. The selective pulmonary vasodilation effect is most pronounced in ARDS patients with the greatest degree of pulmonary vasoconstriction.

Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn lamb.

We determined whether inhaling low levels of nitric oxide (NO) gas could selectively reverse hypoxic pulmonary vasoconstriction in the near-term newborn lamb and whether vasodilation would be attenuated by respiratory acidosis. To examine the mechanism of air and NO-induced pulmonary vasodilation soon after birth, we measured plasma and lung cGMP levels in the newly ventilated fetal lamb. Breathing at FIO2 0.10 nearly doubled the pulmonary vascular resistance index in newborn lambs and decreased pulmonary blood flow primarily by reducing left-to-right blood flow through the ductus arteriosus. Inhaling 20 ppm NO at FIO2 0.10 completely reversed hypoxic pulmonary vasoconstriction within minutes. Maximum pulmonary vasodilation occurred during inhalation of > or = 80 ppm NO. Breathing 8% CO2 at FIO2 0.10 elevated the pulmonary vascular resistance index to a level similar to breathing at FIO2 0.10 without added CO2. Respiratory acidosis did not attenuate pulmonary vasodilation by inhaled NO. In none of our studies did inhaling NO produce systemic hypotension or elevate methemoglobin levels. Four minutes after initiating ventilation with air in the fetal lamb lung, cGMP concentration nearly doubled without changing preductal plasma cGMP concentration. Ventilation with 80 ppm NO at FIO2 0.21 increased both lung and preductal plasma cGMP concentration threefold. Our data suggest that inhaled NO gas is a rapid and potent selective vasodilator of the newborn pulmonary circulation with an elevated vascular tone due to hypoxia and respiratory acidosis that acts by increasing lung cGMP concentration.

Inhibition of Atherogenesis in BLT1-Deficient Mice Reveals a Role for LTB4 and BLT1 in Smooth Muscle Cell Recruitment

Background—It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB4), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB4 signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown. Methods and Results—To directly assess the role of the LTB4-BLT1 pathway in atherogenesis, we bred BLT1−/− mice into the atherosclerosis-susceptible apoE−/− strain. Compound-deficient apoE−/−/Blt1−/− mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE−/− controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB4 triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1+/+ SMCs and absent in Blt1−/− cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions. Conclusions—These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.

Continuous Nitric Oxide Inhalation Reduces Pulmonary Arterial Structural Changes, Right Ventricular Hypertrophy, and Growth Retardation in the Hypoxic Newborn Rat

Breathing low oxygen levels for several weeks produces progressive pulmonary artery hypertension and smooth muscle hypertrophy and hyperplasia in many species. Because nitric oxide (NO) is an important regulator of pulmonary vascular tone, we examined whether the continuous inhalation of low levels of NO gas would attenuate pulmonary arterial structural changes in hypoxic rat pups. Nine-day-old rat pups and their mothers continuously breathed at FIO2 0.21 or 0.10 with or without adding 20 ppm (by volume) NO for 2 weeks. Lung tissue was obtained for vascular morphometric analysis, and the hearts were dissected to measure right ventricular weight and levels of mRNA encoding rat atrial natriuretic factor (rANF). In addition, femur and skull length were radiographically determined. Breathing at FIO2 0.10 for 14 days increased pulmonary arterial wall thickness and the proportion of muscular arteries in the lung periphery. Right ventricular weight and right ventricular rANF gene expression increased, whereas body weight and skeletal growth were reduced (all P < .05). Continuous inhalation of 20 ppm NO at FIO2 0.10 for 2 weeks decreased hypoxic pulmonary vascular structural changes and somatic growth retardation and prevented the increase of right ventricular weight and right ventricular rANF mRNA levels. These observations suggest that chronically breathing NO attenuates pulmonary vascular smooth muscle hypertrophy and/or hyperplasia and extension into distal arterial walls, right ventricular hypertrophy, and growth retardation of newborns breathing at a low oxygen level.

Chronic Inhalation of Nitric Oxide Inhibits Neointimal Formation After Balloon-Induced Arterial Injury

Systemic and local intravascular NO administration inhibits neointimal formation after vascular injury in animal models. NO appears to attenuate smooth muscle proliferation both directly and indirectly by preventing the release of growth factors. Inhalation of low concentrations of NO dilates pulmonary vascular smooth muscle but does not cause systemic vasodilatation. Recently, NO inhalation was found to inhibit platelet function in vivo. We studied the effects of NO inhalation on neointimal formation after balloon-induced injury of the adult rat carotid artery. Beginning 60 minutes before carotid injury, rats breathed either air with 0 or 80 ppm NO for 14 days. Rats were killed, carotid arteries were fixed and paraffin-embedded, and neointimal formation was measured by analyzing the ratio of intimal to medial areas (I/M ratio) in carotid artery cross sections. Intimal hyperplasia was evident in both groups of animals, but I/M ratios were 43% less in animals breathing 80 ppm NO for 2 weeks than in animals breathing air alone (0.78 +/- 0.12 and 1.37 +/- 0.11 [mean +/- SE], respectively; P < .02). Similarly, 1 week after carotid injury, neointimal formation was less in rats breathing 80 ppm NO than in rats breathing air alone (I/M ratio, 0.39 +/- 0.11 versus 0.76 +/- 0.06; P < .02). Breathing 20 ppm NO for 2 weeks or 80 ppm NO for 1 week followed by air alone for 1 week did not attenuate neointimal formation measured at 14 days. In anesthetized rats breathing 80 ppm NO or air alone for 1 hour, neither systemic blood pressure nor bleeding time differed. These observations demonstrate that inhaling 80 ppm NO inhibits neointimal formation after balloon-induced carotid artery injury in rats. NO inhalation may represent a safe and novel method of preventing restenosis after percutaneous angioplasty.

Effect of nitric oxide on the survival rate and incidence of lung injury in newborn lambs with persistent pulmonary hypertension

We previously showed that inhaling nitric oxide (NO) for up to 30 minutes selectively dilates the pulmonary circulation and improves oxygenation in newborn lambs with persistent pulmonary hypertension. In the current study we determined whether inhaling NO for 23 hours increased the survival rate of newborn lambs with persistent pulmonary hypertension, oxidized hemoglobin to methemoglobin, or damaged the lungs. Persistent pulmonary hypertension was created in newborn lambs by ligating the ductus arteriosus 13 days before delivery. Six lambs were randomly selected to breathe NO at 80 parts per million for 23 hours, and 7 control lambs were untreated. Each lamb was delivered at 135 days of gestation (term is 146 days), and the lungs were ventilated at a fraction of inspired oxygen of 0.92. Each of the control lambs died before the end of the study, whereas only one of the NO-treated lambs died (p < or = 0.05). Arterial oxygen tension was greater in the NO-treated lambs by 15 minutes after delivery (63 +/- 17 vs 14 +/- 4 mm Hg). Oxygen tension increased with time in the NO-treated lambs. Inhaled NO increased the concentration of methemoglobin, but this concentration reached a plateau at 3.0% +/- 0.4%. There was evidence of early airway damage in both groups of lambs but no difference between the groups. We conclude that inhaled NO increased survival rates without increasing the incidence of acute lung injury in newborn lambs with persistent pulmonary hypertension.