I. Definition

a.

NO or endothelium-derived relaxing factor is produced within endothelial cell from L-arginine by nitric oxide synthase (see Figure).

b.

NO is a potent vasodilator of vascular smooth muscle and when delivered by the inhalational route is a selective pulmonary vasodilator.

II. Mechanism of Action

a.

Diffuses rapidly from alveolus to pulmonary vascular smooth muscle

b.

Stimulates guanylate cyclase activity which increases the concentration of cyclic GMP which causes vasodilation

c.

Selectively reverses acute pulmonary vasoconstriction caused by hypoxia or thromboxane

d.

Rapidly inactivated by forming methemoglobin therefore does not cause systemic hypotension

III. Dosing of NO (see guidelines for use)

a.

Continuous inhalational agent given through inspiratory limb of the breathing circuit

b.

Serum half-life is 3-4 seconds

c.

Theoretical effective range: 6-80 ppm

d.

Verify inhaled concentration of NO by using inline chemiluminescence

IV. Side Effects of NO

a.

Methemoglobinemia - (NO + Hgb) - NO avidly binds to Hgb, thus Hgb is not available to carry oxygen (see Table)

1. metabolic acidosis - increased dyspnea and tachypnea on exam

2. gray central cyanosis occurs at levels of 10-15% (NL < 2%)

3. blood appears brown even with a high PaO2

4. treatment: 100% O2, methylene blue, exchange transfusion, hyperbaric oxygen

b.

Nitrogen Dioxide (NO2)

1. levels > 3 ppm: cell injury, increased lung fluid

2. normally < 2% of NO level

3. NO2 and H2O -- H2NO3 (nitric acid)

c.

Inhibits platelet aggregation

References:

1) Kinsella JP, Neish SR, Ivy DD, et al. Clinical responses to prolonged treatment of persistent pulmonary hypertension of the newborn with low doses of inhaled nitric oxide. J Pediatr 1993; 123:103-108.

2) Geggel RL. Inhalational nitric oxide: A selective pulmonary vasodilator for treatment of persistent pulmonary hypertension of the newborn. J Pediatr 1993; 123:76-79.

3) Davidson, D. Inhaled nitric oxide (NO) for neonatal pulmonary hypertension. Am Rev Respir Dis 1993; 147:1078-1079.

4) Kinsella JP, Abman SH. Inhalational nitric oxide therapy for persistent pulmonary hypertension of the newborn. Pediatr 1993; 91:997-998.

5) Kinsella JP, Neish SR, Shaffer E, et al. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:819-820.

6) Roberts JD, Polaner DM, Lang P, et al. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992; 340:818-819.

7) Fineman JR, Wong J, Soifer SJ. Hyperoxia and alkalosis produce pulmonary vasodilation independent of endolithium-derived nitric oxide in newborn lambs. Pediatr Res 1993; 33:341-346.

8) Rossaint R, Falke KJ, López F, et al. Inhaled nitric oxide for the adult respiratory distress syndrome. New Eng J Med 1993; 328:399-431.

9) Bone RC. A new therapy for the adult respiratory distress syndrome. New Eng J Med 1993; 328:431-432.

10) Kinsella JP, Toews WH, Desmond H, et al. Selective and sustained pulmonary vasodilation with inhalational nitric oxide therapy in a child with idiopathic pulmonary hypertension. J Pediatr 1993; 122:803-806.