Nitric Oxide Therapy
Nitric oxide or NO is a gaseous signaling molecule present in all mammals including humans. It is also present in the atmosphere as a toxic pollutant released by automobiles and power plants. The concentrations in the atmosphere range from 10 and 500 parts per billion (Griffiths, p.2683). It is toxic because after inhalation, the gas dissolves in the airway lining fluid and reacts with oxygen species forming powerful oxidants like peroxyntrite (Griffiths, p.2683). Endogenously, it is produced by many cells in the body including the vascular endothelium. It diffuses readily across cell membranes and regulates many physiologic and pathophysiologic processes. Of these, the most important role is regulation of blood flow. Presence of certain concentrations of NO is essential to prevent certain important organs from undergoing ischemic damage. Abnormal production of nitric oxide which can occur in many disease states can lead to defects in blood flow and other vascular functions. On the other hand, sustained levels of NO in the body can lead to tissue toxicity related conditions like multiple sclerosis and ulcerative colitis.
Endogenous Nitric Oxide
In the body, NO is produced from L- arginine by the enzymatic action of nitric oxide synthetase or NOS and the presence of cofactors like oxygen, NADPH, tetrahydrobiopterin and flavin adenine nucleotides. It has a half life of only a few seconds (Klabunde, Cardiovascular Concepts). There actuallly 2 types of NOS: endothelial NOS and neutral NOS. While endothelial NOS helps in the production of NO, neutral NOS functions as a neurotransmitter in the brain and certain peripheral nerves. Endothelial NOS is present in 2 forms: constitutive NOS and inducible NOS. Under normal circumstances, NO production is catalyzed by constitutive NOS. Inducible NOS comes into action in certain conditions like inflammation. As soon as NO is formed in the vascular endothelium, it diffuses into the blood and into the adjacent smooth muscle. In the blood it immediately binds to the hemoglobin and then breaks down. In the vascular smooth muscle cells, it binds to guanylyl cyclase and then activates it. Activation of this important enzyme causes dephosphorylation of GTP to cGMP (Klabunde, Cardiovascular Concepts). cGMP is a second messenger for many cellular functions. It inhibits calcium entry into the cells thus decreasing intracellular calcium concentrations and enhancing smooth muscle relaxation; it activates K+ channels leading to hyperpolarization and relaxation and finally, it stimulates a cGMP-dependent protein kinase causing activation of myosin light chain phosphatase. This enzyme dephosphorylates myosin light chains and causes smooth muscle relaxation (Klabunde, Cardiovascular Concepts). Thus NO has direct effects on the vascular smooth muscle causing vasodialatation. It also inhibits angiotensin- II and sympathetic vascular constriction, thus causing indirect vasodilatation. Other than vasodilatation, NO has anti-thrombotic, anti-inflammatory and anti-proliferative effects. Hence deficiency in the production of NO can lead to vasoconstrictive conditions like coronary spasm and hypertension, thrombosis, inflammation and vascular hypertrophy and stenosis (Klabunde, Cardiovascular Concepts).
Nitric Oxide Therapy
NO is a significant vasodilator. Many endothelium dependent vasodilators such as acetylcholine and bradykinin act by increasing calcium levels which induce NO synthesis. NO also has antithrombotic and anti-atherogenesis effects. It reduces endothelial adhesion of monocytes and leukocytes which is the first step in the formation of atheromatous plaques. NO is also an anti-oxidant. It blocks the oxidation of low density lipoprotein, thus preventing the formation of foam cells on the wall. Various studies have proved the benefits of inhaled NO in respiratory failure in both adults and children. Inhaled nitric oxide does not have much effect on the pulmonary vasculature of healthy humans (Griffiths, p.2683). However, it dose have selective pulmonary vasodilator properties in patients with pulmonary hypertension (Pepke-Zaba et al, 1991 as quoted in Griffiths, p.2683). Nitric oxide used for therapeutic purpose is colorless and odorless at room temperature. It is relatively insoluble in water. Though it is poorly reactive with most of the biologic molecules, the free electron in it causes the molecule to react rapidly with other free radicals, certain amino acids and metal ions (Griffiths, p.2683). When inhaled, NO decreases pulmonary vascular resistance, pulmonary arterial pressure, and right ventricular afterload by relaxing pulmonary vessels.
Advantage with NO is that it is inactivated by hemoglobin immediately and when inhaled only the vasculature associated with ventilated lung units within reach of an inhaled gas diffusing across the alveolar-capillary membrane is affected. Due to selective dilatation, the ventilation- perfusion match improves. The therapeutic effect of NO depends on the extent to which pulmonary vasoconstriction and ventilation–perfusion mismatching are contributing to respiratory failure.
Respiratory failure occurs as a result of ventilation- perfusion mismatch, intrapulmonary shunt or hypoventilation. When delivered by inhalation, the gas increases pulmonary blood flow to well-ventilated parts of the lung and thus causes improvement in the ventilation- perfusion matching. Hemoglobin inactivates NO quickly, and hence this therapy is relatively safe. However methemoglobin and nitrogen di oxide levels must be monitored during the therapy (Priestley, Emedicine).
In those with acute lung injury NO is useful for improving oxygenation. Many of these patients may have increased pulmonary vascular resistance and such patients may further benefit with NO. Following lung transplantation, ischemia and reperfusion and oxidative stress is an important cause of morbidity and mortality. Also, there is decrese in the production of endogenous NO production after transplantation. In these patients inhaled NO can be used to provide support. In patients with sickle cell disease, there is widespread chronic inflammation and recurrent ischemia–reperfusion injury in organs such as the lungs. Studies have shown that use of high-dose inhaled nitric oxide (80 ppm for 1.5 hours) in these patients reduces the scavenging potential of hemoglobin within the circulation.
Nitric oxide for therapeutic purposes is delivered mainly in patients on mechanical ventilation. Hence in those patients it is delivered through the ventilator. It can also be given by face mask or nasal cannulae. Since NO has its own toxic effects too, it must be delivered in safe doses. Studies have shown that a dose of less than 40ppm for up to 6 months has minimal pulmonary side effects and causes no methemoglobinemia (Griffiths, p.2683). Monitoring of the concentrations of NO can be done by electrochemical analyser. Methemoglobin concentrations must be checked within 6 hours after initiation of nitric oxide therapy and also after each increase in dose (Griffiths, p.2683).
In newborns, it is useful in those with pulmonary hypertension (persistent pulmonary hypertension) and acute respiratory distress syndrome. Currently, the treatment for severely defective gaseous exchange in the newborns is extracorporeal membrane oxygenation which actually does not cause a fall in the pulmonary vascular pressures as in case of inhaled NO therapy.
Rapid withdrawal of inhaled nitric oxide can lead to rebound pulmonary hypertension and hypoxemia (Jaffrey, 309).
Higher doses are usually required to treat pulmonary hypertension than just to improve oxygenation. The response to the drug varies over a clinical course and in a patient with severe respiratory failure, even a 10% improvement may be life- saving. In case of pulmonary hypertension, a 30% decrease in the pulmonary vascular resistance with a dose of 10 ppm for 10 minutes is an indication to start calcium channel blockers or such agents to benefit the patient in the long term (Griffiths, p.2683).
Nitric oxide is a potential vasodilator. It is produced endogenously in the vascular endothelium and other cells in our body. It functions to maintain normal vascular function and prevent ischemia. However it is decreased in certain conditions and may need to be supplemented. When inhaled, it causes pulmonary vascular dilatation and thus decreases pulmonary vascular resistance. It also increases oxygenation by causing proper matching of ventilation and perfusion. Thus it plays an important role in the management of acute respiratory distress syndrome, acute lung injury and elevated pulmonary hypertension.
Griffiths MJD, Evans TW. “Inhaled nitric oxide therapy in adults.” N Engl J Med 2005: 2683-95.
Jaffrey, Samie. “Nitric Oxide.” Basic and Clinical Pharmacology. 10th edition, New York: Mc Graw Hill Lange, 2007: 309- 312.
Klabunde, Richard. “Nitric Oxide.” Cardiavascular Physiology Concepts. 2008. 4th August, 2008 <http://www.cvphysiology.com/Blood%20Flow/BF011.htm>
Priestley, Margaret. “Respiratory Failure.” Emedicine from WebMD. 2008. 4th August, 2008 <http://www.emedicine.com/PED/topic1994.htm>