Nitric oxide

Nitric oxide

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  NITRIC OXIDE THERAPY -DR.RAVIKIRAN H M The potent pulmonary vasodilator nitric oxide (NO), and helium-O2 mixtures. Physiology: Endogenous NO is produced from oxygen and l-arginine by a group of enzymes called nitric oxide synthases with l-citrulline as a by-product. NO is a key endothelial-derived vasodilator molecule. Figure 1: Vicious cycle of right ventricular (RV) failure triggered by pulmonary hypertension. This vicious cycle may continue unless the pulmonary artery pressure (PAP) is reduced, permitting an increased RV ejection fraction.
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  Unfortunately, treatment ofpulmonary hypertension with intravenous vasodilators may worsen the systemic hypotension. Inhalation of nitric oxide (NO) produces selective pulmonary vasodilation without reducing the systemic arterial pressure in patients with acute or chronic pulmonary hypertension. Additionally, a number of other inhaled pulmonary vasodilators are now described in the literature, which might provide potential alternatives to inhaled NO. Mode of Action It is a colorless, odorless, highly diffusible, and lipid soluble free radical that oxidizes quickly to nitrogen dioxide (NO2) in the presence of O2. NO is normally produced in small amounts within the human body and activates guanylate cyclase, which catalyzes the production of cyclic guanosine 3′,5′-monophosphate (cGMP). The end result is that increased cGMP levels cause vascular smooth muscle relaxation. NO may directly modulate other signaling systems. For example, inhaled NO may be directly involved in posttranslational protein modification, including nitrosylation of proteins. Because NO rapidly binds to hemoglobin (Hb) with a high affinity, the vasodilatory effect of inhaled NO is limited to the lung. The therapeutic benefit of inhaled NO stems from improved blood flow to ventilated alveoli. The result is a reduction in intrapulmonary shunting, improvement in arterial oxygenation, and a decrease in pulmonary vascular resistance and pulmonary arterial pressure. In contrast to intravenously administered vasodilators, inhaled NO selectively improves the perfusion of ventilated regions, thereby reducing intrapulmonary shunting and improving arterial oxygenation.
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  Figure 2: Schematicof the NO signaling pathway in the lung. NO, formed by endothelial cells or administered by inhalation, diffuses to vascular smooth muscle cells. Numerous targets of NO contribute to the wide variety of effects of this molecule on the cardiovascular system. One of the primary targets for NO is soluble guanylate cyclase (sGC). NO binds to the heme moiety of sGC and stimulates the synthesis of the intracellular second messenger cyclic guanosine monophosphate (cGMP). cGMP interacts with a variety of targets, including ion channels, cGMP-regulated phosphodiesterases (PDEs), and cGMP-dependent protein kinases G (PKG). PKGs have been shown to phosphorylate various proteins in vascular smooth muscle cells. PDEs metabolize cGMP to GMP. On arrival in the bloodstream, the majority of NO rapidly binds to hemoglobin with high affinity, whereas small amounts of NO may remain to react with other molecules, including proteins. GMP, Guanosine monophosphate; GTP, guanosine-5’-
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  triphosphate; Hb, hemoglobin;L-arg, L-arginine; NO2 −, nitrite; NO3 −, nitrate; NOS, nitric oxide synthase; O2, oxygen; RSNO, S-nitrosothiol. Figure 3: Diagram illustrating the differing pathophysiologic effects of inhaled pulmonary vasodilators and intravenous vasodilators. Qs/Qt: R→L shunt. Figure 4: Inhaled NO is a selective pulmonary vasodilator with actions on the systemic vasculature. A schematic of an alveolar-capillary unit is presented, highlighting the ability of inhaled NO to dilate pulmonary arterioles and reduce pulmonary artery pressure (PAP). Although inhaled NO does not dilate systemic arterioles or alter systemic arterial pressure (SAP) under normal conditions, inhaled NO has systemic effects that are described in the text and may be mediated by circulating cells exposed to NO in the lungs and bloodborne NO derivatives:
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  SNO-proteins or S-nitrosoproteins including SNO-albumin; SNO-Hb or S-nitrosylation of hemoglobin (nitrosylated on Cys of the β chain); NO-Fe-Hb or nitrosyl-hemoglobin; and nitrite. Note:  Atmospheric concentrations of NO usually range between 10 and 500 parts per billion (ppb) by volume but can exceed 1.5 parts per million (ppm) in areas of heavy traffic or lightning.  In the inhaled smoke of a burning cigarette, NO is produced by the oxidation of nitrogen from the atmosphere and nitrogen-containing compounds in the tobacco and can reach levels of 1000 ppm.  NO is unstable in air and undergoes spontaneous oxidation to form the more toxic nitrogen oxides (NO2, N2O4). NO is therefore stored in cylinders and diluted in an inert gas, usually nitrogen. Potential Uses for Inhaled Nitric Oxide 1. ARDS 2. Persistent pulmonary hypertension of the new born 3. Bronchopulmonary dysplasia (BPD) is an important chronic lung disease of prematurely born infants that results, in part, from the inhibition or disruption of normal pulmonary alveolar and microvascular development as a result of oxygen- and ventilator-induced lung injury 4. Primary pulmonary hypertension 5. Pulmonary hypertension after cardiac surgery 6. Cardiac transplantation 7. Acute pulmonary embolism 8. COPD 9. Congenital diaphragmatic hernia 10. Sickle cell disease 11. Testing pulmonary vascular responsiveness 12. Cardiogenic Shock as a Result of Right Ventricular Myocardial Infarction 13. Insertion of Left Ventricular Assist Device. RV dysfunction occurs in 20% to 50% of patients after insertion of a left ventricular assist device (LVAD) 14. Treatment of Pulmonary Ischemia-Reperfusion Injury. Ischemia-reperfusion (I-R) injury is one of the major causes of early graft failure after lung transplantation. Adhesion and sequestration of activated leukocytes by activated pulmonary endothelium are believed to
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  be important mechanismsof I-R injury. NO possesses anti-inflammatory properties, and inhaled NO has been shown to attenuate pulmonary I-R injury in preclinical studies. Figure 5: Biologic Effects Of Breathing Nitric Oxide With Selected Physiologic Impacts And Potential Therapeutic Applications. Dosing The amount of NO needed to improve oxygenation or decrease pulmonary vascular pressure in neonates or adults is relatively low. The therapeutic range of NO is 2 to 20 ppm, and an initial dose of 20 ppm is commonly used. Treatment should be continued until underlying oxygenation desaturation has resolved. For many patients, dosages often can be reduced to less than 20 ppm at the end of 4 hours of initial treatment, as tolerated. At these levels, NO has minimal toxicity. Toxicity and Adverse Effects
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  Most of thetoxic effects of NO are caused by its chemical by-products, especially NO2. NO2 is produced spontaneously whenever NO is exposed to O2. NO2 is more toxic than NO. Levels greater than 10 ppm can cause cell damage, hemorrhage, pulmonary edema, and death. The U.S. Occupational Safety and Health Administration has set the safety limit for NO2 exposure at 5 ppm. Other harmful chemical by-products produced in reaction with NO include methemoglobin and peroxynitrite (produced when NO reacts with superoxide) 1. Poor or paradoxical response 2. Methemoglobinemia 3. Increased left ventricular filling pressure 4. Complications of certain cardiac anomalies(coarctationof theaorta) 5. Rebound hypoxemia, pulmonaryhypertension NO inhibits platelet agglutination; however, no significant increase in bleeding time has been reported in NO trials with human subjects. patients receiving both inhaled NO and other NO-related compounds such as nitroglycerin and the possible development of methemoglobinemia or systemic hypotension Features of Ideal Nitric Oxide Delivery System  Dependability and safety  Delivery of a precise and stable dose of NO  Limited production of nitrogen dioxide  Accurate monitoring of NO and nitrogen dioxide levels  Maintenance of adequate patient ventilation Example: INOmax® DSIR® Plus (Delivery System-Infrared) (Ikaria, Hampton, New Jersey) NO can be safely inhaled when delivered by facemask, nasal cannula, or endotracheal tube. Withdrawing Therapy Care must be taken when NO therapy is withdrawn to prevent the rebound effect.
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  1. First, theNO level should be reduced to the lowest effective dose (ideally ≤5 ppm). 2. Second, the patient’s condition should be hemodynamically stable, and the patient should be able to maintain adequate oxygenation while breathing a moderate FiO2 (≤0.4) on low levels of positive end expiratory pressure. 3. Third, the patient should be hyperoxygenated (FiO2 0.6 to 0.7) just before discontinuation of NO inhalation. Close monitoring of patients and use of these measures usually avoid an increase in pulmonary artery pressure and hypoxemia with withdrawal of nitric oxide. OTHER INHALED PULMONARY VASODILATORS The successful clinical use of inhaled NO as a selective pulmonary vasodilator prompted the search for other alternatives, at least, in part, as a result of the significant cost of inhaled NO therapy. A wide variety of intravenous vasodilators were clinically tested via the inhaled route. These vasodilators include 1. Prostacyclin (PGI2) 2. Milrinone 3. Nitroglycerine 4. Sodium nitroprusside 5. Prostaglandin E1 6. Stable analogue of PGI2, epoprostenol; and iloprost. It was expected that inhalation of intravenous vasodilators would maximize drug levels in the lung while minimizing their systemic effects. Off-label use of these drugs via off-label route of administration (i.e., inhalation)
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  INHALED EPOPROSTENOL It hasbeen used to treat  intraoperative pulmonary hypertension during cardiac surgery and postoperativepulmonary hypertension,  RV dysfunction, or  refractory hypoxemia in the ICUs in adult and pediatric patients. Dose: In adults, inhaled epoprostenol (30,000 ng/mL) is administered using a syringe pump and jet nebulizer connected to the inspiratory limb of the ventilator. The usual starting dose is 30 ng/kg/min and can be increased up to 50 ng/kg/min. In pediatric patients, drug concentration and air flow is adjusted accordingly. Figure 6: Diagram illustrating a sample setup of inhaled administration of epoprostenol in patients on ventilation. O2, Oxygen. Limitation:  Although a brief exposure to inhaled PGI2 or its analogues decreases PVR similar to inhaled NO, PGI2 and its analogues are known to cause systemic hypotension when large doses are inhaled.
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   The plasmahalflife of epoprostenol is sufficiently long (~6 minutes) to allow for systemic effects, and systemic arterial levels of an active metabolite have been measured during inhalation of even small doses of epoprostenol.  epoprostenol must be dissolved in a highly viscous and basic glycine diluent (pH = 10.5) that is associated with tracheitis,interstitial pneumonia, and ventilator valve malfunction.  Replacement of the ventilator filter every 2 hours is recommended to avoid possible valve malfunction.  drug cost associated with inhaled epoprostenol is claimed to be smaller than that of inhaled NO, a robust cost comparison taking into account the impact of prolonged therapy on the overall cost has not been made. For example, if one therapy reduced ICU stay by 1 day or the need for a RV assist device or ECMO perfusion, then the difference in drug cost would be incidental.  Further studies appropriately designed to address these issues are needed to better define the role of other less selective inhaled pulmonary vasodilators. Reference: 1. Millers anesthesia 8th ed 2. Egan's text book 11th edition