Indications
- Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])
- Chronic Obstructive Pulmonary Disease (COPD) (see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]])
- Ischemia-Reperfusion Injury (see Chronic Thromboembolic Pulmonary Hypertension, [[Chronic Thromboembolic Pulmonary Hypertension]])
- Perioperative Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- General Comments: although early studies of iNO in the treatment of pulmonary hypertension used concentrations of 5-80 ppm, concentrations >20 ppm usually provide little additional hemodynamic benefit
- Congenital Heart Disease
- Cardiac Transplantation
- Insertion of Ventricular Assist Device (VAD) (see Ventricular Assist Device, [[Ventricular Assist Device]])
- Persistent Pulmonary Hypertension of the Newborn (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Pulmonary Vasoreactivity Testing in the Cardiac Catheterization Lab (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
Pharmacology
Actions of Inhaled Nitric Oxide (iNO)
- Selective Pulmonary Vasodilation with Improvement in Pulmonary V/Q Matching: due to increased perfusion to well-ventilated lung units and decreased shunt
- In contrast, IV pulmonary vasodilators cause diffuse pulmonary vasodilation, resulting in worsening V/Q matching and increased shunt -> worsening pO2
- Bronchodilation
- Anti-Inflammatory Effects
- Anti-Proliferative Effects
Mechanism
- Inhaled Nitric Oxide Inhalation rapid diffusion across alveolar-capillary membrane -> entry into adjacent pulmonary vascular smooth muscle -> iNO activates soluble guanylate cyclase
- Soluble guanylate cyclase converts GTP to cGMP -> intracellular cGMP relaxes smooth muscle via a number of different mechanisms
- cGMP is hydrolyzed to GMP by cyclic nucleotide phosphodiesterases (PDE) or by export from the cell
- PDE5 is the most active cGMP-hydrolyzing PDE in smooth muscle
- PDE5 is selectively inhibited by zaprinast, sildenafil, and verdenafil
Inhaled Nitric Oxide Metabolism
- After Diffusing into the Bloodstream, iNO is Scavenged by Hemoglobin and Rapidly Inactivated: prevents systemic vasodilation
- In contrast, IV vasodilators can cause systemic vasodilation and systemic arterial hypotension
- iNO Rapidly Reacts with Oxyhemoglobin: formation of methemoglobin + nitrate
- About 70% of iNO is excreted within 48 hrs as nitrate in the urine
- iNO Rapidly Reacts with Deoxyhemoglobin: formation of iron-nitrosyl-Hb
Administration
- iNO Delivery Methods
- Endotracheal Tube/Mechanical Ventilator: start at 10-20 ppm
- Although early studies of iNO in the treatment of pulmonary hypertension used concentrations of 5-80 ppm, concentrations >20 ppm usually provide little additional hemodynamic benefit
- Face Mask
- Nasal Cannula
- Weaning: gradual weaning is advised (to prevent rebound pulmonary hypertension)
Adverse Effects
Cardiovascular Adverse Effects
- Rebound Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
- Epidemiology: associated with rapid discontination of iNO
- Physiology: likely related to downregulation of endogenous iNO or endothelin-1 synthesis
- Clinical: consequently, gradual weaning of iNO is advised
- Increased LV Filling Pressure
- Epidemiology: may be observed in patients with LV dysfunction
- Physiology: due to augmented LV filling of a stiff ventricle (rather than negative inotropy)
Toxicologic Adverse Effects
- Formation of Nitrogen Dioxide
- Physiology: iNO concentration-dependent
- Clinical
- Bronchospasm (see Obstructive Lung Disease, [[Obstructive Lung Disease]]): can occur with as little as 1.5 ppm of NO2
- Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]]): occurs at higher NO doses, probably not clinically significant at 20 ppm of iNO
- Methemoglobinemia (see Methemoglobinemia, [[Methemoglobinemia]])
- Clinical: although this is usually not clinically significant at iNO doses <80 ppm, monitoring of methemoglobin is advised
References
- Inhaled nitric oxide: basic biology and clinical applications. Anesthesiology. 1999;91:1090 –1121
- Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current Uses and Therapeutic Potential. Circulation. 2004; 109: 3106-3111