Nitric Oxide (NO)

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