4.1 Inhaled Nitric Oxide & Vasodilators

Inhaled Nitric Oxide (iNO)

Inhaled Nitric Oxide (iNO) is a gaseous, selective pulmonary vasodilator. It is indicated as a rescue therapy for patients with severe refractory hypoxemia in Acute Respiratory Distress Syndrome (ARDS) and for the management of acute pulmonary hypertension or acute right ventricular failure in the intensive care unit.

Biochemical Mechanism of Action

iNO is delivered directly into the inspiratory limb of the mechanical ventilator circuit. Upon inhalation, it diffuses rapidly across the alveolar-capillary membrane into the adjacent vascular smooth muscle cells of the pulmonary capillaries.

1. Within the smooth muscle cells, iNO activates the enzyme soluble guanylyl cyclase.
2. This enzyme catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
3. Increased cGMP levels reduce intracellular calcium, leading to smooth muscle relaxation and vasodilation.
4. Selective Pulmonary Vasodilation: Because iNO is inhaled, it only reaches well-ventilated alveoli. The capillaries surrounding these healthy alveoli dilate, while capillaries near collapsed or fluid-filled alveoli remain constricted. This diverts blood flow away from shunt pathways and toward functional lung units, significantly improving Ventilation-Perfusion ($V/Q$) matching and arterial oxygenation.
5. No Systemic Effects: Once iNO enters the capillary lumen, it binds instantaneously to hemoglobin, forming nitrosylhemoglobin, which is rapidly oxidized to methemoglobin and nitrate. Because it is inactivated within milliseconds, it does not enter the systemic circulation, preventing systemic hypotension.

Clinical Dosing and Delivery Systems

• Standard Dosing: The initial therapeutic dose is 20 parts per million (ppm). Doses up to 40 or 80 ppm do not yield additional pulmonary vasodilation or oxygenation benefits but exponentially increase the risk of toxicity.
• Delivery Setup: iNO must be delivered using a specialized delivery system (e.g., INOmax DSIR) that injects a constant concentration of nitric oxide gas into the inspiratory limb of the ventilator circuit, adjusting flow dynamically in response to the ventilator's inspiratory flow rate.

Toxicity Monitoring and Management

1. Methemoglobinemia: The binding of nitric oxide to hemoglobin oxidizes the iron molecule from the ferrous state ($Fe^{2+}$) to the ferric state ($Fe^{3+}$), producing methemoglobin (MetHb). Ferric iron cannot bind oxygen, and its presence shifts the oxygen-hemoglobin dissociation curve to the left, impairing oxygen unloading to tissues.
   • Monitoring: Co-oximetry must be performed via arterial blood gas daily or every 12 hours.
   • Intervention: If the MetHb level exceeds 5%, the iNO dose must be reduced (e.g., to 5 or 1 ppm). If MetHb exceeds 10% or the patient exhibits signs of tissue hypoxia (unexplained lactic acidosis), iNO must be discontinued, and the antidote Methylene Blue (1 to 2 mg/kg IV over 5 minutes) should be administered.
2. Nitrogen Dioxide ($NO_2$) Formation: Nitric oxide reacts with oxygen in the ventilator circuit to produce nitrogen dioxide ($NO_2$), a highly toxic gas that causes airway inflammation and parenchymal lung injury.
   • Monitoring: The delivery system continuously measures $NO_2$ levels. The level must be kept < 2 ppm.
   • Prevention: Place the iNO injector module as close to the ventilator outlet as possible (before the humidifier) to minimize the contact time between nitric oxide and oxygen.
3. Rebound Pulmonary Hypertension: Abrupt cessation of iNO can cause life-threatening rebound pulmonary hypertension and severe hypoxemia due to the suppression of endogenous nitric oxide synthase.
   • Weaning Protocol: Weaning should be gradual: 20 ppm $\to$ 10 ppm $\to$ 5 ppm $\to$ 1 ppm. The patient should spend at least 4-6 hours at each step. Discontinuation is attempted only when the patient is stable on an $FiO_2 < 60\%$ and PEEP $< 10$ cm H2O.

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Inhaled Epoprostenol (Flolan)

Inhaled epoprostenol is a synthetic prostacyclin ($PGI_2$) that serves as a cost-effective alternative to iNO for selective pulmonary vasodilation.

Mechanism and Clinical Dosing

Like iNO, inhaled epoprostenol stimulates adenylate cyclase in vascular smooth muscle cells, increasing cyclic adenosine monophosphate (cAMP) and causing vasodilation. It is administered via continuous nebulization into the inspiratory limb of the circuit.

• Dosing: The typical dose range is 20 to 50 nanograms/kg/minute of ideal body weight.
• Delivery System: Delivered using a continuous micro-pump nebulizer (e.g., Aerogen Solo) placed before the humidifier.

Critical Safety Precautions and Circuit Management

Epoprostenol is a highly viscous, alkaline solution. When nebulized continuously, the drug crystallizes upon cooling, which presents unique risks to the ventilator circuit:

• Expiratory Filter Clogging: The crystallized drug accumulates on the ventilator's expiratory filter. This increases expiratory resistance, leading to a rapid rise in auto-PEEP and high peak airway pressure alarms.
• Mitigation Protocol:
  • The expiratory filter must be changed routinely every 4 to 6 hours.
  • A heated expiratory filter system must be used to minimize crystallization.
  • A dual-filter system or a specialized scavenger filter should be inline.
  • The clinician must monitor the expiratory flow waveform and plateau pressures closely for signs of gas trapping.