Chapter 35: Inhaled Drug Delivery

Oxygen and air are mixed to provide the prescribed Fio₂. Rarely, nitric oxide, helium, or volatile anesthetics are added to the inspired gas. Aerosol medication can also be added to the inspired gas. This chapter covers aspects of inhaled gas and aerosol administration.

Nitric Oxide

Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator. As such, improved blood flow in ventilated lung units may occur, often resulting in improved ventilation-perfusion mismatch, better oxygenation, and lower pulmonary arterial pressure. In adults with acute respiratory distress syndrome (ARDS), iNO is associated with a transient improvement in oxygenation. However, no survival benefit or reduction in ventilator-free days has been reported with use of iNO for ARDS. With iNO, there is an increased risk of developing renal dysfunction. Although iNO may result in systemic methemoglobinemia or in generation of inhaled nitrogen dioxide, these effects are rare unless high doses are used. Oxygenation benefit typically occurs with an iNO dose of 20 ppm or less. Rebound hypoxemia can occur when iNO is discontinued. Despite the lack of evidence that iNO improves important outcomes, it is used as rescue therapy for refractory hypoxemia. The cost of iNO in the United States is very high and is not offset by third-party reimbursement or in cost savings from fewer days on the ventilator.

Heliox

Heliox is a mixture of helium (60%-80%) with oxygen (20%-40%). The use of heliox in severe asthma can improve gas exchange and decrease the work-of-breathing. Heliox has also been used with invasive and noninvasive ventilation (NIV) in patients with chronic obstructive pulmonary disease (COPD) exacerbation. The low density of helium reduces the pressure required for flow through a partially obstructed airway. Ideally, a gas mixture containing 80% helium is preferred, but improved clinical status may occur with as low as 40% helium. Heliox can be administered through some mechanical ventilators, but it adversely affects the function of others. High-level evidence is lacking to support improved outcome in patients with obstructive lung disease (eg, asthma and COPD). There is contradictory evidence related to the benefit of heliox to improve aerosol delivery; heliox may improve aerosol delivery, but it is unclear whether this improves patient outcomes. Heliox might be considered in patients who develop postextubation stridor, but there is concern that the heliox will mask the symptoms with progression to life-threatening airway obstruction.

Volatile Anesthetics

Inhaled anesthetic agents have been used to achieve improved gas exchange in patients with severe acute asthma. Inhaled anesthetics have bronchodilatory properties, which is the basis for their use in the setting. The anesthetic properties of these agents also provide sedation to facilitate synchrony. Halothane, enflurane, sevoflurane, or isoflurane have been used in adult patients with asthma refractory to traditional therapies. Isoflurane is most commonly used, primarily due to its safety profile relative to other agents. The use of inhaled anesthetics for the treatment of acute asthma is uncommon due to the need for experienced providers and appropriate equipment for the delivery and scavenging of volatile agents. Integration of ventilator technology and capabilities in modern anesthesia machines may allow for safer delivery of these agents in the intensive care unit (ICU). However, evidence is lacking that the use of these agents improves important outcomes such as mortality, ventilator days, or complications of mechanical ventilation.

Therapeutic aerosols are often used in mechanically ventilated patients, most commonly to administer beta-agonist bronchodilators. However, beta-agonists should be avoided in ARDS, in which they have been shown to increase mortality. Other aerosols that might be administered during mechanical ventilation included anticholinergics, steroids, antibiotics, and prostacyclins. Therapeutic aerosols can be delivered using a nebulizer or MDI. A variety of factors affect aerosol delivery during mechanical ventilation (Table 35-1).

Nebulizer

With the traditional jet nebulizer, about 5% of the dose placed into the device is deposited in the lower respiratory tract. There are a number of disadvantages associated with jet nebulizer use during mechanical ventilation. Contamination of the lower respiratory tract can occur if the nebulizer is the source of bacterial aerosols. The continuous flow from the nebulizer may increase tidal volume during volume ventilation or pressure during pressure ventilation. Continuous flow from the nebulizer makes triggering more difficult and increases resistance of expiratory filters and pneumotachometers. Some of these disadvantages can be offset by using the nebulizer control of the ventilator, which powers the nebulizer only during inspiration and may compensate for the additional flow added by the nebulizer.

The vibrating mesh nebulizer uses a mesh or plate with multiple apertures to produce an aerosol. They require electric power for operation of the control unit. These devices have a high drug output, and their residual volume is negligible. The mesh nebulizer overcomes some of the issues associated with the jet nebulizer because it adds no gas flow into the circuit and the device can remain in the circuit between treatments. The mesh nebulizer is placed between the ventilator and the humidifier (Figure 35-1). Aerosol delivery is more efficient with the mesh nebulizer compared to the jet nebulizer.

Continuous Aerosol Delivery

Continuous aerosols can be delivered into the ventilator circuit using a mesh nebulizer and syringe pump. Continuous aerosol bronchodilators are used for severe acute asthma. Continuous aerosol vasodilators (eg, prostacyclin) are used to improve oxygenation with refractory hypoxemia and to decrease pulmonary artery pressure with pulmonary hypertension.

Metered Dose Inhaler

Many of the complications of jet nebulizer during mechanical ventilation are avoided by use of a MDI. Pulmonary deposition from a MDI is similar to the jet nebulizer (5%). Either MDI or nebulizer can be used effectively in mechanically ventilated patients. The MDI can be introduced into the ventilator circuit using an elbow adapter, inline adapter, or chamber adapter. However, for the same number of actuations, the greatest pulmonary deposition occurs with the chamber adapter. To maximize delivery, the MDI should be actuated at the beginning of inhalation. As with the nebulizer, the endotracheal tube is a formidable barrier to aerosol penetration. An issue with the newest generation of MDIs is their cost, which is high compared to that of a nebulizer.

Dosing

The usual dose from a nebulizer is about 10 times the dose with a MDI. Because the usual dose from the MDI is only a fraction of that with a nebulizer and the deposition from each is similar, more drug may be deposited in the lungs with the nebulizer—particularly with a mesh nebulizer. Thus, the mesh nebulizer may be more effective and convenient than MDI if high doses are required (eg, status asthmaticus). The dose of inhaled medications (nebulizer or MDI) may need to be increased in intubated patients due to the decreased pulmonary deposition secondary to the endotracheal tube.

Evaluation of Response

Response to an inhaled bronchodilator includes decreased peak airway pressure, plateau pressure, auto-PEEP, and resistive pressure (peak minus plateau pressure). More sophisticated measurements such as airway resistance and flow-volume loops may be useful in selected patients to evaluate bronchodilator response.

Aerosol Delivery During Noninvasive Ventilation

Aerosol therapy during noninvasive ventilation (NIV) can be delivered by MDI with a chamber spacer or nebulizer. A number of factors affect aerosol delivery during NIV. These include the type of ventilator, mode of ventilation, circuit conditions, type of interface, type of aerosol generator, drug-related factors, breathing parameter, and patient-related factors. Despite the effects of continuous flow, high inspiratory flow, leaks, humidity, and asynchrony, significant therapeutic effects have been reported with inhaled bronchodilator administration during NIV. Careful attention to the technique is required to optimize therapeutic effects of inhaled therapies during NIV.