Amongst the machines that help save lives in the intensive care unit (ICU) environment, aerosol drug delivery devices play a special role. Aerosolization can rapidly achieve high-effective local drug concentration at the site of action with minimal side effects for treating respiratory conditions such as reactive airways diseases [1]. The vast alveolar surface area (100 m2) and pulmonary blood flow (entire cardiac output) provide an alternative avenue for effective systemic therapy as well [1]. However, effective aerosol therapy in ICU is affected by the complex interplay with other machines [invasive mechanical ventilation (IMV), non-invasive ventilation (NIV), high flow nasal cannula (HFNC)] as well as the patient factors [1]. Various aspects of aerosol therapy are covered extensively elsewhere [1]. We provide a summary of the aerosolized therapy in ICU.

Aerosol drug formulations and dosing

In ICU, aerosolized drugs consist of specific aerosol formulations, such as bronchodilators and off-label use of intravenous formulations, e.g., tobramycin. Aerosolized drugs in ICU belong to established drug classes, such as bronchodilators (e.g., salbutamol), anti-infectives (e.g., colistin) and other less common agents such as anticoagulants (e.g., heparin). Ideal characteristics of aerosol formulations especially for off-label uses include preservative-free, non-pyrogenic, sterile, adjusted osmolality (150–1200 mOsm/L) and pH (4.0–8.0) [2]. Ideal aerosol characteristics consist of particle size (1–5 µm), electrical charge, lipophilicity, solubility, and molecular weight (< 40 kDa) [1].

While pulmonary and systemic pharmacokinetic data can guide optimal aerosol drug dosing in the critically ill, there are limited pharmacokinetic–pharmacodynamic data with aerosolized therapy in ICU affecting effective drug dosing.

These and other regulatory aspects should be considered when choosing a formulation for aerosol drug therapy in ICU.

Aerosol delivery devices

Pressurized metered dose inhalers (pMDI) and nebulizers [jet (JN), ultrasonic and vibrating mesh (VMN)] are the common aerosol devices used in ICU. These are covered in detail elsewhere [3] and summarized in Table 1.

Table 1 Summary of aerosol delivery devices for use in ICU (generated from references [3,4,5]
Full size table

As VMN provides optimal aerosol characteristics, where possible, it is the preferred nebulizer. Whilst pMDI can be used in most critical care settings, it is limited in its application due to few available formulations. Choice of aerosol devices depends on the formulation (limited formulations with pMDI, heat degradation of proteins with ultrasonic nebulizer), ease of use, availability, and cost considerations.

Optimising factors for effective aerosol therapy in ICU

As aerosol therapy is often used with devices, such as IMV, NIV and HFNC, it is necessary to optimize related factors to provide effective therapy.

1. Aerosol therapy is commonly used with IMV, yet challenging due to the interplay between ventilator, circuit, and nebulizer. Airway size, nebulizer position, heated humidification (HH), bias flow, and patient–ventilator dyssynchrony are some factors affecting aerosol drug delivery [1].

Whilst generally larger artificial airways are likely to reduce the airflow resistance and likely to yield better delivery, other studies showed no difference. In vitro studies indicate that positioning the VMN 15 cm from the Y-piece in the inspiratory limb of circuit with bias flow-off provides highest drug delivery [1, 5]. In in vitro studies, high bias flow has been shown to reduce drug delivery [7]. Heat and moisture exchanger (HME) placed between the nebulizer and patient results in lower drug delivery [1, 6]. Turning off the HH during nebulization may not provide significant advantages for aerosol delivery and hence not recommended. Patient–ventilator synchrony likely improves drug delivery. In vitro experiments showed, volume control, slower inspiratory flow and increased inspiratory pause might augment distal delivery of drugs and deposition. However, clinical studies failed to translate these findings [8].

2. Aerosol therapy with NIV avoids the need for disconnecting the patient from the NIV and patient discomfort. Special attention is required in two technical aspects: (1) type of NIV interface, and (2) position of the nebulizer.

It has been shown that nasal passage of the gas reduces drug delivery to the lungs [9]. And the presence of open leak or exhalation ports directly on the face mask also leads to a higher percentage of drug loss before reaching the patient’s lung [10]. Therefore, inhalation with nasal masks or with vented interfaces is not recommended. Some interfaces have open ports in the mask to prevent CO2 rebreathing, suggest capping the ports during aerosol delivery to reduce aerosol loss. Another key aspect is in single-limb non-invasive ventilators, VMN should be positioned between mask and exhalation port to provide optimal drug delivery [11]. At this position, between 5 and 25% of intended dose is delivered [12]. Aerosol therapy is affected by other ventilatory settings, such as inspiratory pressure (higher pressures are associated with higher delivered doses), expiratory pressure (lower pressures are associated with higher delivery), and type of nebulizer (VMN deliver higher doses than JN) [12, 13]. When a dual-limb ventilator is used, the same configuration as suggested for invasive mechanical ventilation is suggested (i.e. VMN 15 cm from the Y-piece in the inspiratory limb of circuit).

3. HFNC use is increasingly prevalent worldwide in many critical care settings.

There is a growing literature for inhaled therapies with HFNC. Two major barriers for effective drug delivery are the nasal passage of the gas (which entraps a high percentage of the aerosol) and the range of clinically useful gas flow during HFNC. Aerosol drug delivery was better at lower airflow as shown in an in vivo scintigraphy study [14]. Even with these limitations, a small clinical study using a VMN placed downstream the humidification chamber to deliver albuterol suggests bronchodilation effect similar to standard facial mask jet nebulization [15]. VMN provides 2–3-fold higher delivery than JN.

Safety considerations of aerosol therapy in ICU

Certain precautions should be taken to ensure safe aerosol therapy in the ICU. Nebulization with mechanical ventilation should include regular change of exhalation filter to prevent barotrauma [6]. Adequate sterility measures should be followed with reusable nebulizers. The ventilator settings should be reset if changed during nebulization [6]. Finally, measures to prevent fugitive emissions and aerosolization of infective particles should be included [16].

Aerosolized therapy provides a rapid, safe, and effective alternative mode of drug delivery in the ICU setting. Future research with newer formulations and devices needs to undergo adequately powered, well-designed randomised controlled trials to improve clinical outcomes.