Antibiotic instillation practices were used in some early studies, but this practice was largely abandoned in the s. Subsequent use of bench models enabled an improved understanding of the aerosolization factors such as optimal ventilator parameters, device position in the circuit and effects of humidity to enable optimal therapy [ 15 — 17 ].
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This work was then supplemented with antibiotic studies in experimental pneumonia that demonstrated higher lung tissue concentrations of antibiotics [ 18 ]. Previously, the formulation of drugs used for aerosolization was the reconstituted form of compounds developed for parenteral administration. These were poorly tolerated by patients due to hyperosmolarity and added preservatives i.
These formulation issues were particularly problematic for antibiotics until the s, when aerosolized tobramycin was evaluated in patients with CF chronically infected with increasingly resistant Pseudomonas aeruginosa [ 21 , 22 ]. A number of high-quality studies using preservative-free and iso-osmolar formulations of tobramycin showed improvements in lung function, a decreased exacerbation rate and reductions in sputum bacterial load [ 21 — 23 ].
These results have encouraged further developments in the application of aerosolized antibiotics in non-CF patient populations such as critical care. In the critically ill patient, certain anatomico-physiological changes can significantly affect the pharmacokinetics PK —pharmacodynamics PD characteristics, thus causing dosing difficulties [ 24 ].
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Mechanically ventilated patients pose a challenge for the effective delivery of aerosolized drugs [ 25 ]. These various factors need to be considered and optimized to achieve desired therapeutic outcomes with aerosolized drug therapy [ 25 ]. The research interest in aerosol drug therapy in critically ill patients is not yet reflected in the bench-to-bedside transfer of knowledge. This report also highlighted the lack of application of scientific principles during therapy and indicated the need for education and research in the bench-to-bedside transfer of knowledge [ 26 ].
In another study, every fourth critically ill patient and every fifth ventilated patient received aerosol therapy [ 27 ]. Given the commonness of use of aerosolization in critical care, yet the uncertainty over the optimal approach for administration, this article aims to discuss the essential concepts related to aerosolized drug therapy in critical care. An aerosol is defined as a suspension of liquid or solid in a gaseous medium [ 29 ].
For successful aerosolization, consideration of the aerosol system is required. The aerosol system includes the drug, the aerosol device, the disease i. The aim of the aerosol system is to produce aerosols with characteristics suitable for drug delivery to the lungs. Drug deposition, absorption, metabolism and elimination are essential determinants of the pharmacokinetic profile resulting from the aerosol system. Key expressions used to evaluate the aerosol system performance include [ 30 ] the following:.
Fine particle fraction FPF —the mass of particles below a cut-off diameter [ 31 ]. The overall efficiency of the aerosol system is a composite of the ED, the dose delivered to the lung FPF as a surrogate marker and lung bioavailability. The ED and FPF are normally determined in vitro and are governed by particulate properties and device design. The bioavailability of the drug is influenced by patient factors such as airway and lung anatomy, drug permeability across membranes, metabolism of the drug and phagocytic clearance in the lung [ 32 ] as well as FPF.
The efficacy of the aerosolized drug depends on the dose deposited at the target site of action as well as its distribution in the lungs [ 33 ]. Deposition in the airways can occur by inertial impaction, gravitational sedimentation or diffusion Brownian motion Fig. Because of the turbulence and high air velocity associated with aerosolization, an inertial impaction method is predominant in the first 10 branchings of the airway [ 34 ].
This proximal region is the target for aerosol therapy for diseases such as COPD, asthma and ventilator-associated tracheobronchitis. In the distal five to six airway generations, however, sedimentation predominates due to lower air velocity [ 34 ]. At the alveolar level, minimal air velocity means no effect of impaction will occur and a combination of sedimentation and diffusion will influence drug deposition [ 34 ]. The optimal technique for aerosolization is important to achieve distal airway and alveolar deposition. Drug concentrations in lung tissue are affected by the aerosolized dose administered, patient factors, device factors and the formulation of the drug.
Mechanical ventilation MV introduces additional elements such as the circuit and the ventilator and associated factors. For the purposes of describing the factors affecting aerosol therapy, critically ill patients could be classified into two groups: ventilated patients and non-ventilated patients [ 35 — 38 ].
Drug Formulation Development
Factors favourable for aerosol drug delivery in critically ill patients. Airflow and tidal volume influence the effect of airway anatomy on aerosol deposition. Patients suffering from airway obstruction such as asthma or COPD have impaired mucociliary clearances and mucous retention [ 39 ]. For drugs with poor trans-mucous permeability e. Chronic inflammation may result in airway remodelling, which changes the dynamics of airflow [ 33 , 35 ], and impaired mucociliary clearance, thus reducing the pulmonary drug deposition [ 33 , 41 ]. These changes lead to a proximal shift in the airway deposition pattern of the aerosols [ 42 ].
Significance— Abnormal airways and impaired mucociliary clearance serve as a barrier to effective aerosolized drug therapy when the target site is the lung parenchyma. The airflow is not homogeneous throughout the lungs even in health. The result in an upright patient is that the apical portions of the lungs receive lung deposition of the order of a higher ratio compared with the basal regions [ 43 ].
This difference is significantly reduced in the supine position [ 44 ]. Moreover, most lung diseases are regional which adds to the heterogeneity to regional airflow, an important determinant of aerosol deposition [ 45 ]. For example, it has been shown that there is lower deposition in areas of poor air flow i. In the area of antibiotics, there is a large body of work with experimental pneumonia models which have demonstrated that lung tissue concentrations of nebulized amikacin, using a ultrasonic nebulizer, was significantly higher than the concentrations resulting from administration via the intravenous route [ 47 , 48 ].
Indeed, even though deposition of nebulized drug decreased with more severe pneumonia, it still resulted in higher lung tissue concentration than that achieved from intravenous administration. The same group also demonstrated that nebulized amikacin resulted in greater bactericidal activity leading to greater sterility rates compared with the intravenous route [ 49 ].
When compared with continuous intravenous infusion of ceftazidime, frequent nebulization achieved higher lung tissue concentrations with better bactericidal effects in an experimental model of Pseudomonas pneumonia [ 50 ]. Effects of regional lung aeration and pneumonia on drug concentration in lungs. Pulmonary concentrations derived from homogenized lung tissue specimens measured by an immunoenzymatic method. Figure derived from Elman et al. Significance —Differences in regional lung aeration may explain some of the variability in therapeutic outcomes amongst different lung diseases.
In a critically ill, spontaneously breathing patient, air flow is likely to be turbulent leading to impaction in the proximal airway. For drugs dependent on lung deposition for their effect, this results in a decreased pharmacological effect. In contrast, laminar flow patterns are considered to enable optimal lung deposition [ 51 ].
In the critically ill patient, certain MV settings e. Using pressurized metered dose inhalers pMDIs with valved holding chambers VHCs or spacers could mitigate this effect. Significance —Whilst a laminar flow pattern would be beneficial for aerosolized drug delivery, mechanistic data need to be confirmed using clinical trials. Drugs with high solubility will probably have a uniform dispersion compared with insoluble drugs. Inferentially the soluble drugs are likely to have longer and more effective lung residence times, thus improving drug potency [ 55 ]. Surfactant deficiency is associated with atelectasis, which in turn impairs drug deposition [ 42 ].
Studies on surfactant replacement therapy in acute lung injury and ARDS, however, have failed to demonstrate benefit and may even be deemed harmful [ 56 , 57 ]. Aerosolized surfactant therapy has been studied as a mucokinetic agent in specific conditions [ 58 ]. Its application for this purpose in critically ill patients needs further study.
Significance —Uncertain benefits requiring further studies to demonstrate effects of surfactant.
A major fraction of the aerosolized drug is entrapped in the mucous in the conducting airways. Factors such as particle size, solubility, lipophilicity and charge govern the ability of the drug to penetrate this mucous barrier. For example, steroids and antimicrobial agents are seen to have reduced trans-mucous transport [ 39 , 40 ].
Atelectasis is a common occurrence in the majority of critically ill patients. This may have adverse effects on drug deposition and may result in heterogeneous distribution in the lung [ 59 ]. Significance —Both, mucous and atelectasis serve as a barrier to effective aerosolized drug therapy. A detailed discussion on the effect of device-related factors has been reviewed elsewhere [ 20 , 60 ]. Appropriate particle sizes are important to enable adequate concentrations at the target site.
Aerosol Drug Delivery Optimization by Computational Methods
Particle size also determines the mechanism of deposition in the respiratory system [ 31 ]. In this regard, the efficiency of the aerosol device can be defined to be the ability to generate the aerosol in the desired particle size range. These features may make DPIs the preferred delivery device.
In critically ill patients, however, poor respiratory reserve and diminished patient efforts are barriers to achieving the desired respiratory pattern for effective use of DPIs.
Optimization of Aerosol Drug Delivery
The DPIs also vary widely in their efficacy [ 66 ] and their use in mechanically ventilated patients is not typically possible with a standard set up [ 67 ]. Thus, DPIs are presently used in stable and unventilated patient groups.
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Nebulizers are different devices that are used to transform liquid formulations and suspensions into an aerosol form. These devices can be used to deliver larger volumes of a drug as an aerosol either intermittently or continuously, for prophylaxis or treatment purposes.
Depending on their mechanism of operation, there are three types of nebulizers: jet, ultrasonic and SMNs.