Antimicrobials can improve outcomes for patients with acute pneumonia. Enteral and parenteral routes remain the benchmark, but drug pharmacokinetics can interfere with delivery to target sites, particularly in critically ill patients with marked alterations in fluid distribution, vascular permeability, and liver/kidney function. Although aerosolised delivery to airways may overcome such issues, evidence demonstrating a clear patient benefit is lacking. Whilst nebulisation has many uses, this article will focus on nebulisation in acute pneumonia.

Background

From inhaled sulphur emitted by Mount Vesuvius in classical antiquity, to smoking for asthma in the Middle Ages, and recent controversy surrounding COVID-transmission risk with nebuliser use, aerosolised drug delivery has played a key role in respiratory medicine. Modern nebulisation emerged in the 19th century with the alarming rise of tuberculosis and discovery of its infectious origins.

Mechanism of Action

Device

There are three mechanisms in use today: pneumatic, ultrasonic, or vibrating mesh nebulisers. Drugs can also be delivered by metered-dose inhalers that deliver emulsified drugs via a propellant—this will not be covered.

Pneumatic (or jet) nebulisers focus a jet of pressurised air to rupture and aerosolise a column of liquid. Airflow carries the aerosols towards a mask or hose for patient inhalation. Drug delivery efficiency can be below 10%.

Several factors affect device performance. Jet velocity correlates negatively with aerosol size and some devices claim to shrink aerosols further by diverting auxiliary air flow (usually from an inspiratory arm of a ventilation circuit) into the nebuliser. Chamber design (e.g., baffles) improves capture of larger droplets that do not have a therapeutic effect, thus reducing drug wastage and environmental contamination. Similar benefits are seen with lower turbulence designs (reducing collision and coalescence of droplets) and vented nebulisers that permit aerosol flow only during inhalation. Ultrasonic nebulisers use vibrating piezoelectric crystals to break up and aerosolise a liquid. Vibration frequency negatively correlates with aerosol size, whilst amplitude determines rate of aerosolisation. Drug delivery efficiency is reportedly superior to pneumatic devices but may only reach 30–40%. Mesh nebulisers push liquid through a mesh plate with microscopic holes to minimise aerosol size variation. A piezoelectric crystal vibrates either the liquid drug reservoir or the mesh plate itself. Some drug collects on the apparatus after aerosolisation and some will be pushed out of the circuit upon exhalation. Durability can also alter performance. Over time, degradation of nozzles, baffles, hoses, vents, and piezoelectric crystals will adversely impact aerosol production accuracy and consistency.

Drug Delivery

Complex interactions between several factors determine effective delivery of the aerosolised drug to the alveoli. Mass median aerodynamic diameter (MMAD), or median particle size, determines the destination in the respiratory tract, from apparatus walls, oropharynx, large airways, down to alveoli. Larger particles (>5 µm) use inertial momentum and typically impact apparatus or upper-airway walls; smaller particles (<5 µm) can follow gravity or convective movement of surrounding air and settle into lower airways; particles <1 µm move randomly through the air via Brownian motion and are most likely to arrive at the alveoli.

Vibrating piezoelectric devices produce smaller MMAD and are currently the favoured technology. However, different drugs behave differently in a nebuliser, thus ideally we should use drugs formulated for nebulisation. Human protocols recommend using preservative-free, non-hyperosmolar, neutral pH solutions that contain a permeant anion, the latter to reduce bronchospasm and coughing.

Additional factors in ventilated patients include:

• Humidity, particularly in a ventilation circuit, causes hygroscopic growth of aerosols, inhibiting movement into alveoli. Humidifiers or exchangers should be disconnected during nebulisation.
• Distance from the patient to the nebuliser in a ventilation circuit impacts the percentage of drug deposited in the alveoli.
• Ventilator settings such as tidal volumes, inspiratory:expiratory ratios, circuit shape, and patient synchrony are essential to optimise for nebulisation.

Once the drug is delivered, efficacy is not guaranteed. Whilst healthy patient studies may demonstrate good results, critically ill patients with pneumonia introduce numerous confounding factors. Sputum antagonism was shown to inhibit tobramycin activity, causing a dramatic increase in target tissue MIC. Inflamed lungs will increase vascular permeability and may increase systemic drug absorption, mitigating a key benefit of nebulised drug delivery. Antimicrobial stewardship demands careful drug dosing based on PK/PD and culture and susceptibility data, none of which is available for nebulised drug use in companion animals. Also, the mechanics of nebulisation (residual drug in the nebuliser, drug lost to the environment, ingested drug, sputum inactivation) prevents quantification of target tissue levels without advanced diagnostic tools reserved for research facilities.

Adverse Effects

Nebulised drug therapy’s purported safer profile has helped its popularity, but safety is not assured. For example, systemic absorption of aminoglycosides is reduced, but not eliminated. This may lead to subtherapeutic systemic levels and increased risk of resistance patterns, especially in hospitalised critically ill patients. Ventilated patients require nebulisation settings that may harm respiratory function. This includes de-recruitment every time the nebuliser is attached and tidal volume and inspiratory:expiratory settings that may not suit the patient’s respiratory status.

Current Evidence

Veterinary

There is insufficient evidence evaluating nebulised drugs in patients with acute pneumonia.

Several veterinary studies confirm efficacy of nebulised drug delivery. A small healthy dog study used scintigraphy to track radiolabelled nebulised corticosteroids and found effective, albeit very inefficient, lung delivery (4.2% of nebulised drug). Similar findings were published in a cat study delivering technetium via a spacer. Both studies report significant ingestion of nebulised drug into the gastrointestinal tract, similar to an experimental study in beagles that found the majority of nebulised albuterol was from gastrointestinal absorption.

Another study found comparable performance between two veterinary spacers (AeroDawg and AeroChamber) and interestingly reported no difference in drug uptake at three and five minutes of nebulisation, only greater drug wastage.

Most antimicrobial studies focus on gentamicin use. Recently, a retrospective case series reported faster clinical improvement in dogs with chronic bordetellosis when nebulised for 10 minutes twice daily at home for at least three weeks using gentamicin 4 mg/kg diluted in 0.9% NaCl or gentamicin 5%. The authors did not provide measured or calculated doses delivered to the lungs.

Such calculations are possible, but require several assumptions. An experimental study comparing nebulised gentamicin in rats and dogs using several nebulisation protocols reported low efficiency (14–21%) and doses up to 8 mg/kg based on the following equations:

• Inhaled dose (mg) = empirically determined aerosol concentration (mg/L) x published average minute volumes (4 L/min) x exposure time (min)
• Inhaled deposited dose (mg) = inhaled dose x published pulmonary deposition fraction

High doses were achieved with one hour nebulisation time performed once daily for 2 weeks. This group of dogs had mild renal tubular lesions attributed to aminoglycoside toxicity, and some tissue drug accumulation at the end of the treatment period.

In a large retrospective case series of dogs with aspiration pneumonia, no survival benefit was associated with nebulisation.¹⁴ However, the authors did not describe the drugs used.

Human

There is abundant literature demonstrating improved outcomes in cystic fibrosis patients who receive nebulised antimicrobials for chronic recurrent drug-resistant infections. For acute pneumonia, the literature focuses on ventilator- and hospital-acquired pneumonia, particularly in mechanically ventilated patients.

A recent systematic review and meta-analysis concluded that there was insufficient high-quality evidence supporting nebulised antimicrobials in critically ill patients with pneumonia. Only 11 studies fulfilled their criteria, of which only six were RCTs. These confirmed good renal safety profile of nebulised gentamicin, but reported respiratory complications in 9% of mechanically ventilated patients. Whilst there was no improvement in key outcome measures such as mortality or duration of ventilation, nebulised patients had lower rates of resistant organisms. An outcome benefit was only found in patients with multidrug-resistant infections (odds ratio, 1.96; 95% CI, 1.30 to 2.96).

Current European guidelines do not recommend use of nebulised antibiotics due to weak evidence. This highlights the need for more high-quality studies to evaluate safety, particularly in hypoxaemic patients, and outlines areas in urgent need of further research.

Hypertonic Saline

Most literature supporting nebulisation with hypertonic saline originates from cystic fibrosis studies that show a clear benefit. In one small RCT in human ARDS patients, patients treated with IV or nebulised hypertonic saline had faster clinical improvement, less need for mechanical ventilation, and shorter ICU stay than the control group. However, a small unblinded study in mechanically ventilated children found no difference when nebulised with hypertonic saline or 0.9% saline.

Mechanistically, it appears saline nebulisation has immunomodulatory benefits, in addition to aiding mucociliary clearance of exudates.

Conclusion

Nebulised drug delivery requires consideration of the device used, the drug in question, and patient status, but can effectively deliver medication to the lower airways. Theoretically, nebulised gentamicin maximises efficacy whilst minimising nephrotoxicity. However, a plethora of confounding factors remain poorly understood, and ultimately it is unclear whether this practice improves outcomes in acute pneumonia of companion animals.

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