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NEONATOLOGY
How to Deliver Respiratory Treatments to
Neonates by Nebulization
Peter R. Morresey, BVSc
Delivery of drugs by aerosol may allow higher concentrations of therapeutic agents to act locally at the
site of pulmonary infection or inflammation, and therefore, the potential for systemic side effects is
minimized. Aerosolization of therapeutic agents acts as a useful adjunct to more conventional
systemic therapies. Author’s address: Rood and Riddle Equine Hospital, PO Box 12070, Lexington,
KY 40580; e-mail: [email protected]. © 2008 AAEP.
1.
Introduction
Successful treatment of respiratory infection and
inflammation can be impaired by the difficulty in
achieving therapeutic levels of pulmonary drugs
given by the systemic route. Aerosol administration of drugs allows the rapid achievement of high
concentrations of therapeutic agents in the pulmonary epithelial lining and bronchiolar fluid. Lower
overall doses of the drug are required to achieve
therapeutic levels compared with systemic therapies
alone. Local delivery can minimize the occurrence
of systemic side effects and drug residues. The alteration of respiratory tract secretion viscosity by
the administration of mucolytic drugs allows easier
removal by clearance mechanisms.
2.
Materials and Methods
Mechanics of Aerosol Therapy
An aerosol is a gas containing finely distributed
solid or liquid particles in suspension. Properties
of the aerosol are governed by both the physical
attributes of the individual particles and their collective behavior. Particle size as well as their mass
NOTES
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and velocity tend to be highly variable within the
aerosol.
Size distribution of particles is the most important
determinant of the quantity of inhaled particles that
penetrate the tracheobronchial tree to reach the
lung. Particles reach different areas of the respiratory tract dependent on their size. As particle size
decreases, site of deposition within the respiratory
tract becomes deeper. To reach the distal airways,
particle sizes ⬍5 ␮m in diameter are required.1
Two different mechanisms exist for the delivery of
medications by nebulization: the high-pressure jet
nebulizer and the ultrasonic nebulizer. With the
jet nebulizer, the aerosol is generated by the flow of
compressed gas through the liquid. The primary
spray contains a wide range of droplet sizes, and the
larger ones strike the wall of the device and drain
back for reaerosolization. The smaller droplets are
able to exit the device. By altering the airflow entering the nebulizer the size of aerosolized particles
generated, and hence their pulmonary distribution
can be altered. The ultrasonic nebulizer uses airflow to carry droplets generated by ultrasonic vibrations. Aerosols can be highly concentrated;
NEONATOLOGY
however, at high-flow rates, particle size is greater
than those generated by jet nebulizers.2
Ability to deliver aerosolized drugs to equine airways has been shown.3 Although both jet and ultrasonic devices are capable of delivering drugs to
the horse by aerosol, the percentage of the dose
released reaching the lungs was significantly lower
with the ultrasonic nebulizer compared with the jet
nebulizer. Peripheral deposition within the airways was also significantly higher with jet nebulization compared with ultrasonic nebulization.3
Drugs Used in Aerosol Therapy
Antimicrobials
High levels of antimicrobials are necessary systemically to achieve therapeutic concentrations in respiratory secretions. This increases the probability of
adverse side effects. The usage of both ␤-lactam
and aminoglycoside antimicrobials has been investigated in the horse.4,5 Both ceftiofur and gentamicin aerosol particle density and size were affected by
the antimicrobial concentration of the solution.
Optimal combinations of particle size and aerosol
density for delivery to the intrathoracic airways of
the horse were achieved with gentamicin (50 mg/ml)
and ceftiofur (25 mg/ml) solutions.4 Compared
with IV therapy with gentamicin at 6.6 mg/kg, levels
of gentamicin in respiratory secretions were considerably higher after nebulization at 2 mg/
kg.5 Gentamicin accumulation or respiratory
inflammation after repeated aerosol was not found
to occur, which suggests that this is a safe procedure
for treatment of horses with bacterial infections of
the airways.5 Ceftiofur sodiuma (2.2 mg/kg) has
recently been shown to achieve high therapeutic
levels in respiratory secretions, which are higher
than those achieved after systemic administration.6
Anti-Inflammatories
Few studies are published regarding the efficacy of
inhaled corticosteroids in veterinary medicine, although the benefits of systemic corticosteroids in
cases of equine airway diseases are well known.7
Differences have also been shown in the efficacy of
reducing signs of inflammation between systemically administered corticosteroids and traditional
methods.8 In human medicine, inhaled corticosteroids have been shown to be highly effective in controlling inflammatory conditions. Furthermore, all act
by binding a common glucocorticoid receptor, but the
difference between individual compounds is in the propensity to cause systemic side effects.9 Many corticosteroid drugs exert a topical effect when deposited in
the lungs but are inactivated after gastrointestinal
absorption. Corticosteroids have a variety of actions that inhibit inflammation, such as decreasing
production and secretion of specific mediators from inflammatory cells and reducing the generation of arachidonic acid metabolites (prostaglandins, leukotrienes).
Pulmonary function testing responses and clinical
signs of airway obstruction are both improved by
administration of inhaled corticosteroids; however,
the magnitude of response is dependent on dosage
and not necessarily improved over the usage of systemic corticosteroids. Therefore, frequency of
treatment and dose rate must be considered when
seeking to achieve superior anti-inflammatory responses by aerosol compared with parenterally administered corticosteroids.7
Bronchodilators
Sympathomimetic agents (␤2 adrenergic agonists)
stimulate receptors on smooth muscle cells of the
airway walls, which promotes relaxation of muscle
and bronchodilation. More recent drugs have been
developed to have more selective binding to respiratory ␤2 receptors as well as to have a more prolonged
action period.
Inhaled bronchodilators have been shown to be
more efficacious than systemic administration of the
same compound in their ability to counter bronchoconstriction.10,11 An increase in mucociliary clearance has also been reported with the use of ␤2
adrenergic agonists, because it enhances ciliary activity and facilitates productive coughing by airway
dilation.12 These drugs also stabilize pulmonary
mast cells.1 Pretreatment with ␤2 adrenergic agonist bronchodilators is, therefore, a rational course
of action to aid in the prevention of medicationassociated bronchoconstriction.
Mucolytics
Removal of mucus from the airways depends on
viscosity, amount produced, and competency of the
clearance mechanisms. Mucolytic drugs decrease
the viscosity of mucus to enable more efficient transport up the tracheobronchial tree. Sterile water,
sterile saline, and N-acetylcysteine are all shown to
decrease the viscosity of mucus and are useful adjuncts to inhalant therapies.1 Aerosolized medications may induce bronchoconstriction, which
suggests that the concurrent use of a bronchodilator
may be beneficial.1
N-Acetylcysteineb displays an ability to alter
meconium’s physical properties, reducing meconium
viscosity by 99% in vitro.13 The mechanism of action involves the breakage of disulfide bonds. Because N-acetylcysteine alters protein structure, it may
also inactivate digestive enzymes shown to exacerbate
pulmonary damage after meconium aspiration.13
Equipment for the Practical Application of Aerosol Therapy
Aerosol delivery of medications (Table 1) may be
conveniently provided by usage of an in-line (jet)
small-volume nebulizerc (Fig. 1). Medication is
placed within the nebulizer jar, and the device is
fitted to a suitable face mask. This can be conveniently and cost effectively achieved by the usage of
a large dog-sized anesthetic mask or modification of
a plastic 1-gal container (Fig. 2). Alternatively, a
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NEONATOLOGY
Table 1.
Dosages of Drugs Suitable for Nebulization Therapy
Antimicrobials
Ceftiofur sodiuma
1 mg/kg q 6 h (author)
2.2 mg/kg q 24 h (Ref. 6)
2 mg/kg q 24 h (extrapolated from McKenzie5 by
author)
0.01–0.02 mg/kg q 12–24 h (author)
2–4 ␮g/kg q 12–24 h (author)
0.025 mg/kg q 6 h (author)
2–5 ml/50 kg q 6 h (Ref. 1)
2–5 ml/50 kg q 6 h (Ref. 1)
4–8 mg/kg q 6 h (Ref. 1)
Gentamicin
Anti-inflammatories
Bronchodilators
Mucolytics
Dexamethasone
Fluticasone
Albuterol sulfated
Sterile water
Sterile saline
N-acetylcysteine 20%b
proprietary product such as the foal-sized Aeromask
ESd can be used. Oxygen or compressed air-flow
rate is set to the nebulizer manufacturer’s recommendation (in this case, 8 l/min).
During nebulization, the foal is supported in sternal recumbency, if unable to rise, or in restrained
standing (Fig. 3). This is to ensure maximal ventilation of the lung fields because of minimal impediment to thoracic excursions. This also serves to
minimize areas of lung collapse (non-aeration)
caused by positioning of the patient.
The 6-ml nebulizer jar is sufficient to contain medications for the neonatal foal. Medication volume
can be adjusted up to 6 ml to achieve the desired
medication viscosity or antimicrobial concentration
by the addition of sterile water or other appropriate
liquid for dilution. This has the added benefit of
providing moisture to decrease the viscosity of respiratory secretions or aspirated materials such as
milk or meconium. The addition of a bronchodilator (albuterol sulfatee) may assist in countering
bronchoconstriction stimulated by other drugs.
Additionally, ciliary clearance is enhanced by ␤2 adrenergic stimulation.1 The total volume will be
nebulized in ⬃10 min, depending on the viscosity of
the solutions used in treatment.
3.
Results
Drug delivery by nebulization is a useful adjunct to
more conventional systemic therapies where diffuse
inflammation, direct airway irritation, and significant consolidation of lung parenchyma are present.
Aerosol therapy is expensive and time consuming;
however, it is safe, and there are few residual effects. Some degree of restraint is necessary with
fractious patients; however, care is needed to avoid
Fig. 1. Nebulization chamber. The nebulization chamber contains the medication through which the compressed gas flow is
forced to generate the aerosol. With this unit,c the manufacturer recommends an 8 l/min gas-flow rate.
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2008 Ⲑ Vol. 54 Ⲑ AAEP PROCEEDINGS
Fig. 2. Mask. An effective mask can be simply made by modification of a plastic 1-gal container. The nebulization chamber is inserted
in a location that makes handling the apparatus convenient.
NEONATOLOGY
Fig. 3. Foal being nebulized. To ensure the best distribution of aerosolized medications throughout the lung fields, avoid impediments to thoracic excursions by having the foal standing (preferred method) or sternally recumbent.
exacerbating respiratory distress caused by excessive struggling by the patient. Confinement by the
mask and the noxious smell of some aerosols (especially N-acetylcysteine) can worsen avoidance reactions by the foal.
Case 1:
Meconium Aspiration in a Newborn Foal
A 1-day-old foal was presented after birth because of
the rapid onset of depression and respiratory distress. Foaling had been assisted because of previously diagnosed placentitis leading to premature
placental separation. Severe meconium staining
was reported at birth. On examination, foal respiratory rate and effort were markedly increased, and
hypoxemia was present (Table 2). Ultrasonography showed widespread pulmonary pleural irregularities. Thoracic radiographs showed a widespread,
diffuse pulmonary interstitial infiltrate. Routine systemic antimicrobial treatment and supportive care
were initiated.
Nebulization therapy using an in-line (jet) smallvolume nebulizerc was started as follows: ceftiofur
(1 mg/kg, q 6 h; antimicrobial coverage), dexamethasone (0.01 mg/kg, q 12 h; anti-inflammatory),
N-acetylcysteine (4 mg/kg, q 6 h; mucolytic), and
albuterol sulfate (0.025 mg/kg, q 6 h; bronchodilation). All treatments were increased to a 6 ml total
volume with sterile water (mucolytic). Dexamethasone was decreased to once daily after 48 h. A total
of 4 days of aerosol treatment was given.
Respiratory rate and effort were appropriate with
hypoxemia resolved at 48 h. Follow-up thoracic radiographs at 5 days showed a marked decrease in
the interstitial infiltrate. The foal was discharged
on systemic antimicrobials.
Case 2:
Milk-Aspiration Pneumonia in a 4-Day-Old Foal
A 4-day-old foal presented after the onset of high
fever and the progressive onset of labored breathing.
A mild period of depression had occurred on the
farm at 48 h of age, and there was development of an
intermittent suckle reflex and loss of affinity for the
mare. Mild hypoxic ischemic encephalopathy was
diagnosed. The foal was supported by bottle feeding of milk and bolus IV fluids. On examination,
the foal was depressed with a 104°F fever and increased respiratory rate and effort (Table 2). A
white mucoid discharge was present bilaterally at
the nares. Auscultation of the lung fields detected
crackles and wheezes predominantly on the right
side and a loss of air sounds ventrally. Ultrasonography of the lung fields showed consolidation and
abscessation of the right cranioventral lung field.
An alveolar pattern was present on thoracic radiographs. A transtracheal aspirate recovered Streptococcus equi subspecies zooepidemicus. Routine
systemic antimicrobial treatment and supportive
care were initiated.
Nebulization therapy using an in-line (jet) smallvolume nebulizerc was begun as follows: ceftiofur
(1 mg/kg, q 6 h; antimicrobial coverage) and albuterol sulfate (0.025 mg/kg, q 6 h; bronchodilation).
All treatments increased to a 6 ml total volume with
sterile water (mucolytic).
Clinical signs of respiratory compromise rapidly
improved, and an appropriate respiratory rate was
achieved by the second day of treatment. A decreased frequency of treatment on day 3 led to deterioration in respiratory effort; this was resolved
when the original treatment schedule was restored.
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Table 2. Clinical Case Values
Rectal Temperature (°F)
Case 1
Admission
48 h
Case 2
Admission
48 h
97.4
100.5
124, gasping
56, normal
104
101.3
88, labored
62, normal
Abnormal auscultation findings resolved within
72 h. A total of 5 days aerosol treatment was given.
The foal was discharged on systemic antimicrobials.
4.
Discussion
Advantages and Disadvantages of Aerosol Therapy
The usage of inhalant therapies in companion animals has recently been reviewed.14 The ability to
localize treatments directly to the tracheobronchial
tree is the chief advantage of aerosol therapy.
Higher local concentrations can be achieved by bypassing gastrointestinal barriers that limit bioavailability
and avoiding metabolic inactivation. Therefore,
smaller total doses of drug can be used, which minimizes the potential for toxicity. The onset of aerosolized drug action is also more rapid compared with
systemic administration.
Disadvantages of aerosol therapy include complicated delivery systems, multiple daily treatments,
exposure of operators to the therapeutic agents, degree of hygiene required to ensure avoidance of infectious-agent transmission between patients, and
lack of drug penetration through obstructed airways
and areas of atelectasis. Aerosolized antimicrobials
and mucolytics may be irritating to the airways and
induce bronchoconstriction; therefore, they should be
administered with bronchodilator therapy.1
Clinical Syndromes
Because of the focus of this presentation, discussion
of the use of aerosol therapy will be limited to the
following conditions of importance to the neonatal
foal.
Pneumonia
Bacterial pneumonia has been described as the most
common cause of respiratory disease in foals. Bacterial pneumonia can be secondary to sepsis or prolonged recumbency in the devitalized neonate.
The most common bacterial organisms associated
with pulmonary disease in foals are the same as
those responsible for systemic sepsis, primarily
Escherichia coli, Streptococcus spp, Klebsiella pneumoniae, Pasturella spp, and Actinobacillus spp.
Less commonly, Salmonella spp, Pseudomonas spp,
and Staphylococcus spp are involved.15 Pneumonia
derived from sepsis tends to have a generalized distribution throughout the lung. Additionally, the
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PaO2 mmHg
52
93
64
102
development of deleterious responses to sepsis
(acute lung injury, respiratory distress syndrome)
can exacerbate severity of the bacterial disease.16
Aspiration of feed material or saliva can also contribute to the development of pneumonia, whether
during suckling or iatrogenically during assisted
feeding.17
The mainstays of infectious respiratory disease
treatment are oral and parenteral antimicrobials.
However, the low bioavailability of many drugs administered by these routes limits their concentration in the lung parenchyma and distal airways.18,19
Aerosol administration may allow higher concentrations of drug to be achieved at the site of infection
throughout the dosage interval.20 Delivery of gentamicin by aerosol caused antibiotic concentrations
in equine bronchial fluids to be higher than those
obtained after IV administration.5 Nebulization of
gentamicin, kanamycin sulfate, and polymyxin B
sulfate have been reported to be effective in foal
pneumonia.21
Meconium Aspiration
Meconium Aspiration Syndrome (MAS) has been
identified as an important cause of neonatal morbidity
and mortality. The free fatty acids in meconium displace surfactant, which results in additional atelectasis and decreased lung compliance.22 Meconium also
induces chemical pneumonitis accompanied by alveolar collapse and edema.23 Type II alveolar cells produce less surfactant, causing an increase in alveolar
surface tension and a decrease in compliance. The
resulting atelectasis leads to pulmonary vascular constriction, hypoperfusion, and lung-tissue ischemia.
Sloughed epithelium, protein, edema, and hyaline
membrane formation further contribute to respiratory
distress.24 The result is dysplasia of the respiratory
epithelium.25 Pneumothorax, pneumomediastinum,
or interstitial emphysema can result in severe cases.
The use of corticosteroids is beneficial. In one
human neonatal study of meconium aspiration,
there was a statistically significant difference in the
duration of stay, duration of oxygen dependence,
and radiological clearance between groups receiving
aerosolized corticosteroids and controls.26 The use
of steroids was not associated with an increased
incidence of sepsis.
NEONATOLOGY
N-acetylcysteine alters meconium’s physical properties by liquefaction. Less viscous and less sticky
meconium is easier to mobilize and remove from the
tracheobronchial tree. Even if not completely removed from the lung, liquefied meconium is less able
to cause mechanical obstruction and a “ball-valve”
effect in the airways.24
Although routinely given in cases of equine neonatal meconium aspiration, the usage of antimicrobials routinely in human neonates suffering
meconium aspiration without risk factors for sepsis
is controversial.27
Inflammatory Airway Conditions
The benefits of anti-inflammatory corticosteroid
therapies in the treatment of inflammatory pulmonary conditions of the horse are well known.28
Inflammatory syndromes of importance to the neonate include bacterial infection and aspiration of
irritant compounds (milk, meconium, particulate irritants, allergens, and noxious gases). Where the
potential for sepsis exists, antimicrobial treatment
should be used concurrently.
The application of adjunctive aerosol therapies
has considerably improved patient welfare and
treatment success in many cases of bacterial pneumonia and meconium aspiration at the author’s institution compared with systemic therapies alone.
Most notably, respiratory rate and effort both decrease to more normal levels in cases of pulmonary
infection and inflammation.
5.
Conclusion
The syndromes detailed above can all be expected to
derive clinical benefit from the application of aerosol
therapies. Control of infection, reduction of inflammation, enhancement of mucociliary clearance, and
reduction in viscosity of aspirated meconium are all
potential benefits of this technique. Direct delivery
of therapeutic drugs more readily enables effective
concentrations at the site of action (airways), because it bypasses barriers to absorption and metabolic degradation while having the potential to
minimize systemic side effects.
Treatment of pulmonary conditions in neonates
can be frustrating to the clinician. In the compromised neonate, prolonged recumbency and generalized debility favor the onset of pneumonic lung
changes. Inability to stand and feed unaided or the
lack of a normal suckle and swallow reflex all contribute to potential milk aspiration. Although parenteral therapies are favored in situations where
the neonate is critically ill, even drugs given by this
route are not always able to effectively penetrate to
the site of action required or last for a sufficient time
to enable a cure.
Although some equipment is required and technical staff needs to be educated on the technique, the
benefit cost is in favor of aerosol therapy. In-line
nebulizers and portable aerosol compressors are
readily and cheaply available from human medical
supply companies, and oxygen to provide a gas flow
is available in many clinic and ambulatory practice
situations. Drugs, because they are commonly
used in veterinary practice, have predictable microbial efficacies and reasonable cost.
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a
Naxcel (ceftiofur sodium), Pfizer, New York, NY 10017.
Mucomyst, American Regent, Shirley, NY 11967.
c
Hudson RCI Micro Mist nebulizer, Teleflex Medical, Research
Triangle Park, NC 27709.
d
Aeromask ES, Trudell Medical International, London, Ontario, Canada N5V 5G4.
e
Albuterol sulfate inhalation solution, USP 0.083%, Nephron
Pharmaceuticals, Orlando, FL 32811.
b