it is diverse topic and with content not evenly distributed.
it covers all guidelines, short comings, and recommendations from latest journals and standard text book.
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Humidification & inhalation therapy
1. HUMIDIFICATION AND
INHALATION THERAPY
Dr Ankit Purohit
Academic SR,
DNBSS, CCM
Dr Sandeep Kumar,
Associate Consultant,
Department of Critical Care Medicine,
ABVIMS & Dr RML Hospital,
New Delhi.
2. What is Humidification
• Respiratory humidification is method of artificially
warming and humidifying of respiratory gases for
mechanically ventilated patients.
• RESPIRATORY GAS CONDITIONING
1) Warming
2) Humidification
3) Purification
• Naturally, the function is performed by upper
airway and lungs.
3. Outlook of topic
1) Physical principles
2) Physiology
3) Guidelines
4) Type of humidifiers & Devices.
4. Physical principles
Absolute humidity (AH) – mass of water vapour in volume of gas at a temperature, when
saturated.
Relative humidity (RH) – Percent saturation, it is percentage of amount of total water
vapour, that can be contained by gas when saturated, at the temperature.
REF – 1)Dorsch & Dorsch.
2) Plotnikow et al; Humidification and heating of inhaled gas in patients with artificial airway. A narrative review. Res
Bras Ter Intensiva 2018;30(1): 86 -97.
5. Interrelationship between AH and RH
• Gas saturated with water vapour, once heated, its capacity to
retain water vapour increases.
• So gas at room temperature( 27◦C), fully saturated, when
enter the respiratory tract and attains 37◦C, would become
desaturated.
• The gas would absorb water from respiratory mucusa, till it
becomes saturated.
• So gradually desiccation of mucusa would occur.
• Hence, optimal conditioning of air for mechanically breathing
patient is required.
REF – Dorsch & Dorsch
6.
7. Physiology of conditioning
• 75% of conditioning takes place in upper airway, rest 25% in
lungs.
• Upper airway cleans and humidifies air ranging from 1000 l to
21,000 litres, everyday, depending on body size and activity.
8. Warming
• Network of capillaries & resistive vessels underlying
nasal and oral mucosa, performs function of
warming.
• Inhaling cold air increase blood flow to mucosa.
• Blood is regulated by autonomic nervous system.
• Diameter of resistive vessels is mediated by SNS,
while PSNS regulates glandular secretions.
• Temperature of nasal mucosa is approx 32◦C.
• Nasal turbinates and conchae generate current in
inhaled air, moving them through sinuses, leading to
warming.
9. Isothermal Saturation Limit
• Isothermal Saturation Limit – The point at airway where
inhaled gas acquires full water vapour saturation at 37◦C . At
4th or 5th generation bronchi.
• Critical as at this limit air doesn't damage mucosa & ciliary
epithelium.
• Artificial respiration require the limit to be obtained at level of
carina.
REF -1) Plotnikow et al; Humidification and heating of inhaled gas in patients with artificial
airway. A narrative review. Res Bras Ter Intensiva 2018;30(1): 86 -97.
2) Andrew D Bersten; Humdification and inhalational therapy, Oh’s intensive care manual;
6th edition.
11. Humidification
• Humidification is progressive as air moves down track.
• Occurs till isothermal saturation point.
• Under normal resting conditions, 250 ml of water is lost in 24
hours & 350 kcal of energy.
• During expiration, upto 25% of moisture is retained by
mucusa. Preserved via condensation.
• Ciliary function is reduces at RH 75% at 37◦C ( AH of 32 gm/m3
) & ceases at RH 50% at 37◦C.
• It is recommended, AH> 33 gm/m3 to be maintained for
normal ciliary function.
13. Mucociliary function; Cleaning
• Clearance of surface particles depends on –
1) Beating cilia.
2) Airway mucus.
3) Transepithelial water flux.
• mucus is derived from goblet cells, Submucosal glands &
Clara cells & capillary transduate.
• Conducting airways lined with pseudostratified, ciliated
columnar epithelium.
• On descending, airway epithelium gradually turns stratified
and cuboidal having less ciliated cells.
• Cilia beats at rate of 10 mm/min at 37◦C and RH 100%.
14. Factors Affecting mucociliary function
1) RH & temperature of
inhaled air.
2) URTI
3) Chronic bronchitis.
4) Cystic fibrosis.
5) Bronchiectasis.
6) Immotile Cilia syndrome
(Kartagener’s syndrome).
7) Dehydration.
8) Hyperventilation.
9) Anesthesia, Opioids,
Atropine
10) Exposure to noxious gases
11) High FiO2 .
12) Beta agonist improve
nasociliary function.
15. Adverse effects of decreased humidification
1) Increased mucus viscosity.
2) Depressed ciliary function.
3) Cytological damage to the tracheobronchial epithelium,
including mucosal ulceration, tracheal inflammation and
necrotising tracheobronchitis.
4) Microatelectasis from obstruction of small airways, and
reduced surfactant leading to reduced lung compliance
5) Airway obstruction due to tenacious or inspissated sputum
with increased airway resistance.
6) Metaplasia of the tracheal epithelium occurs over weeks to
months in patients with a permanent tracheostomy.
16. Bioaerosol
• Defined as collection of particles suspended on a column of air derived
from or incorporating material of biological origin.
• Particles < 100 microns are in inhalable range.
• Airborne dissemination depends on air mass movement, turbulence and
thermal convection.
• Mass Median Aerodynamic Diameter(MMAD) decreases with increase
distance of spread.
• Particles 1 to 100 micron. Particles >8 micron get trapped to airways,
thrown out by cilia.
• Particle size 1 – 3micron reach alveoli and deposits there.
• Aerodynamic size 0.5 – 5 micron have maximum tendency to reach alveoli.
17.
18. REF – Thomas R; particle size and pathogenecity in the respiratory tract; virulence4:8, November 2013,847-
858. Landes Bioscience.
19. Ideal Humidification
1) The inspired gas is delivered into the trachea at 32–36°C with a
water content of 30–43 g/m3.
2) The set temperature remains constant and does not fluctuate.
3) Humidification and temperature remain unaffected by high flows.
4) The device must be simple to use and to service.
5) The humidifier could be used with spontaneous or controlled
ventilation.
6) There must be safety mechanisms, with alarms, against
overheating, overhydration and electrocution.
7) The resistance, compliance and dead-space characteristics must
not adversely affect ventilation.
8) The sterility of the inspired gas must not be compromised.
REF- Andrew D Bersten; Humdification and inhalational therapy, Oh’s intensive care manual;
6th edition
20. Guidelines
• DESCRIPTION-
1) Upper airway gives 75%
humidification and warming.
2) Optimal required moisture at
carina at 37◦C with optimal RH 44
mg/l. Temperature range (34◦C –
41◦C).
3) Inspired gas with temperature
>37◦C & 100% RH, gives reduces
viscosity and increased
pericellular fluid depth.
21. Indications & Settings
• Humidification –
1) Critical care, acute care, operating theatre, transport.
2) Humidification is inspired gas during mechanical ventilation
is mandatory for ETT and tracheostomy.
3) Humidity level 33 mg/l to 44 mg/l at temperature between
34◦C to 41◦C.
4) Optional for NIV - Heated humidifier provides better CO2
clearance and lower work of breathing than does heat-and-
moisture exchanger, because heated humidifier adds less
dead space.
5) Inspired gas should never exceed 41◦C and alarm set at 43◦C.
22. Types of Humidifiers
• PASSIVE – Heat and moisture exchangers with filter.
• ACTIVE – 1) Unheated bubble type.
2) Heated ; pass over ( stream of gas over heated
water)/ Blow by ( Stream of gas passing over wicks dipped in water)
23. HME( heat moist exchangers)
• Efficient, simple & convenient passive humidifiers used in ICU.
• Principle of heat and moisture conservation of expired air.
• Simple condensers made of disposable foam, synthetic fibers
or paper.
• Have large surface area to create entrapping heat and
moisture of exhaled gas.
• Retained heat and moisture is delivered in next inspired
breath.
• Modern HME are light with dead space of 30 – 95 ml.
• They have male and female connectors of 15 mm or Y piece
connector of 22 mm (concentric).
24. REF - Plotnikow et al; Humidification and heating of inhaled gas in patients with artificial
airway. A narrative review. Res Bras Ter Intensiva 2018;30(1): 86 -97.
25. Hygroscopic HME
• Also known as Hygroscopic condenser humidifiers.
• Made of synthetic fiber coated with hygroscopic
material(Calcium chloride or Lithium chloride)
• Synthetic fiber help to decrease accumulation of condensed
water.
• Tends to increase their efficiency ( AH around 30 g/m3)
compared to hydrophobic HMEs (i.e. AH 20–25 g/m3).
• DRAWBACK – 1) tend to loose filtration efficiency when wet.
2) resistance increases on being wet.
26. Hydrophobic HME
• Contains hydrophobic membrane with small pores.
• Moderate humidity (RH at 37◦C of 25 mg/l).
• Efficient bacterial and viral filter.
• Prevent transmission of Hepatitis C virus.
• Better than hygroscopic filters.
• Allow only small passage of water vapour.
• Add less resistance to circuit, when wet.
• DRAWBACK – high ambient temperatures decrease its
performance.
27. HME with filter
• Filter material is embedded with electrostatic charge.
• The charge help to prevent flow of bacteria & viruses.
• Types of available filters
1) HMEF – heat moisture exchanger with filter.
2) HCHF – Hygroscopic condenser humidified filter.
3) HHMEF – Hygroscopic heat and moisture exchange filters.
• HMEF have not shown to reduce the incidences of
nosocomial pneumonia, as they are mostly attributed to
aspiration.
28. Combined HME
• Contain both hygroscopic and hydrophobic elements.
• Better performance than hygroscopic ones.
• They have better retention of moisture and maintain humidity
levels to 30 mg/l at 37◦C.
29. Comparison of hydrophobic & hygroscopic HME
• Type
1) Heat moisture
exchanging capacity
2) Effect of increased
TV
3) Filtration efficiency
(dry)
4) Filtration
efficiency(wet)
5) Resistance (dry)
6) Resistance(wet)
7) Effect of nebulisation
Hygroscopic
Excellent
Slight decrease
Good
Poor
Low
Slight increase
Great increase in
resistance
Hydrophobic
Good
Significant decrease
Excellent
Excellent
Low
Slight increase
Little effect.
30.
31. HME for aerosol Therapy
• Gibeck Humid –Flo
• Remain in line with circuit
during application of aersols.
• Reduce opening &
contamination of breathing
circuit.
• HME mode – conventional
• AEROSOL mode – aerosol
directly reach patient without
contacting humidifier.
• REF - Plotnikow et al; Humidification and
heating of inhaled gas in patients with
artificial airway. A narrative review. Res Bras
Ter Intensiva 2018;30(1): 86 -97.
Gibeck® Humid-Flo Heat & Moisture
Exchanger (HME)
32. HME Booster
• Hybrid active humidifier.
• ‘T’ connector contain self regulated heater.
• Small volume chamber for continuous
infusion of distilled water.
• Upper part of device has hydrophobic
membrane to allow passage of water, only
when it evaporates.
• Dead space is only 9 ml.
• Active humidification & passive retention
during expiration.
• Advantage –
1) Easy to use
2) Have bacterial filter.
3) Useful for hypothermic patient.
4) Eliminates excessive condensation in
tubing
• Disadvantage –
1) No temperature monitoring.
2) Increased resistance.
3) Require source of electricity
33. Dead Space of HME
• Higher volume of condenser material will yield better
performance.
• Ideal dead space for humidifier is 50 ml, for standard adult
patients.
• Dead space is compensated by increasing Ventilatory minute
volume.
• Additional dead space leads to CO2 retention.
• This increase work load of breathing in patients.
• HME with smaller dead space volume have been developed.
• Low humidification capacity and it worsens with increase in
TV and supplementary O2.
34. Resistance
• Normally unused HME have low resistance; 5 cmH2O/sec.
• It increases with impaction of secretions, condensation of
water, increase in flow and TV.
• So it is important to change filters regularly.
35. Volume of HME & Relation to Humidification capacity
• Internal volume of HME & AH
are factors affecting delivery of
humidity to patient.
• Eckerbom et al, conducted
study relating dead space of
HME to AH.
• They found poor correlation.
• But they used only 6 devices.
36. Volume of HME & Relation to Humidification capacity
• Branson et al conducted similar study with more devices.
• Excluding bacterial filter, they found strong correlation (r = 0.91, p < 0.0001).
• The ratio of delivered AH to Dead space in ml is efficacy measure for device.
• Humidifiers reach level recommended of 30 mg/l at 60 ml dead space.
37. Performance of HME & Minute volume
• Increase in MV decrease the humidification of HME.
• Decrease in delivery of AH with increase in TV.(Lucato et al,
Eckerbom et al).
• The flow has variable effect on performance (Unal et al).
• In 2014, Lellouche et al found no effect of minute ventilation
and room temperature on performance of new generation
devices.
• MV = TV X Resp frequency.
• Eckerbom et al & Branson et al, found TV to be affecting factor
on performance of device.
• Increasing TV decreased performance.
38. HME & Time of contact with air
• Eckerbom et al , found no comparable differences between
delivered humidity , when compared to time of contact of
inspired air at 1st second & 2nd second.
• Branson et al found, as expiratory flow increases, the time of
contact between the gas and the HME decrease with decrease
in the AH delivered to the patient.
39. Time of changing HME
1) Due to excessive condensation increasing resistance of
circuit.
2) Visible impaction of blood or secretions.
3) In COPD patients, every 48 hours.
4) 96 hours to 1 week in remaining patients.
40. Indications
1) Preferred first device for humidification while initiating
mechanical ventilation.
2) In OT, while performing elective surgeries.
3) Transporting intubated patient.
4) On tracheostomized patients, breathing spontaneously.
5) On supraglottic airway, to supplement oxygen,by connecting
oxygen tubing to gas sampling port.
41. Contraindications for HME
1) In patients with bloody thick mucus secretions.
2) When expired TV is less than 70% of inspired
(bronchopleurocutaneous fistula, ETT cuff malfunction).
3) In pediatric age group, increase dead space.
4) In acute respiratory failure , HME increase work of breathing.
5) When patient temperature is less than 32◦C.
6) When patient has high spontaneous minute
ventilation.(relative)
7) When patient is being nebulised, HME to be removed.
8) NIV, large mask leak.
42. Active Humidifiers
• Electric heater placed in plastic casing with metal base in
which sterile distilled water is placed.
• Parts –
1) Humidification chamber – clear chamber disposable, made f
plastic.
2) Heat source – supplied by heating rods immersed in water or
heating case at bottom of container.
3) Inspiratory tube- it carries heated humidified air. It contains
heated element to maintain temperature.
4) Temperature monitor – temperature sensors placed at
inspiratory end and at thermostat.
5) Thermostat (SERVO CONTROLLED) – it is equipped with
temperature sensors and autoregulation .
43. Bubble type Humidifiers
• The gas flow passes through the water
level (bubbled through).
• May be heated or non heated.
• Rising air gains temperature and
humidity.
• Amount of water and Flow rate affects
the humidification.
• Higher water column, more air water
interfacing.
• Increased flow , decreased performance.
• Inexpensive, but are inefficient.
• Water content of around 9m g/l (i.e.
about 50% RH at ambient temperatures).
• They are also a potential source of
microbiological contamination.
• Leads to aerosol formation, source of
infection.
44. Pass over humidifiers
• Air flows over the heated water
interface.
• Attains humidity and gain the
temperature.
• The water bath temperature is
thermostatically controlled (e.g. at 45–
60°C) to compensate for cooling along
the inspiratory tubing, targeting an
inspired RH of 100% at 37°C.
• A heated wire is seated in the inspiratory
tubing to maintain preset gas
temperature and humidity.
• They produce microdroplets (<5
microns), decreased probability of
infection.
REF – Haitham et al; Humidification during Mechanical Ventilation in the Adult Patient; Hindwai, May 2014.
45. Wick & Hydrophobic membrane Humidifiers
• Porous membrane absorbs humidity as it is dipped in water.
• The dry air enters chamber and comes in contact with water saturated wicks.
• It increases gas liquid interface.
• Hydrophobic membrane humidifiers, gas passes through membrane and attains water
vapour.
46. Standard Requirement for humidifiers
1) Must produce an output of
10 mg/l of water. For
supraglottic airways, it is
33mg/l.
2) Average temperature at
delivery outlet would not
exceed by 2◦C from set
temperature.
3) Volume of liquid exiting
humidifiers will not exceed
1 ml/min or 20 ml/hr. For
neonates, it is 5 ml/min or
20 ml/hour.
4) Maximum temperature set
at gas delivery outlet is 41◦C.
5) Accessible surface
temperature of the delivery
tube must not exceed more
than 44◦C within 25 cm of
connection port.
6) All calibrated controls must
be within 5% of their range.
7) Flow direction should be
marked on humidifiers.
47.
48. Hazards & complications
1) Potential for electrical shock.
2) Hypothermia when Heated humidifier(HH) is inadequately
set.
3) Hyperthermia due to overheating.
4) Burn injury or melting of circuit due to heated wires.
5) Underhydration ( <26 mg/l of AH).
6) Hypercapnia due to added dead space with inadequate air
flow.
7) Condensation of water in circuits leads to rise in nosocomial
infection.
49.
50. Inhalational Therapy
• Route of choice to deliver drugs for respiratory disorders.
• Provides high concentration at pulmonary site and less
systemic concentration.
• This accounts for less side effects.
• PHARMODYNAMIC AIRWAY SELECTIVITY –
1) ratio of pulmonary efficacy to airway selectivity.
2) It is favourable to this route.
3) Faster onset of action with less systemic side effects.
51. Inhalational therapy
• Lungs should not be considered as single organ.
• Various morphologic structures, network of intricate airways,
bronchioles , capillaries and interstitial tissues.
• Lungs have unique Pharmacokinetics(PK).
• Multiple PK processes with each one having unique
characteristics & have their interplays.
• Depends on aspects of inhaled medications, their
physiochemical characteristics of the drugs, drug formulation
& Inhalational device.
52.
53. PHARMACOKINETICS
1) Drug or droplet deposition
2) Drug dissolution in the lung fluids
3) Mucociliary clearance in the larger airways & macrophage
clearance in the alveolar space.
4) Absorption of the drug in lung space
5) Pulmonary tissue retention and metabolism
6) Absorptive blood clearance.
54.
55. Drug particle/ Drug deposition
• Total dose in device, a fraction is deposited in device only.
• LUNG DOSE – amount of drug deposited in lungs.
• Central (larger airways) and peripheral (smaller airways)
• Deposition depends on
1) Aerodynamic size
2) Inhalational flow
3) Device characteristics
4) Disease related factors
• Independent of drug own physiochemical characteristics.
56. Aerodynamic particle diameter
• It the diameter of particle aerosol generated from device.
• 0.5 – 5 microns size easily deposited at the airways.
• Smaller particles (1-3 microns), more peripheral distribution.
• Larger (>5 microns) distributed at the larger airways, mouth
throat areas.
1) Inertial impaction- large particle travel less, deposit at early.
2) Maximum airflow velocity – cause larger particle to impact
on airways. Faster rate less peripheral deposition and vice
versa.
3) Sedimentation – smaller particles. Due to gravity. Enhanced
by breath holding once inspiration is over.
4) Diffusion or Brownian motion - submicron particles.
57.
58.
59. Pulmonary Drug Dissolution
• Particles to diffuse through fluids of lung epithelium.
• Depends on
1) Drug formulation
2) Physiochemical drug properties.
3) Physiologic factors.
• Biphasic gel (mucus)– aqueous layer present at
CONDUCTING AIRWAYS. Mucus hinders absorption.
• Surfactant & alveoli fluid at alveolar level. Surfactant
enhance absorption.
• Properties of drug – free water soluble drugs(albuterol)
diffuse easily into pulmonary lining. Fat soluble lesser
diffusion.(steroid)
• Slow dissolution is rate limiting factor.
60.
61. Mucociliary & Phagocytic Clearance
• Upward movement of mucus by underlying beating cilia of
epithelium.
• Drugs particles here are transported to pharynx and
undergoes GI absorption.
• Larger airway diameter , faster clearance.
• Mucus thickness and higher viscosity decreases the
mucociliary clearance.
• Phagocytic - macrophages at alveoli phagocytise drug.
• Slower than mucociliary.
62.
63. Absorption to lung tissue
• Lipophilic drugs are more rapidly absorbed once dissolution
through diffusion occurs.
• Hydrophillic drugs undergoes paracellular diffusion through
aquaporin pores at gap junction.
• Physiologic characteristics of pulmonary environment .
1) Phagocytosis increases absorption.
2) High perfusion at pulmonary level increase the absorption.
3) Large alveolar surface area.
4) Epithelial layer thickness.
64. Pulmonary tissue retention and tissue thickness
• Physiochemical characteristic –
1) Tissue affinity.
2) Pulmonary tissue partition coefficient.
• partition coefficient is the ratio of the concentration of a
substance in one medium or phase (C1) to the concentration in a
second phase (C2) when the two concentrations are at
equilibrium.
• Here, ratio of amount of drug at outside to inside. Defines
convenience of diffusion.
• Patient specific characteristic - Alveolar membrane interface.
• LONG ACTING BETA AGONIST. – low permeability, longer
retention.
• Long permeability – enhanced efficacy.
• Metabolising enzymes - CYP1A1 CYP2E1, more active in smokers.
65. Absorptive drug Clearance to systemic perfusion
• Largely dependent on perfusion.
• Larger airways have lower perfusion so less drug absorption.
• Alveoli have fluent absorption of drugs.
• Short half life of same drug.
• Despite high tissue retention of drug in alveoli, rapid diffusion
to circulation, makes drug short acting. In larger airways, long
tissue retention means , longer half life as drug reached
circulation at constant rate.
76. HIGHLIGHTS
• MDI showed highest dose
deposition, administering at Y
piece of circuit.(38% of nominal
dose).
• Constant output jet nebulizers
deposited only3 – 7% of
nominal dose.
• Inspiratory synchronized jet
nebulizers deposited 1 – 16% of
nominal doses.
• Constant output nebulizer
deposited 5% of nominal doses.
• SPECT CT showed 33% & 17%
deposition of drug to right and
left lungs, when drug is directly
instilled to ETT.
• Post operative intubated
patients SPECT CT is showed
predominant proximal
deposition of nebulized drugs.
• Jet nebulizers showed 50% of
ND retained in resevoir and T
piece.
• 15 – 30 % with ultrasonic
nebulizers.
• 3 – 10 % with vibrating mash
nebulizers.
• 10 – 44% was trapped in
circuits.
• No data on MDI
77. Administration technique
• Nebulizer placed at inspiratory limb.
• Vibrating mash type preferred.
• TV – 8 ml/kg, respiratory rate 12 /min (to prevent expiratory
phase loss).
• Flow rate of 30 l/min with end inspiratory pause of 20%.
• Heating humidifier system not to be used.
• 63% of ND reached airways and only 37% deposited at
circuits.
78.
79. Highlights
1) ARDS- limited to patients with optimal ventilation,
maintianing PEEP and on IRV. NO is introduced when they
have PaO2 less than 90 mmHg at Fio2 100%.
2) RV failure due to PULMONARY HTN - defined as severe RVF
with PUL HTN( mean PAP >24 mmHg), PVR > 400
dyne/sec/cm5. NO decreases PAP and PVR and help alleviate
RVF. 20 – 40ppm.
3) If there is no response to 20 ppm dose for 30 minutes (more
than 20% rise of PaO2), it is increased to 40 ppm.
4) Toxicity – methemoglobinemia, mucous membrane irritation.
87. Highlights
• Nebulised antibiotics were
associated with higher rate of
clinical cure.
• No association was found with
microbiological cure, improved
mortality, duration of
mechanical ventilation, ICU
length of stay & renal toxicity.
• Used as adjunct to main
therapy.
• Delivery of aerosolized particles
to lungs
1) Ultrasonic or vibrating mesh
type nebulizers are best.
2) Spontaneous ventilator modes
are associated with high
turbulent flows and more
proximal distribution of drug
3) Ventilator circuits should have
smooth surface and no acute
angle connections.
4) HME removed.
88. Epinephrine Nebulisation in children
• Numa et al ,in their article, the effect of nebulized
epinephrine on respiratory mechanics and gas exchange,
Resp critical care med journal, 2001.
1) Gave 0.5 mg/kg epinephrine (undiluted) with maximum dose
of 5 mg to infants with bronchiolitis, asthma.
2) They measured respiratory mechanics and hemodynamics.
3) They found decrease in total resistance in airway pressure
post nebulisation.
4) There was rise in heart rate and mean BP post nebulisation.
5) Oxygenation and ventilation didn't show much improvement.
89. 1) They found no difference in length of hospital stay in infants of
bronchiolitis.
2) They recommended use of nebulised epinephrine in hospitalized infants
only as rescue agents.
3) There is no good evidence to support treatment with nebulized
epinephrine in infants.