Continuous bronchodilator therapy during mechanical ventilation
New Technology Offers New Opportunities: Continuous Bronchodilator Therapy
Key words: aerosol, ventilator, nebulizer, pMDI, DPI
Mr. Fink was previously an employee of Aerogen, Inc., and involved in the
development of the Aeroneb vibrating mesh technology and its use in critical care
Patients with severe exacerbations of asthma, refractory to standard dose and
frequency of inhaled bronchodilators may benefit from continuous bronchodilator
therapy (CBT). CBT is commonly described in the literature for treatment of non-
intubated patients little has been written about appropriate techniques for CBT
during mechanical ventilation. Historically, lower respiratory tract deposition with
standard nebulizers is diminished in mechanically-ventilated patients compared to
ambulatory patients. Appropriate selection of techniques and devices can result in
deposition and efficacy during mechanical ventilation that equals of exceeds
delivery of aerosols in nonintubated spontaneously breathing patients. Multiple
factors -- including the type of aerosol generating device, particle size, placement in
the ventilator circuit, circuit humidity, flow rates and duty cycle --
efficacy of aerosol delivery and deposition in mechanically-ventilated patients.
Use of CBT in spontaneously breathing patients should serve as a basis for similar
application during mechanical ventilation.
The Need for Bronchodilator Resuscitation
Patients often arrive at the Emergency Department with severe exacerbation of
asthma or acute bronchospasm. Many of these patients have been taking their
beta agonist and failed to respond to standard doses prior to presenting in the
ED or clinic. A common response is to order another nebulizer treatment with
standard dose of bronchodilator, and if the patient continues not respond, to
ordering treatments at a high frequency until the patient responds. This strategy
requires several hours of delay in giving the patient relief, and hours of additional
Role of CBT
Several alternative strategies for bronchodilator resuscitation have been
advocated including high dose MDI with holding chamber, administration of
undiluted bronchodilators and high dose continuous nebulization. As we speak
of high dose bronchodilator administration, it is important to remember that
symptoms such as severe airway obstruction, with the
goal to provide the patient relief of their respiratory distress, with the greatest
improvement in airflow in the shortest period of time and a minimum of toxic side
effects, often while waiting for systemic anti-inflammatory agents to affect the
underlying pathology. In the absence of symptom relief, the more severe
patients become exhausted and require ventilatory support. This also
exacerbates the challenges of aerosol delivery in that standard jet nebulizers are
less effective during mechanical ventilation. Best methods for providing both
intermittent and continuous bronchodilator therapy (CBT) during mechanical
Clues to effective CBT during mechanical ventilation come from the literature
describing CBT in non-ventilated patients. A standard SVN treatment with 2.5
mg of albuterol takes 10 - 15 minutes to administer. When the patient fails to
respond, end on end treatments may be ordered until the patient “opens up”.
With severe exacerbation, a patient may receive up to 4 - 6 treatments in an
hour, equivalent to a nebulizer nominal dose of 10 - 15 mg of albuterol in an
hour. To be fair, the literature is mixed on the benefits of continuous vs high
frequency intermittent nebulizer therapy (1) The one clear benefit with CBT, is
the decreased requirement for personnel at the bedside during adminmistration.
And in the case of mechanical ventilation, the reduction of disruptions in
mechanical ventilation required to periodically remove and fill the SVN jet
CBT in non-ventilated patients
Candidates for CBT are patients who, despite frequent beta-agonist treatments,
remain in extremis with bronchospasm, dyspnea, cough, chest tightness, and
Papo et al (2) described a method of continuous nebulization in which a harvard
pump is adjusted to inject an albuterol/saline mixture into a SVN. A blender and
humidifier were incorporated to control oxygen concentration with higher than
ambient humidity. Papo found that continuous nebulization with pediatric
patients cømpared to standard intermittent treatments with SVN reduced the
duration of hospital stay (p<0.04), duration of therapy, therapist time (p<0.001)
and provided greater reduction in asthma score within one hour of therapy.
Moler et al. (3) described an SVN system using an infusion pump to continuously
fill the nebulizer, with a valved O2 mask and reservoir bag (figure 1).
Large volume nebulizers such as the HEART (Westmed) or Hope (Band
B) nebulizers have become commercially available to deliver CBT. A 20 ml
bottle of albuterol solution is mixed with 180 ml of .09% NaCl with dose roughly
regulation by changes in the flow rate driving the nebulizer (10 lpm 10 mg/hr
and 15 lpm 15 mg/hr). There is great variability in flow rate between individual
nebulizers of the same model, so dosing can vary a great deal (4). During CBT
patients are commonly placed in monitored beds with EKG and pulse oximetry.
If treatment extends beyond 3 hours, serum K+ should be monitored, with
repetition q 4h. Linn et al (5.) studied the effects of such dosage levels and
found minimal toxicity in treatment of acute exacerbation of asthma. The patient
must be observed for adverse drug responses, including worsening tachycardia,
palpitations, and vomiting. In these situations, the attending physician must be
A positive response is indicated by an increase in PEFR of at least 10% after the
first hour of therapy. The goal is to achieve a PEFR of at least 50% of predicted.
For small children, improved oxygenation (oxyen saturation by pulse oximeter
[SpO2] >92% on room air) with evidence of decreased work of breathing
indicates a favorable response. Once the patient “opens up,” intermittent
bronchodilator therapy can be resumed on a prm basis.
If you accept the premise that all of these methods of high dose
administration of albuterol have similar clinical effectiveness and safety, the
choice of method should be based on other criteria such as disruption of
mechanical ventilation, infection risk and personnel time.
CBT during mechanical ventilation
Many patients undergoing mechanical ventilation receive aerosolized
medications, with variable effects.(6) In cases in which bronchospasm does not
resolve with standard intermittent bronchodilator therapy CBT has been initiated.
To date, this has been most commonly relied on jet SVNs, with a port to allow
infusion of broncodilator into the nebulizer from an IV type infusion pump. This
allows refilling of the nebulizer without removing it from the ventilator circuit and
Although in vitro models demonstrate up to 40% higher aerosol delivery in a dry
ventilator circuit, the risks of increased airway irritability and bronchospasm
associated with administering cold dry gas through an endotracheal tube has
been well established. When performing CBT, do not turn off humidification.
Heat moisture exchangers (HMEs) act as a barrier to aerosol, and should be
removed from between the nebulizer and the patient airway.
Use of SVN During Mechanical Ventilation
Aerosol administered by common jet SVNs to intubated patients receiving
mechanical ventilation tends to be deposited mainly in the tubing of the ventilator
circuit and expiratory limb or filter. Under normal conditions with heated
humidification and standard jet nebulizers, pulmonary deposition ranges between
1.5% and 3.0%.(ref: egan chapter) When nebulizer output, humidity level, tidal
volume, flow, and I:E ratio are optimized, deposition can increase to as much as
15%. There are several disadvantages with SVN use during mechanical
ventilation in that they add additional flow through the circuit,
The addition of gas flow into the ventilator circuit may change parameters of flow
and delivered volumes requiring changes to ventilator parameters and alarm
settings both during and after nebulization. The smaller the patient, the greater
the impact of this additional flow into the ventilator circuit where 6 L/min of
additional gas flow can more than double tidal volumes and inspiratory
pressures, placing the patient at risk. Perhaps the greatest risk is the tendency
for condensate and secretions to drain into the nebulizer reservoir, contaminating
medication being delivered to the lungs. It is not uncommon for a nebulizer with
3 mL of drug to run for 30 minutes and be found to contain 4 mL of fluid. This
additional fluid is contaminated condensate which is then aerosolized and
Use of a VM Nebulizer During Mechanical Ventilation
The Aeorneb Pro and Solo (Aerogen) are vibrating mesh (VM) nebulizers with a
small plate that contains 1,000 funnel shaped apertures or holes. This plate (or
mesh) is domed and attached to a washer. The mesh is vibrated by a piezo
ceramic element that Is also attached to the washer, moving the plate up and
down by about 1 micron at 128kHz (or 1/10th the frequency of an ultrasonic
nebulizer). Liquid medication is extruded or pumped through the narrow end of
the apertures, about 3 micron In diameter, creating very small, consistent
particles. These apertures are so narrow, that gas from the ventilator does not
leak out during ventilation (even with heliox) and liquid placed in the reservoir
does not leak through the holes unless the nebulizer is actuated. The allows the
VM nebulizer to be refilled without removal from the ventilator circuit or
interruption of ventilation. The VM does not add gas into the ventilator circuit, so
no changes in ventilator parameters occur, even in neonates.
The Aeroneb® Pro is a multi-patient, autoclavable VM nebulizer, designed to
deliver aerosol for periods of 15 or 30 minutes. The Aeroneb Pro has been
shown to deliver between 10 - 20% of nominal dose past the endotracheal tube
during mechanical ventilation of both adults and infants without the addition of
gas into the ventilator circuit. The low residual drug volume and small particle
size are associated with higher efficiency. The Aeroneb Pro can be operated
properly in the ventilator circuit for up to one week without requiring removal from
the circuit for cleaning. The nebulizer reservoir can be opened without
interrupting ventilation, even with heliox administration.
The Aeroneb® Solo is a single patient use disposable nebulizer that can be
operated continuously for CBE. The inlet port as an adapter that can be attached
to a standard IV infusion set, and connected to an infusion or syringe pump to
allow filling of the nebulizer over extended periods of time. Testing with the
nebulizer has shown that it has similar performance and efficiency as the Pro.
Unlike both jet and ultrasonic SVNs, the medication reservoir of Aerobeb Pro and
Solo nebulizers is superior (above) the ventilator tubing, reducing the risk of
contamination from circuit condensate to the medication in the reservoir.
Use of CBT
In order to use any nebulizer for CBT during mechanical ventilation it is important
the maximum rate infusion of medication into the nebulizer does not exceed the
mimimum output rate of the nebulizer. Overflow of the nebulizer with SVNs
obstruct the ventilator circuit and patient airway while compromising ability of the
nebulizer to function, reducing drug delivery. With the vibrating mesh nebulizer,
overflowing the reservoir does not affect the ventilator circuit or nebulizer
function, but wastes medication and can be messy.
Nebulizer manufacturers should provide minimum output rates for their products
under standard operating conditions, however individual units, even of the same
type of nebulizer may vary. Nebulizer output rate can be quantified by placing a
known volume of medication into the nebulizer reservoir, and noting the time
from turning on the nebulizer and the point that aerosol is no longer produced.
SVNs have residual drug volumes as high as 1.5 mL, so larger volumes should
be used for testing. Since SVNs begin to stutter and output decreases near the
end of dose, output rates should be determined gravimetrically. For SVNs, weigh
the loaded nebulizer prior to aerosol generation, run for one minute, weigh again
and determine the difference in weight. For water or albuterol sulfate, 1mg is
equivalent to 1 mL. This will provide the mL/min.
With the Aeroneb Solo, place a known volume of liquid in the nebulizer (100 µl,
0.5 mL or 3.0 mL). Measure time from beginning to end of aerosol generation.
Output rate does not vary with dose volume and it is easy to determine when
aerosol generation is complete since there is no period of sputtering, and aerosol
output simply stops. Determine output by dividing dose volume by time of
Once the minimum output rate of the nebulizer is determined, the rate of flow
into the nebulizer should be determined by the amount of bronchodilator you
wish to nebulize each hour (e.g., 10, 15 or 30 mg/hour). Keep in mind that
pulmonary deposition efficiency will vary between types of nebulizer and
differences in ventilator parameters. Consequently, dose rate should be titrated
based on patient response. For beta- agonists, changes in heart rate or
presence of tremor suggest that the rate is too high and should be lowered.
Techniques for assessing the response to a bronchodilator in intubated patients
undergoing mechanical ventilation differ from those used in the care of
spontaneously breathing patients because (1) expiration is passive during
mechanical ventilation, (2) forced expiratory values (PEFR, FVC, FEV1) cannot
normally be obtained. Additional techniques can be used for mechanically
ventilated patients because (1) a change in the differences between peak and
plateau pressures (the most reliable indicator of a change in airway resistance
during continuous mechanical ventilation) can be measured, (2) automatic
positive end-expiratory pressure (auto-PEEP) levels which may decrease in
response to bronchodilators (see Chapter 41), and (3) breath-to-breath variations
make measurements more reliable when the patient is not actively breathing with
Fink J, Dhand R. Bronchodilator resuscitation in the Emergency
Department, Part 2: Dosing. Respir Care 2000.45:5: 497-510.
Papo MC, Frank J, Thompson AE. A propsective, randomized study of
continuous versus intermittent nebulized albuterol for severe status
asthmaticus in children, Crit Care Med 1993;21:1478-86.
Moler FW, Johnson CE, Van Leanen C, Paomissano JM, Nasr SZ,
Akingbola O. Continuous versus intermittent nebulized terbutaline:plasma
levels and effects. Am J Respir Crit Care Med 1995;151:602-6.
Fink JB. Aerosol device selection: evidence to practice. Respir Care
Lin RY, Smith AJ, Hergenroeder. High serum albuterool levels and
tachycardia in adult asthmatics treated with high-dose continuously
aerosolized albuterol. Chest 1993; 103:221-5
Fink JB ,and Dhand R. Aerosol therapy in mechanically ventilated
patients: recent advances and techniques. Seminars in Respir and Crit Care
Fink JB. Aerosols in mechanical ventilation: a revolution in the making.
Duarte AG, Fink JB, Dhand R. Inhalation therapy during mechanical
Respir Care Clin N Am. 2001 Jun;7(2):233-60, vi. Review.
Table 1: Factors affecting respiratory tract deposition during mechanical
Physicochemical properties of medication
Aerosol generating characteristics of delivery device
Ventilator circuitry and endotracheal tube
Table 2 - Comparison the Aeroneb Pro (continuous) and three common jet
nebulizers during adult mechanical ventilation. Particle size, fine particle fraction,
residual volume and dose of albuterol sulfate delivered to the distal tip of an
Figure 1: OnQ vibrating mesh technology. The Aerogen OnQ™ aerosol
generator (left) with a microscopic view of tapered apertures (upper middle), and
cross section of apertures (upper right). High speed microscopic photograph of
aerosol generated from a single aperture (lower right).
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