Inhaled bronchodilator administration during mechanical ventilation: how to optimize it, and for which clinical benefit?

Volume 21, Number 1, 2008
Mary Ann Liebert, Inc.
Pp. 85–95
DOI: 10.1089/jamp.2007.0630

Inhaled Bronchodilator Administration During Mechanical Ventilation: How to Optimize It, and CLAUDE GUERIN, M.D., Ph.D.,1,2 THOMAS FASSIER, M.D.,2 FRÉDÉRIQUE BAYLE, M.D.,2 STÉPHANE LEMASSON, M.D.,2 and JEAN-CHRISTOPHE RICHARD, M.D., Ph.D.1,2 ABSTRACT
Bronchodilators are frequently used in ICU patients, and are the most common medications
administered by inhalation during mechanical ventilation. The amount of bronchodilator that
deposits at its site of action depends on the amount of drug, inhaled mass, deposited mass,
and particle size distribution. Mechanical ventilation challenges both inhaled mass and lung
deposition by specific features, such as a ventilatory circuit, an endotracheal tube, and ven-
tilator settings. Comprehensive in vitro
studies have shown that an endotracheal tube is not
as significant a barrier for the drug to travel as anticipated. Key variables of drug deposition
are attachments of the inhalation device in the inspiratory line 10 to 30 cm to the endotra-
cheal tube, use of chamber with metered-dose inhaler, dry air, high tidal volume, low respi-
ratory frequency, and low inspiratory flow, which can increase the drug deposition. In vivo
studies showed that a reduction by roughly 15% of the respiratory resistance was achieved
with inhaled bronchodilators during invasive mechanical ventilation. The role of ventilatory
settings is not as clear in vivo
, and primary factors for optimal delivery and physiologic ef-
fects were medication dose and device location. Nebulizers and pressurized metered-dose in-
halers can equally achieve physiologic end points. The effects of bronchodilators should be
carefully evaluated, which can easily be done with the interrupter technique. With the non-
invasive ventilation, the data regarding drug delivery and physiologic effects are still lim-
ited. With the bilevel ventilators the inhalation device should be located between the leak
port and face mask. Further studies should investigate the effects of inhaled bronchodilators
on patient outcome and methods to optimize delivery of inhaled bronchodilators during non-
invasive ventilation.

halation route is to enhance the therapeutic/tox-icity index of the agent. However, a drawback is BRONCHODILATORSAREFREQUENTLYUSEDin ICU lack/variability in efficiency. Because the clini-
patients receiving invasive mechanical venti- cal/physiological efficiency largely depends on lation (IMV) and commonly delivered through amount of drug available at its site of action, the inhalation route.(1) The main advantage of in- namely 2 or muscarinic receptors in the smooth 1Creatis INSERM, CNRS, Lyon, France.
2Service de Réanimation Médicale, Hôpital de la Croix Rousse, Lyon, Université Claude Bernard, Lyon, France.
muscular cells in the wall of the bronchial tree,and given that there are numerous causes of druglosses in intubated patients, it has long beenthought that inhaled bronchodilators are ineffec-tive or exhibited markedly variable clinical ef-fects. Bench studies have shown that it should benot the case if the drug inhaled mass and de-posited mass are properly measured(2,3) and ven-tilator-related key factors involved in the drugdelivery carefully controlled.(2,4) A substantialamount of nebulized drug may actually reach itstarget in patients,(4) and guidelines have been de-veloped to optimize the administration of agentduring IMV.(3,5) With increasing use of noninva-sive ventilation (NIV) in ICU,(6) the issue of the Schematic drawing of the experimental setup to efficiency of inhaled bronchodilators in this set- measure the pharmacological determinants of aerosol de- ting has also to be examined. This review will go position and to test the effects of various ventilator-re- over pharmacological concepts of the aerosol ad- lated factors on the drug lung deposition applied to in- ministration, devices used to generate aerosol, vasive mechanical ventilation. The pneumatic nebulizeris filled by the active drug and fed by the gas from the ventilator-related factors for an optimal delivery ICU ventilator at the recommended specific flow (usu- of drug inhaled during IMV and NIV, indications ally 6–8 L/min). The nebulizer is activated during the in- and effects of inhaled bronchodilators in ICU pa- spiratory phase (black-filled arrow), the tidal volume be- tients during mechanical ventilation.
ing kept constant. The gas reaches filter A where theinhaled mass of the drug is determined. During inspira-tion some amount of nebulizer charge can be exhaled Pharmacological concepts of aerosolization during without being inhaled, and is captured in filter B. In sep-arate experiments, a cascade impactor can be inserted to measure the particle size distribution of the aerosol. Theresistance (R) and/or compliance (C) of the lung model During mechanical ventilation, the aerosolized can be changed to mimick various clinical scenarii.
drug travels the inspiratory line and the endo-tracheal tube then deposits in the lungs, whilesome amounts flows out with the next expira- of the nebulizer charge and 53% of the inhaled tion (Fig. 1). By applying the mass balance law, it comes that the amount of drug inhaled minus Furthermore, by accommodating a cascade im- the amount of drug exhaled is equal to the pactor in the setup (Fig. 1) during a separate ex- amount of drug deposited in the lungs. The periment, the mass median aerodynamic diame- setup shown in Figure 1(2,4,7–9) depicts these ter (MMAD) can be determined. Particles with components relative to the initial amount of ac- MMAD Ͼ 5-m impact the endotracheal tube tive drug filled in the nebulizer (nebulizer and the ventilatory circuit during IMV and the charge). The inhaled fraction is the ratio of the pharynx during NIV. Particles with MMAD be- amount of drug captured by the filter A (Fig. 1) tween 1 and 5 m mainly deposit in the airways to the nebulizer charge. It reflects the amount of by sedimentation while particles with MMAD be- drug available for inhalation by the patient be- tween 1 and 3 m have the potential to reach the cause it takes into account the amount of drug lost into the nebulizer, the ventilator circuit andthe endotracheal tube. But the drug can also be Devices to generate aerosols during directly exhaled without being inhaled or ex- haled from the lungs after inhalation, and thisamount is captured on the filter B (Fig. 1). O’Ri- In patients receiving mechanical ventilation in- ordan et al.(4) combined in vitro (Fig. 1) and in haled bronchodilators can be administered by vivo experiments in seven mechanically venti- nebulizer or pressurized metered-dose inhaler lated patients, computed the exhaled fraction (MDI) devices. A nebulizer device is character- and found that: (1) the inhaled fraction averaged ized by a function curve that relates the cumula- 31%, and (2) the lung deposition averaged 15% tive output of the drug against time. The nebu- INHALED BRONCHODILATORS DURING MECHANICAL VENTILATION
lizer function curve has an initial slope and a sition(13) with differences among the spac- plateau. The time interval to the plateau is the ers.(14–16) The MDI actuation should be synchro- time during which the inhaled mass increases.
nized with the inspiratory phase of the ventilator Once the plateau is reached the amount of in- to increase the delivery.(17) Performing an end-in- haled drug no longer increases and, hence, there spiratory pause after actuation has been recom- is no advantage to continue nebulization further.
mended.(1) Compared to chlorofluorocarbon, gas In clinical practice there is a good correlation be- propellant hydrofluoroalkane protects environ- tween plateau onset and sputtering. Depending ment better,(18) and MDIs powered by the latter on the function curve of the nebulizer, both treat- are as efficient as those propelled by the former.
ment time and amount of inhaled drug may varybetween devices.(2) The nebulizer fill volume can Ventilator-related factors of inhaled drugs also influence inhaled mass: the higher the vol- deposition during mechanical ventilation ume fill the greater the inhaled mass for a givennebulizer.(10) The performance of jet or pneumatic Comprehensive in vitro studies have investi- nebulizers depends on the powering flow of the gated the role of ventilator-related factors to the gas, which is usually between 6–8 L/min (Fig. 2).
lung deposition during mechanical ventilation Ultrasonic nebulizers can also be used during me- (Table 1). Ventilatory settings, location of the de- chanical ventilation.(11) Contrary to pneumatic vice in the circuit, density, and humidity of the nebulizers, their performance is independent on gas powering the device, the endotracheal tube, the ventilatory settings (Table 1). Devices that uti- lize a vibrating mesh or plate may be interesting Among the ventilatory settings, low inspiratory because they are highly efficient to deliver flow, high tidal volume, low respiratory frequency, and long duty cycle applied during the inhalation In ambulatory spontaneously breathing pa- have been shown to increase lung deposition with tients, MDIs require training to ensure coordina- both nebulizer and MDI. The location of nebulizer tion for optimal delivery. However, up to 70% of in the ventilatory circuit influences deposition,(10,19) these patients fail to use MDIs properly.(3) For the manifold location being more efficient than Y ICU patients receiving mechanical ventilation, it piece placement (Table 1). This is also true using is caregivers’ responsibility to optimize MDI ad- MDI with a chamber.(20) During NIV, the optimal ministration. Of notice, MDI canister has to be position of the nebulizer is between the leak port shaken vigorously, and must be connected to an and the patient connection to maximize the deliv- inhalation chamber with the drug delivery port of the canister placed bottom up (Fig. 2). The use The modern ICU ventilators can directly power of chamber with a MDI increases the drug depo- the nebulizer, making the nebulization synchro- Proper installation of pneumatic nebulizer (left panel) and pressurized metered-dose inhaler (MDI) (right panel) in the ventilatory circuit. Both devices should be located 20–30 cm upstream from the Y piece. The pneumaticnebulizer should be powered with optimal gas flow. The MDI-canister should be actuated using a chamber.
TABLE 1. VENTILATOR-RELATED FACTORS OF LUNG DEPOSITION AFTER DRUG INHALATION: IN VITRO STUDIES patient adaptor, respiratory rate 20/min, increasing inspiratory pressure anddecreasing expiratory pressure(58) CPAP, continuous positive airway pressurre; CMV, controlled mechanical ventilation; AC, assisted controlled me- chanical ventilation; PS, pressure support; VT, tidal volume.
nized with the inspiration and, hence, enhancing does not mean that the inhaled mass of the drug its efficiency by as much as four times more than is increased with helium. The humidity of air has a continuous administration.(8) The flow diverted a major impact on lung deposition during me- from the ventilator to the nebulizer is automati- chanical ventilation. Lung deposition may be re- cally compensated to maintain tidal volume and duced by as much as 40% with wet air compared minute-ventilation constant. Use of helium–oxy- to dry air with either nebulizer(7,8,10) or MDI.(24) gen mixture may be attractive to increase the in- Taken together, the above data provide the ICU haled mass by reducing impaction in ventilator physician with recommendations to optimally circuit and promoting a more peripheral deposi- deliver inhaled bronchodilators during mechani- tion. In vitro, with MDI, albuterol deposition in- creased by 50% with 80% helium–20% oxygen Endotracheal tube has long been viewed as a compared to oxygen feeding the ventilator.(22) significant barrier to the deposition of inhaled However, the performance of the nebulizer was medications.(25) In vitro, the delivery to filter de- impaired with heliox compared to oxygen at creased with the reduction of the inner diameter same flow.(22) Finally, the maximal drug deposi- of the endotracheal tube.(17) In vivo, however, the tion was obtained by powering the nebulizer with endotracheal tube was not a significant barrier to oxygen and feeding the ventilator with heliox.(22) the deposition because it was found that only This situation combines the maximal energy sup- 2.6% and 7% of the nebulizer charge deposited in ply to the nebulizer and the facilitation of drug the endotracheal tube during inspiration and ex- transport to the airways. However, this result INHALED BRONCHODILATORS DURING MECHANICAL VENTILATION
TABLE 2. THE 10 STEPS TO OPTIMIZE AND SECURE THE AEROSOL DELIVERY WITH MDI OR NEBULIZER IN PATIENTS RECEIVING INVASIVE MECHANICAL VENTILATION IN VOLUME-CONTROLLED MODE expiratory line before theexhalation valve flow 30–50 L/min: make sure thatintrinsic PEEP does not rise c. Allows at least 30 sec between b. Select optimal flow to powerc. two actuations.
a.a. the nebulizer. If unknown, choose 6–8 Adjust minute ventilation if required tokeep VT constant.
d. Set the optimal duration of nebulization.
a. b. Patient–ventilator synchronization aa. .or nebulizerb. Reset previous ventilatory Adapted from refs 1, 2, and 10.
MDI, metered-dose inhaler; VT, tidal volume, PEEP, positive end-expiratory pressure; SpO2, transcutaneous oxy- Indications of inhaled bronchodilators in for using inhaled bronchodilators in the ICU set- mechanically ventilated ICU patients ting. The studies supporting this level of recom-mendation are essentially physiologic and short The medications usually employed for inhala- term. No controlled study to date in asthma or tion therapy in France are provided in Table 3.
chronic obstructive pulmonary disease (COPD) Inhaled bronchodilator therapy has been graded evaluated the impact of inhaled bronchodilators as level B, that is, of probable value, in patients on clinical outcomes as duration of mechanical receiving mechanical ventilation and exhibiting ventilation or weaning process. In a single ICU, bronchospasm or asthma.(26) Wheezing, intrinsic it has recently been observed that: (1) one-third PEEP, elevated airway resistance, difficult to of patients did receive inhaled bronchodilating wean, ventilator dependence are also indications agents for unclear reason, (2) mechanical ventila- ȇ Ǟ ȇ ȇ 10%, 18%, 6% PEEPi 16%, 17%, 16% PEEPi Expiratory iso-flow 0.1 L/sec with MDI or NEB g MDI vs. 2.5 mg NEB g MDI vs. 200 g MDI vs. 40–100 For adults. Higher doses, that is, more frequent administrations, may be required in patients experiencing severe acute bronchoa AO, airway obstruction; MDI, pressurized metered-dose inhaler; NEB, nebulizer; Rrs, total resistance of the respiratory system; -adrenergic Albuterol-Salbutamol sulfate pressure of the respiratory system; IP, ipratropium bromide.
tion duration was longer in patients who were Dose. Contrasted dose–response effects on res- treated with inhaled bronchodilators than in piratory mechanics have been observed with those who were not; and (3) related cost was MDI and nebulizer. Dhand et al.(35) found that maximal reduction of Raw was obtained after 4 Promising findings have been obtained in pa- puffs of albuterol administered via an MDI with tients with the acute respiratory distress syn- no further reduction up to 16 puffs. Bernasconi et drome (ARDS) in whom intravenous albuterol al.(33) found that nebulized fenoterol resulted in was able to reduce extravascular lung water and significantly greater reduction of Raw than neb- plateau pressure compared to placebo.(28) Be- ulized saline but no dose–effect relationship with cause nebulization can achieve relevant concen- fenoterol. Manthous et al.(36) found no dose–re- trations of albuterol in the edema fluid of patients sponse relationship with albuterol administered with ARDS,(29) the efficacy of this route to in- via an MDI but a 10% decline in resistive pres- crease the alveolar clearance of lung edema sure while delivering the same molecule at 2.5, 5, and 7.5 mg via a nebulizer. In this study(36) themodest reduction of respiratory resistance may Effects of inhaled bronchodilators in mechanically be attributed to the case mix because only two patients were COPD. The lack of effect of MDI inthis work(36) may result from an administration Physiologic effects. The primary objective of not optimized because the device was attached bronchodilator treatment in intubated and me- directly to the endotracheal tube via an elbow chanically ventilated COPD patients is to reduce without any chamber. In this connection, the pulmonary dynamic hyperinflation and resis- same group found, in a further study,(37) a sig- tance of the respiratory system to reduce the work nificant reduction of respiratory resistance with of breathing.(30) Respiratory mechanics was es- the same molecule delivered by an MDI located sentially assessed from the interrupter technique during constant-flow inflation.(31) This technique Increasing the dose of the molecule may also is very popular in the ICUs because it is easy and increase the risk for cardiac arrhythmias. Above quick to perform at the bedside and allows par- 4 puffs of albuterol, any further reduction of res- titioning of total inspiratory resistance into its air- piratory resistance was obtained while heart rate way (Raw) and tissue components. It requires, significantly increased.(35) In a previous study, however, fully relaxation of the patient during the same group did not observe any significant the maneuvre. A reduction of respiratory system change in heart rate with 10 puffs of albuterol via resistance, mostly stemming from a decline in Raw, and of intrinsic PEEP, has consistently beendocumented after administration of inhaled bron- Administration. It has been shown in vitro (Table chodilators in intubated COPD patients by 1) that it was possible to optimize the delivery of inhaled medication by accommodating the ven-tilator and its adjuncts. Accordingly, recommen- Duration of effects. The beneficial effects of al- dations were provided for patients receiving IMV buterol inhalation on respiratory mechanics (Table 2). However, Mouloudi et al.(39) demon- were no longer observed after 240 min in stable strated that some of these ventilator-related fac- mechanically ventilated COPD patients, sug- tors were no longer significant in the real life. The gesting that this drug may be administered authors studied the effects on respiratory me- every 4 h.(32) However, 120 min after fenoterol chanics of albuterol delivered via an MDI in in- inhalation the resistance of the respiratory sys- tubated and mechanically ventilated COPD pa- tem did not significantly differ from the base- tients. Although albuterol induced a significant line.(33) Furthermore, the time course of respi- reduction of respiratory resistance, the accom- ratory mechanics after inhaled albuterol was modation of tidal volume (8 vs. 12 mL/kg)(39) or highly variable among patients, which pre- inspiratory flow rate (0.6 vs. 1.2 L/s)(40) or pat- cludes any fixed standardization of dosage tern (decelerating versus constant)(41) or end-in- schedule.(34) This lack of predictability is an ad- spiratory pause (none or 5 sec)(42) at the time of ditional argument to thoroughly evaluate the inhalation did not influence the reduction of res- piratory resistance and intrinsic PEEP. These re- GUERIN ET AL.
sults demonstrated that once dosage was ade- were improved with the combination of PEEP quate (200–600 g albuterol(39–42)) and adminis- tration optimized (MDI plus spacer), manipula-tion of the ventilator settings did not produce Nebulizer or MDI. Both devices were equally ef- additional measurable effects on respiratory me- fective to improve respiratory mechanics in most studies (Table 4). Therefore, other arguments The application of external PEEP in COPD pa- than effectiveness should be taken into account tients under invasive mechanical ventilation has to prefer one device to the other. MDI are easier been largely investigated in the last years.(43–50) to use. Nebulizers are cumbersome and more As far as the patient is sedated and receives pas- costly. Whatever the device, the physician has to sive mechanical ventilation the use of external be familiar with the one she/he uses routinely PEEP is not necessary. If it is nevertheless used, and, of notice, with particle size distribution gen- its level should be less than 85% of the static in- erated and optimal powering flow in the case of trinsic PEEP to avoid any hemodynamics com- promise.(49) However, there may be a rationalefor using low levels of PEEP in passively venti- lated COPD patients to reopen small airwaysclosed during the tidal breathing.(51,52) Further- Although NIV is increasingly used in ICUs, more, by maintaining small airways patency, ex- the data regarding the effects of bronchodilators ternal PEEP may facilitate the distribution and in this setting are still scanty. NIV may be a physiological effects of inhaled bronchodilators method to increase the deposited mass in adults medication. In vitro studies have shown that in- with acute bronchospasm(56) or in children with cystic fibrosis.(57) The mechanisms by which PEEP.(9,53) The interaction between external NIV can increase deposited mass are: dry air, PEEP and inhaled bronchodilator was recently larger tidal volume than during unassisted investigated in two studies on COPD patients spontaneous breathing, improvement of effi- who received INV, which gave discrepant re- ciency of the nebulizer,(57) combination with ex- sults. In 10 COPD patients, Guérin et al.(54) stud- ternal PEEP,(55) absence of endotracheal tube. In ied the time course of the effects on respiratory vitro, significant increase in inhaled mass was mechanics of nebulized fenoterol either on zero obtained during NIV by locating the nebulizer external PEEP (ZEEP) or external PEEP amount- between the leak port of the single limb circuit ing to 85% intrinsic PEEP. They found that after and the patient(58,59) and by using high inspira- fenoterol administration respiratory mechanics tory or expiratory pressures.(58,59) In a random- improved with ZEEP but remained unchanged ized controlled study in 18 stable COPD pa- with external PEEP. The authors explained the tients, Nava et al.(60) found that salbutamol results by the fact that intrinsic PEEP declined delivered via an MDI and a chamber during NIV with fenoterol, and once its level became lower exhibited a greater bronchodilating effect than than external PEEP dynamic hyperinflation in- placebo, but might be less efficient than during creased as did respiratory resistance. Tzoufi et al.(55) in 10 COPD patients, measured respiratorymechanics during five conditions: (1) baselineZEEP, (2) 30 min after nebulization of 5 mg al- CONCLUSIONS
buterol on ZEEP, (3) 8 h after albuterol inhala-tion on ZEEP, (4) 30 min after application of The administration of bronchodilators in ICU PEEP equal to intrinsic PEEP, (5) 30 min after patients receiving mechanical ventilation is pos- nebulization of 5 mg albuterol on the same level sible and efficient, using either nebulizer or MDI.
of PEEP as in condition 4. The authors found that Based on in vitro studies, practical recommenda- PEEP and albuterol had additive beneficial ef- tions have been issued to help clinicians in opti- fects on intrinsic PEEP which went from 7 cm mization of this therapy. Future studies should H2O at baseline to 4.8 cm H2O with albuterol assess the effects of inhaled bronchodilators alone, to 3.7 cm H2O with external PEEP alone on patient outcome as duration of mechanical and to 2 cm H2O with both interventions. Fur- ventilation/weaning/ICU stay/cost-effectiveness and determine how to optimize the delivery of INHALED BRONCHODILATORS DURING MECHANICAL VENTILATION
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