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* From the Division of Critical Care (Dr. Marik), Washington Hospital Center, Washington, DC; and the Department of Respiratory Services (Messrs. Hogan and Krikorian), St. Vincent Hospital, Worcester, MA.
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Abstract |
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Methods: Mechanically ventilated patients who had not received a bronchodilator in the previous 48 h and who had normal renal function were randomized to receive the following: (1) five puffs (450 µg) of albuterol delivered by the MDI with a small volume spacer; (2) five puffs of albuterol delivered by the MDI port on a right-angle adaptor; or (3) 2.5 mg albuterol delivered by a nebulizer. Urine was collected 6 h after the administration of the drug, and the amounts of albuterol and its sulfate conjugate were determined in the urine by a chromatographic assay.
Results: Thirty patients were studied, 10 in each group: their mean age and serum creatinine level were 62 years and 1.3 mg/dL, respectively. With the MDI and spacer, (mean ± SD) 169 ± 129 µg albuterol (38%) was recovered in the urine; with the nebulizer, 409 ± 515 µg albuterol (16%) was recovered in the urine; and with the MDI port on the right-angle adaptor, 41 ± 61 µg albuterol (9%) was recovered in the urine (p = 0.02 between groups). The level of albuterol in the urine was below the level of detection in four patients in whom the drug was delivered using the right-angle MDI adaptor.
Conclusion: The three delivery systems varied markedly in their efficiency of drug delivery to the lung. As previous studies have confirmed, this study has demonstrated that using an MDI and spacer is an efficient method for delivering inhaled bronchodilators to the lung. The pulmonary bioavailability was poor with the right-angle MDI port. This port should not be used to deliver bronchodilators in mechanically ventilated patients.
Key Words: albuterol • ß-adrenergic agonist • bioavailability • bronchodilator • mechanical ventilation • metered-dose inhaler • nebulizer
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Laboratory studies have demonstrated that many factors may affect the delivery of aerosols to the respiratory tract, including the delivery system, warming and humidification of the inspired gasses, position of the aerosol generator in the ventilator circuit, timing during the respiratory cycle, endotracheal tube size, and mode of ventilation.7 8 9 10 However, these in vitro studies do not take into account patient-related factors, such as airway geometry, type and severity of pulmonary diseases, and pulmonary secretions. It is unclear how closely these studies duplicate the delivery of drugs in patients.
Unlike nonintubated patients, the direct deposition of aerosol into the oropharynx with subsequent enteral absorption will not occur in mechanically ventilated patients. Furthermore, because urinary excretion is the major route of elimination for both unchanged albuterol and its sulfate conjugate, quantitation of the urinary excretion of albuterol provides a noninvasive method for determining the bioavailability of the drug using different delivery systems. The aim of this study was to compare the bioavailability of albuterol among the following methods used to deliver bronchodilators in mechanically ventilated patients: the nebulizer, the MDI and spacer, and the MDI port on a right-angle adaptor.
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Materials and Methods |
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MDI Technique
With the patient on assist-control mode of ventilation, the
ventilator was set such that the tidal volume was > 500 mL, with an
inspiratory time of > 0.3 of the total breath duration.
Attempts were made to ensure that the ventilator and patient were
synchronous. The albuterol MDI (Glaxo Wellcome Inc; Research
Triangle Park, NC) was vigorously shaken and then placed in
either the actuator of a small volume spacer (Aerovent; Tiger Medical
Corp; Amesburg, MA) situated at the patient Y on the
inspiratory limb of the ventilator circuit, or the MDI port on a
right-angle adaptor (Trachcare; Ballard; Draper, UT), which is attached
to the end of the endotracheal tube. The MDI was actuated to
synchronize with the precise onset of inspiration by the ventilator.
After 30 s, this cycle was repeated four times (a total of five
puffs) for a total dose of 450 µg albuterol.
Nebulizer Technique
The tidal volume was set at > 500 mL, with a duty cycle of
> 0.3. Flow-by (if in use) was turned off. A unit dose (2.5 mg in 3
mL) of albuterol solution (Glaxo Wellcome Inc; Research Triangle Park,
NC) was placed in a nebulizer ("T" Up-Draft II Neb-U-Mist; Hudson;
Temecula, CA). The nebulizer was placed in the inspiratory limb at
least 30 cm from the patient Y, with an airflow of 6 to 8 L/min through
the nebulizer. When no further visible aerosol was produced, the
nebulizer was removed from the ventilator circuit, and the ventilator
was set to the original settings.
Once the ß-adrenergic agonist had been delivered to the patient, the urine bag was emptied, and the urine was collected for the next 6 h. A 6-h collection period was used because the largest percentage of the drug is excreted during this time period, and therefore, it allows for uninterrupted administration of the bronchodilator to the patients (every 6 h).11 The volume of the 6-h urine collection was measured using a calibrated cylinder. A 20-mL aliquot of urine was placed in a 50-mL sterile container and then stored in a refrigerator at -20°C until it was analyzed.
Sample Analysis
Materials and Reagents: Albuterol sulfate, United
States Pharmacopeia reference standard, was purchased from USPC, Inc
(Rockville, MD). The internal standard bamethane sulfate was obtained
from Sigma Chemical Company (St. Louis, MO). High-pressure liquid
chromatography (HPLC) grade acetonitrile, dichloromethane, ethyl
acetate, and methanol were used. Ammonium hydroxide, acetyl
strophanthidin reagent grade, was purchased from Aldrich Chemical
Company (Milwaukee, WI). Ultrapure bioreagent grade sodium dodecyl
sulfate and potassium dihydrogen phosphate were obtained from JT Baker
(Phillipsburg, NJ).
Apparatus and Conditions: The HPLC system consisted of a pump (Waters 600E; Waters Corp; Milford, MA), an autosampler (Waters 712 WISP; Waters Corp), a fluorescence detector (FP 920; JASCO Corp; Easton, MD), and a computer system (Version 4.1 Turbochrom; PE Nelson; Norwalk, CT). Also used was a 4.6 x 250-mm analytical column (Waters Symmetry C18; Waters Corp) and a 3.9 x 20-mm guard column (Waters Sentry Guard Column; Waters Corp). The mobile phase was composed of methanol and water (60:40 v/v) containing 10 mM potassium dihydrogen phosphate and 20 mM sodium dodecyl sulfate as an ion-pair reagent. The mobile phase was adjusted to a pH of 3 with 1.0 M phosphoric acid. The flow rate was 1.2 mL/min, and detection wavelengths were 276 nm for excitation and 609 nm for emission.
Standard Preparation: Duplicate spiked urine standards were prepared at six different concentrations using two independently prepared stock solutions (A and B) to cover the sample analysis, which ranged from approximately 50 to 2,500 ng/mL.
Sample Preparation: The urine sample (0.5 mL) was added to a 10-mL glass centrifuge tube containing 2 mL 0.1N hydrochloric acid. The tube was capped with a screw top and then was placed in a boiling water bath for 30 min. After cooling, an aliquot of 2 mL 0.1N sodium hydroxide was added to the sample and vortexed. An aliquot of 50 picoliters bamethane sulfate internal standard working stock solution (10 pg/mL) was added to the resulting solution. The mixture was vortexed and then extracted as described below.
The Bond Elut Certifyo LRC columns were conditioned using 1 mL methanol followed by 1 mL Milli-Q water. The urine mixture was drawn through the columns slowly by using a vacuum manifold. The columns were then washed with 2 mL 25% methanol in water (v/v) followed by 1 mL dichloromethane, 0.2 mL ethyl acetate, and 2 mL acetonitrile. The columns were then dried for approximately 5 min, and they were eluted using 0.5 mL 30% ammonium hydroxide in methanol (6:94 v/v). The eluate was evaporated to dryness under a stream of nitrogen by using an evaporation workstation (TurboVap; Zymark Corp; Hopkinton, MA) at approximately 60 ± 50°C. The residues were reconstituted with 0.5 mL of the mobile phase, and they were transferred to HPLC vials with limited-volume inserts for injection. A volume of 10 pg/mL from each sample was injected into the HPLC system.
Calculations: Standard curves were generated by plotting peak-height ratios (albuterol/internal standard) as a function of albuterol concentration and by least-squares linear regression analysis for the line of best fit. The final concentration represented the sum of both unchanged albuterol and its sulfate conjugate.
Data Collection and Analysis
The following demographic and clinical data were recorded on
each patient and stored in a computerized database (Access 97;
Microsoft; Redmond, WA): age, sex, reason for admission to the ICU,
serum chemistries, and ventilator settings. The total urinary excretion
of albuterol during the study period was calculated by multiplying the
urinary albuterol concentration by the volume of the urine collected
during the 6-h collection period. In addition, the percentage of the
administered drug excreted during the collection period was recorded.
Summary statistics were computed for each study group.
2 analysis of contingency tables was
used to compare categorical data, and analysis of variance was used to
compare continuous variables. Post hoc testing was done
using Duncan's multiple comparison test. The outcome variable of
interest was the percentage of the administered drug excreted during
the 6-h study period. Unless otherwise stated, all data are expressed
as mean (± SD), and probability values of 
0.05 have been declared
statistically significant.
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Results |
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Discussion |
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The high pulmonary bioavailability achieved with the MDI and spacer in our study is similar to that reported by investigators using in vitro models.9 10 12 13 In these studies, a model of the airway was constructed and attached to a test lung, which had a cuffed endotracheal tube placed in the "trachea" and connected to a ventilator. The amount of aerosol deposited on filters placed at the end of the endotracheal tube or at the end of each "bronchus" was quantified by spectrophotometry. In these studies, approximately 30% of the dose administered with an MDI and spacer was delivered to the lower respiratory tract.9 10 12 13 The lung deposition using the MDI port on a right-angle adaptor was reported to be 7.2% by Diot et al,10 and 7.3% by Rau et al.12 The degree of pulmonary deposition reported in these in vitro models and that of our study differ appreciably from the in vivo studies using radiolabeled tracers. Fuller et al14 measured the percentage of lung deposition of radiolabeled fenoterol using an MDI and spacer and a jet nebulizer in ventilated patients. Lung deposition was 5.6% with the MDI and 1.2% with the nebulizer. In a more recent study using the same technique, Fuller et al15 reported the lung deposition to be 6.3% with the MDI and a large volume spacer and 3.9% with the right-angle MDI adaptor fitted directly onto the endotracheal tube. Other in vivo studies have reported that between 1% and 2.9% of the dose placed in the nebulizer is actually deposited in the patient's lung.14 16 17 However, O'Riordan et al18 reported a lung deposition of 15.3% with the radiolabeled aerosol and the jet nebulizer. The large differences in pulmonary deposition between the in vivo studies and the in vitro models, together with our present study, question the validity of the methodology used in the in vivo studies.
In our study, the pulmonary bioavailability was 38% for the MDI and spacer, 9% for the MDI port on the right-angle adaptor, and 16% for the nebulizer. These values represent an underestimation of the true pulmonary bioavailability due to the 6-h collection period. Notwithstanding this limitation, our study enabled us to compare the relative pulmonary bioavailability of the three delivery systems. Hindle and Chrystyn, 11 using the same methodology as in our study, measured albuterol and its conjugate in the urine of healthy subjects during the 24-h period after patients inhaled albuterol. These authors recovered 32% of the inhaled dose after 6 h and 57% of the inhaled dose after 24 h. However, because these were nonintubated patients, it is likely that a large percentage of the excreted dose represented absorption from the oropharynx and GI tract. The urinary excretion of albuterol in our patients reflects the systemic absorption of the drug deposited in the lower respiratory tract because the cuffed endotracheal tube prevents deposition in the oropharynx and GI tract. Furthermore, the urinary assay is highly specific for albuterol and its conjugate.11 19 We, therefore, believe that this methodology provides a reliable technique for assessing aerosol delivery and pulmonary bioavailability in mechanically ventilated patients. Although the absorption of albuterol is reported to be more rapid from the lungs than from the oropharynx or GI tract, it is unclear from our study what percentage of the drug deposited in the lungs was excreted within the 6-h study period.11
Duarte et al20 demonstrated that the administration of albuterol with an MDI and spacer produces serum levels in mechanically ventilated patients that are similar to those in healthy control subjects. However, the serum levels achieved with inhaled ß-adrenergic agonists are very low and close to the limits of detection, resulting in analytical problems in measuring the levels and in determining the bioavailability of the drug. The concentration of inhaled ß-adrenergic agonists in the urine is, however, much higher and offers a better method for assessing the bioavailability of the drug after inhalation.
In conclusion, the currently used methods for delivering inhaled bronchodilators to mechanically ventilated patients differ markedly in their efficiency of drug delivery. As previous studies have done, this study has demonstrated that using an MDI and spacer is a highly efficient delivery method. The MDI port on right-angle adaptors should not be used to deliver bronchodilators because of its low and unreliable bioavailability. Due to the inherent limitations of our study, additional studies are required to confirm our findings.
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Footnotes |
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Correspondence to: Paul E. Marik, MD, FCCP, Department of Medicine, Washington Hospital Center, 110 Irving St NW, Washington DC 20010-2975; e-mail: pmarik@erols.com
Abbreviations: HPLC = high-pressure liquid chromatography; MDI = metered-dose inhaler
Received for publication September 11, 1998. Accepted for publication December 17, 1998.
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