Relative Amount of Albuterol Delivered to Lung Receptors from a Metered-dose Inhaler and Nebulizer Solution

Relative Amount of Albuterol Delivered to Lung Receptors from a Metered-dose Inhaler and Nebulizer Solution

Relative Amount of Albuterol Delivered to Lung Receptors from a Metered-dose Inhaler and Nebulizer:·Solution* Bioassay by Histamine Bronchoprovocation...

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Relative Amount of Albuterol Delivered to Lung Receptors from a Metered-dose Inhaler and Nebulizer:·Solution* Bioassay by Histamine Bronchoprovocation Kathryn V. Blake, Pharm.D.;t Michael Hoppe, Pharm.D.;:f:. Eloise Harman, M.D.;§ and Leslie Hendeles, Pharm .D .1I The results of previous studies comparing bronchodilatation from beta agonists administered by metered-dose inhaler (MDI) and nebulizer solution have been confticting. We therefore evaluated a range of a1buterol doses administered by these two methods, using histamine bronchoprovocation as a bioassay for the amount of drug reaching the P. receptors in the lung. Twelve stable asthmatic volunteers received, in a double-blind, randomized, crossover design on different days, placebo or one, two, four, or six puffs from an MOl attached to an lnspirEase device (90 fLg per pull) or 0.625, 1.25, 2.5, or 5.0 mg of solution delivered in 2 ml of buffered saline through a Hudson Updraft n nebulizer. The histamine concentration required to decrease FEV, by 20 percent (PC.) was measured 1 h before and 30 min after administration of each treatment and expressed as the increase in pc.. from baseline. The doseresponse curves for change in PC.. indicated that the higher doses of the nebuIizer solution delivered more drug to P. receptors in the lung than the lower doses from the MDI.

For example, the geometric mean increase in PC.. was 1.1±1.6 (SD) after placebo, 7.5±2.7 after two puffs from the MDI, and 20.0 ± 2.1 after 2.5 mg of nebulizer solution (p
Inhaled 132 agonists are the treatment of first choice for acute asthmatic symptoms in both children 1 and adults." These agents are generally administered by nebulization in hospitalized patients, whereas a metered-dose inhaler (MDI) offers a more convenient method of administration for ambulatory patients. Recently, there has been interest in using an MOl for

save money, it is unclear whether the two methods deliver equivalent amounts of drug to the 132 receptors in the lungs. Differences in the amount of drug delivered to the lung may be important in patients with acute exacerbations of asthma, since the amount of inhaled beta-agonist required to produce maximum bronchodilatation is greater in the presence of severe obstruction than in patients with mild obstruction.6 The results of published studies comparing recommended doses of the most potent 132 selective agonist, albuterol, delivered by MOl and nebulizer solution have been conflicting. However, most of them compared only a single dose of the drug without documenting the efficacy of the nebulizer system. As in the study by Alvine et al? (see page 316) and other stud ies,8.9 the amount of drug delivered from nebulizers or systems varies greatly. Some studies included subjects who had incompletely reversible airway obstruction (eg, COPD), while others included subjects whose baseline lung function was at the top of the dose-response curve, (ie, there was little capacity for bronchodilatation). Each of these factors can influence the results when bronchodilatation alone is used as the end point. Several recent reports indicate that bronchoprovocation with histamine," methacholine, Jl or exercise"

For editorial comment see page 298 therapy in hospitalized patients to eliminate the substantial charges incurred when respiratory therapists administer nebulized bronchodilator therapy at frequent intervals (eg, $160 to $240/d).3-5 While such a change in mode of administration will undoubtedly *From the Department of Pharmacy Practice, College of Pharmacy (Drs Blake, Hoppe, and Hendeles), the Division of Pediatric Pulmonary Disease/Cystic Fibrosis (Drs Hannan and Hendeles), and the Pulmonary Division, Department of Medicine (Dr Harman), University of Florida , Gainesville. tCurrently Clinical Research Scientist, Nemours Children's Clinic. Jacksonville, Fla. tCurrently Clinical Pharmacist , Arnold Palmer Hospital for Children and Women, Orlando . §Professor of Pulmonary Medicine . IlClinical Pharmacist , Regional Pediatric Pulmonary Center, and Professor of Pharmacy and Pediatrics. Supported by a competitive research award from the Research Institute, American College of Clinical Pharmacy. Manuscript received March 28; revision accepted August 13.

ANOVA= analysis of variance; DAR = drug activity ratio; MDI=metered-dose inhaler; pC.. = concentration required to decrease FEV, by 20 percent

CHEST I 101 12 I FEBRUARY, 1992


increases the ability to quantitate the intensity and/or duration of action of an inhaled 132 agonist over measurement of FEV. alone, particularly in patients with mild asthma. We, therefore, hypothesized that bronchoprovocation with histamine might serve as a more sensitive bioassay than bronchodilatation alone to determine the relative amount of albuterol that reaches 132 receptors in the lung from a wide range of doses delivered by MDI and nebulizer. METHODS

Subject Selection

The protocol was approved by the University of Florida Institutional Review Board, and written Informed consent was obtained from each subject. Twelve subjects (ten men aged 20 to 34 years (mean, 24 years) with a well-defined history of mild asthma completed the study. One subject was replaced because it was inconvenient for her to complete the protocol; none of the data from this subject were included in the analysis.Allsubjects had a baseline FEV, of at least 65 percent of predicted for age, height , and sex" and at least a 20 percent decrease in FEV, after inhalation of histamine, :54 mg/ml (Table I). No subject had received oral or inhaled corticosteroids, had been treated in an emergency room, or had required hospitalization for acute asthmatic symptoms in the previous 90 days. None of the subjects gave a history of of an upper respiratory tract infection during the study or for 30 days before screening. Prior to each study day, inhaled albuterol , terbutaline, or metaproterenol MOl was withheld for 6 h and isoproterenol waswithheld for 2 h. No subject was taking any other medication or had any other condition known to alter airway reactivity to histamine . Studies were conducted at the same time of day and in the same laboratory, where temperature, humidity, and ventilation were kept constant. Study Procedures

Spirometry was measured at the start of each study day. The study proceeded only when the baseline FEV, was within 90 to IIO percent and the histamine concentration required to decrease FEV,

by 20 percent (PC,.) was within one twofold concentration of the values measured on the qualifying day. At least I h after completion ofthe histamine challenge (when the FEV, had returned to baseline), the study medication was administered. Thirty minutes later, a score was obtained for headache and tremors (on a scale of 0 to 3, where 0 = absent and 3 = bothersome), and a second histamine challenge was performed, Blood pressure and heart rate were measured prior to each histamine challenge. Although two previous reports suggested that tachyphylaxis to histamine occurs with repeated challenges,..... more recent studies indicated that an interval of 1.5 h between challenges circumvents this problem .'"'' The fact that the mean ratio of the PC,., obtained 30 min after placebo to the PC,., 1.5 h earlier was 1.1 provides further evidence that tachyphylaxis does not occur at this interval of challenges. Blood pressure and heart rate were measured prior to each histamine challenge. The study was conducted over an Ll-month period . Subjects completed the nine treatment days in an average of six weeks (range, 3 to II weeks). Spirometry

The FEV. was measured by a Collins survey spirometer, and values were calculated with an Eagle I microprocessor (Warren E. Collins, Braintree, Mass). For baseline spirometry measurements prior to both histamine challenges on each study day, the best of three attempts was recorded and expressed as both the actual value and the percentage of the predicted value for age, height, and sex.

Albuterol Administration Nebulized albuterol doses were prepared by diluting 0.5 percent albuterol solution for nebulization (Proventil; Shering, Kenilworth, N]) with a bicarbonate-buffered saline solution (AlOOy; Holliste rStier, Spokane, Wash) to a final volume of 2 ml. This volume was selected so that the solution could be nebulized over 6 to 8 min;" this is approximately the same amount of time required to deliver six puffs from the MOl (the maximum dose studied) with a l-mm pause between puffs. The entire 2-ml dose was administered by tidal breathing from an open system consisting of a Hudson Updraft II nebulizer (Hudson Oxygen Therapy, Wadsworth, Ohio) connected to a mouthpiece by a T joint and driven by a DeVilbiss air compressor (DeVilbiss, Somerset, Fa). Subjects wore a nose clip during drug administration, but it was apparent that drug was lost

Table I-Demographic Data, Mean FEV. and Ainooy Beacticity to Hiatamifle before Each Study Day, and Previoua Inhaler Use

Subject/Age, yr/Sex 1I2OIF 2I25IM 3I24IM 4I26IM

5I34IM 6132/M 71201M 8I26IF

91201M HV201F lU22IM l2I24IM

Baseline FEV, for 9 Study Days, % predicted76.6±4.9 78.3±1.4 81.4±4.0 72.I±2.6 74.7±4.8 89.1±4.7 73.9±4.6 82.8±2.4 74.3±3.4 74.5±4.I 76.5±5.5 84.0±4.0

Baseline Histamine PC,., for 9 Study Days, mglmlt 4.0 2.4 2.0 3.5 0.9 0.8 0.7 1.0 1.7 0.4 0.7 1.9

(2.7-6.7) (1.3-4.0) (1.1-4.0) (2.1-5.5) (0.6-1.3) (0 .~2 .5)

(0.4-1.4) (0.6-1.6) (0.6-2.5) (0.3-1.6) (0.3-1.6) (1.3-2.8)

Prior ~Agonist Inhaler Use* Ud 21wk 21d 21d Umo Umo 31d 21d 41wk 21d 41d 31d

-Value is expressed as mean ± SO. t Value is expressed as geometric mean (range). Although the values obtained at the beginning of each study day were all within one twofold dilution of the value obtained on the study qualifying day, they were not always within one twofold dilution of the values obtained on all other study days. *Valueis expressed as number of doses per time period . 310

AIluterol via MOl and Nebulizer (Blake et 81)

to the atmosphere from the exhaust part of the T joint during expiration. The effective Row rate from the air compressor was reduced from 12 Umin to 4 Umin after attachment of the nebulizer. The mean output of this nebulizer was 0.267±0.15 (SD) mllmin with an aerodynamic mass median diameter of 4.6 (geometric SD of 4.2).'· Subjects received placebo (2 ml of diluent alone) and 0.625, 1.25, 2.5, and 5.0 mg of the albuterol nebulizer solution on different days. Placebo and albuterol MDis (90 ILg per pufl) were attached to an InspirEase device (Schering) to standardize administration technique . The InspirEase mouthpiece used in this study was not the Universal mouthpiece recalled by the manufacturer in spring 1990. Subjects were instructed to actuate the device with one puff, inhale slowly, and hold their breath for 5 s. The breath was exhaled back into the InspirEase device, inhaled again, and held for an additional 5 s. Subjects received placebo and one, two, four, and six puffs of albuterol from the MDI on different days. There was a I-min interval between puffs. All treatment regimens and placebo were administered in a double-blind, randomized, crossover design with at least a 24-h washout period between treatments. A double-dummy technique was used whereby placebo nebulizer solution was administered on study days of active drug from the MDI and placebo MOl was administered on study days of active drug from the nebulizer solution. On the placebo day, subjects inhaled both placebo nebulizer solution and placebo MDI solution. The nebulizer solution was administered prior to the MOl on all study days. Histamine Bronchoprovocation

Bronchoprovocation was performed by a modification of the tidal breathing method of Coclccroftet al.'· BrieRy, bicarbonate-buffered saline was inhaled for 2 min from a Wright nebulizer (Roxon MediTech, Montreal) calibrated weekly to provide an output of precisely 0.13 mllmin. At 30, 90, and ISO s after inhalation, a single spirometric maneuver was performed, and the FEV, was recorded. If FEV. did not begin to return to baseline by ISO S, spirometry was repeated at 2 min intervals until FEV. increased . The lowest FEV. was selected to ensure that the maximal bronchoconstrictor response had been achieved prior to administering the next higher concentration of histamine. When spirometric tracings indicated a poor effort, maneuvers were repeated until an acceptable tracing was obtained. The initial concentration of histamine in buffered saline on the screening day was based on initial FEV. and history

of medication use." This concentration was nebulized for exactly 2 min and spirometry was repeated, as above, until the lowest FEV. was recorded. This procedure was repeated with twofold increasing concentrations of histamine until FEV, decreased by 20 percent or more . The pc.. was interpolated from the line connecting the last two data points of percentage change in FEV. and log histamine concentration. On subsequent study days, the initial concentration of histamine was two twofold dilutions below the pc.. measured on the screening day.

Data Analysis The effect of albuterol or placebo on airway reactivity to histamine was expressed as a ratio of pc.. values as follows: . .. pc.. after study drug d d ' Drug Activity Ratio (DAR)= PC bef .. lore stu y rug where DAR represents the increase in PC.. (decrease in airway reactivity) resulting from albuterol or placebo ." The bronchodilator response measured 30 min after drug administration was calculated as the percent predicted FEV, and as the change in FEV. expressed as a percentage of maximum achievable improvement as follows: FEV. after albuterol- baseline FEV, % improvement = X 100, Maximum FEV. - baseline FEV. where the baseline FEV. was measured at the start of each study day, the FEV. after albuterol was measured 30 min after drug or placebo administration, and the maximum FEV. was the highest FEV, ever recorded for that subject during ten observations (qualifying day and nine study days). This method of expressing FEV. reflects the degree to which a patient's ventilation returns to maximal possible function as a result of drug therapy and allows comparison of subjects independent of their body size and severity of airway obstruction. It emphasizes dilferences when obstruction is mild and there is less capacity for improvement, and adjusts for day-to-day dilferences in baseline pulmonary function .II Other investigators have suggested that this is the best method of expressing FEV. from a clinical standpoint.·····..

Statistical Methods An analysis of variance (ANOVA) for repeated measures was used to evaluate differences among treatments in log DAR, percentage



i= 00( a:











=> ~











O.625 mll

1.25 mll

2. 5mll



FIGURE 1. Dose-response relationship for drug activity ratio (shown as geometric mean ± SD) after placebo and a range of doses of albuterol administered by MOl and nebulizer (NEB) in 12 subjects with mild asthma . All doses from the nebulizer and four and six puffs from the MDI provided significantly greater protection against histamine-induced bronchoconstriction than one or two puffs from the MOl (p<0.05), which in turn provided significantly greater protection than placebo. CHEST I 101 I 2 I FEBRUARY, 1992


of predicted FEY" and percentage of maximum achievable improve ment in FEY, . The Ryan-Einot-Cabriel-Welsch multiple companson procedure was used to determine the source of a difference when ANOYA was sigmficant .'" The log DAR versus log doseresponse curve for the MOl and nebulizer solution provided the best fit of the data and was tested li>r linearity, parallelism , curvature, and differences in curvature." Friedman's ANOYA and multiple comparison procedure" were used to determine differenees in adverse effects (headache and tremor) and changes in blood pressure and heart rate from baseline (pnstdrug value minus predrug value). All results were expressed as mean ~ SO and were considered statistically significant when pSO .05. RESULTS

The FEV I was within 90 to 110 percent and PC oo was within one twofold dilution of the screening day values for all subjects at the beginning of each study day (Table 1). There were no significant differences between study days in baseline FEV I (p=0.63) or baseline PC oo (p=0.14). The dose-response curve for DAR was continuous, indicating that the amount of albuterol reaching the 132 receptors in the lung increased with dose (Fig 1). The highest dose, 5 mg, did not appear to be the top of the dose-response curve with this end point since no portion of the curve was flat. All doses provided significantly greater protection than placebo, which had a geometric mean DAR of 1.1 ± 1.6 (SO). After the standard 2.5-mg dose of nebulizer solution , the geometric mean DAR was 20.0 ± 2.1, compared with 7.5 ± 2.7 after the standard 100






two puffs from an MOl (p

1 1

l.· ·············J;··············I




a: w c,

40 .... ...... ....... X Predicted 20

X Max


II 1










FIGURE 2. Dose-response curves of a1buterol after placebo and a range of doses adm inistered by MOl and nebulizer presented as mean + SO values for percent predicted FEV, (dotted line) and mean - SO percent of maximum achievable improvement in FEV, (solid line) in 12 subjects with mild asthma. All doses of a1buterol produced greater bronchodilatation than placebo regardless of how results were expressed. However. there was no significant difference between any dose or treatment regimen when analyzed by percent predicted F~V, (ie. the dose-response curve was flat). All doses from the nebulizer (NEB) and six puffs from the MOl produced a greater percentage of maximum achievable improvement in FEY, than two puffs from the MOl (p

AIluIeroI via MOland NebuIlzer(Blake et eI)

no significant differences in FEV I between any of the doses studied (p = 0.13), although all doses provided significantly greater bronchodilatation than placebo (p
The results of this study clearly demonstrate that PC 20 increases with increasing doses of inhaled albuterol regardless of the mode of administration (Fig 1). Thus, the amount of albuterol delivered to the ~2 receptors in the lung must increase with increasing doses. Using histamine bronchoprovocation as a bioassay, we found that the standard dose of the nebulizer solution (2.5 mg) delivered more albuterol to the receptors than the standard two puffs of the MOl (0.180 mg), but with considerably less efficiency. We estimate that ten puffs from an MOl (0.9 mg) would Table 2-Changea in Heart Kate and l#.ood Preuure 30 min after 'lreatment with Placebo or Albuterol*



Systolic Diastolic Heart Rate, Blood Pressure, Blood Pressure , mmHg beats/min mmHg 1.8 (8.5)

1.9 (11.5)

4.3 (8.6)


1 puff 2.7 (6.6) 2 puffs 4.2 (5.4) 4 puffs 1.3 (12.0) -5.8 (8.8) 6 puffs Nebulizer solution 0.625mg 5.3 (10.5) 1.25 mg 3.7 (9.3) -0.2 (11.2) 2.5mg -6.5 (6.3) 5.0mg

6.0 -0.5 -3.6 -4.7

(8.9) (6.1) (15.0) (14.8)

-0.2 -0.1 2.0 2.9

(6.7) (6.7) (4.0) (6.9)

1.3 3.0 2.8 -1.5

(8.9) (8.9) (5.8) (4.4)

0.3 -2.1 1.7 5.5

(5.0) (5.3) (2.7) (6.6)

·Values are expressed as mean (SO) change from baseline.

be required to deliver the same amount of albuterol to the receptors as 2.5 mg of the nebulizer solution with the administration techniques employed in this study. . Others have noted a similar difference in efficiency between MOl and nebulizer solutions.26 •27 The dose of drug delivered from a nebulizer is a function of the diluent volume, gas flow rate, nebulizer model, and whether the system is open or closed.?" Even with the most efficient administration techniques, however, less drug will be delivered to the lungs from a nebulizer system because of loss of drug in the tubing and atmosphere and retention in the nebulizer. Nevertheless, our results indicate that because more drug is placed in the nebulizer, more drug will reach the ~2 receptors with this mode of administration. The clinical relevance of the difference in amount of drug that reaches the receptors is dependent on the severity and reversibility of the airway obstruction. In the subjects in this study, we could not find a significant difference in FEV, between one puff from the MOl (0.09 mg) and 5 mg of the nebulizer solution when expressed as percent predicted because baseline airway obstruction was relatively mild and there was little capacity for improvement (Fig 2). Expressing the results as a percentage of maximum achievable improvement in FEV I resulted in a steeper dose -response curve for MOl than when they were expressed as percent predicted, but the curve flattened out after nebulizer solution, indicating that the top of the doseresponse curve was approached (Fig 2). In the presence of severe airway obstruction, however, the dose-response curve is shifted to the right (ie, it takes more drug to achieve the same degree of improvement)," Under these circumstances, therapeutic response is likely to be better if more drug reaches the receptors. This principle was evident in two studies demonstrating greater effectiveness of albuterol nebulizer solution over the albuterol MOl in acute asthma. 28.29 In the study by Morley et al,28 patients with acute asthma received either three puffs of albuterol MOl through an InspirEase device, 2.5 mg of albuterol from a jet nebulizer, or 15 mg of nebulized metaproterenol every 4 to 6 h . Thirty minutes after administration of the first dose, FEV, improved approximately 6 percent in the group that received albuterol by MOl, compared with approximately 34 percent in the group that received the same drug by nebulizer. However, 24 h after admission, there was no significant difference among the three groups in rate of improvement or duration of hospitalization, suggesting that the acute process subsided slowly regardless of how much albuterol reached the lung receptors. Thus, the nebulizer solution was more effective only during the period of greater airway obstruction, suggesting that when there is a capacity CHEST I 101 12 I FEBRUARY, 1992


for greater response, giving larger doses of albuterol, either higher doses of MOl or the standard dose of nebulizer solution, will result in greater response. Three other studies comparing albuterol MOl and nebulizer solution in patients with stable asthma demonstrated no significant difference between modes of administration. 26 •30 •3 1 However, none of these studies reported the statistical power of the analysis; thus, an inadequate sample size may have contributed to finding no difference. These inconsistent findings may also be due to other differences in method, such as comparison of single doses by each mode of administration and variability in the efficacy of the nebulizer system employed. Variation in nebulizer performance is great enough to account for much of the conflict in results from studies comparing response obtained with different modes of administration. Hess et al" recently demonstrated large differences between various brands of nebulizers in the amount of the dose delivered to the mouthpiece. Even for the same nebulizer model, the amount of solution nebulized was affected by the flow rate of air used to drive the nebulizer and the final volume of solution placed in the nebulizer. Alvine et al? clearly demonstrated unacceptable variations in particle size between different brands of nebulizers and sometimes between different units of the same model manufactured by the same company. Their results suggest that, with some models, the particle size would be too large to reach peripheral airways and, thus, might result in reduced therapeutic response. Our results using bronchoprovocation with histamine as a bioassay for the relative amount of albuterol that reaches 132 receptors in the lung confirm the results of previous radionuclide studies of lung deposition of albuterol. Using technetium-99m labeled Teflon particles, for example, Zainudin et al32 demonstrated that about 11 percent of an albuterol dose was delivered to the lungs with either MOl or nebulizer administration. Since the percentages of the dose reaching the lungs from an MOl and from a nebulizer were the same and since a larger amount of drug is usually placed in the nebulizer, their results support the proposition that more drug reaches the lung from a nebulizer than from an MOL CONCLUSIONS

In subjects with mild asthma, histamine bronchoprovocation is a more sensitive bioassay for the amount of beta-agonist reaching 132 receptors in the lung than FEV. alone . Using this technique, we were able to determine that the standard dose of albuterol administered by nebulizer delivers more drug to the 132 receptors in the lung than the standard dose administered by MOl, but less efficiently. Administering ten puffs from an MOl is likely to deliver approximately 314

the same amount of albuterol as administering 2.5 mg of the nebulizer solution. Since patients with severe airway obstruction require a larger dose of beta-agonist to achieve maximum bronchodilatation than patients with mild airway obstruction, delivering a larger amount of drug to lung receptors, with either higher MOl doses or standard doses of a nebulizer solution, is likely to result in greater therapeutic response. The equivalence of these two modes of administration, however, is dependent on the patient being able to utilize an optimal administration technique with the MOl and selection of a brand of nebulizer that efficiently and reproducibly delivers the drug in an appropriate particle size. ACKNOWLEDGMENTS: The authors gratefully acknowledge Mike Conlon. Ph.D .• Department of Biostatistics, University of Florida. for the many hours he spent helping Dr Blake with PCSASand Joy Mitchell for editing and word processing the typescript. REFERENCES

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CHEST I 101 12 I FEBRUARY, 1992