Case Report of Eosinophilic Gastroenteropathy and a Sandra Roberto A,1, Rómulo Bonilla G, MD,2 Gabriel Pérez G, MD.3 1 Fourth year medical student at the Hospital Universitario de Santander of the Universidad Introduction: Eosinophilic gastroenteropathy is a rare disease characterized by infiltration of eosinophils into one Industrial de Santander in Bucaramanga, Colombia
Dev.chestpubs.orgOriginal Research Population Pharmacodynamic Model
of Bronchodilator Response to Inhaled
Albuterol in Children and Adults With
Kathryn Blake, PharmD; Rajanikanth Madabushi, PhD;Hartmut Derendorf, PhD; and John Lima, PharmD Background: Because interpatient variability in bronchodilation from inhaled albuterol is large
and clinically important, we characterized the albuterol dose/response relationship by pharma-
codynamic modeling and quantified variability.
Methods: Eighty-one patients with asthma (24% African American [AA]; 8 to 65 years old; baseline
FEV1, 40 to 80% of predicted) received 180 g of albuterol from a metered-dose inhaler (MDI),
and then 90 g every 15 min until maximum improvement or 540 g was administered; all then
received 2.5 mg of nebulized albuterol. FEV1 was measured 15 min after each dose. The
population cumulative dose/response data were fitted with a sigmoid maximum effect of albuterol
(Emax) [maximum percentage of predicted FEV1 effect] model by nonlinear mixed-effects
modeling. The influence of covariates on maximum percentage of predicted FEV1 reached after
albuterol administration (Rmax) and cumulative dose of albuterol required to bring about 50% of
maximum effect of albuterol (ED50) and differences between AA and white patients were explored.
Results: ED50 was 141 g, and Emax was 24.0%. Coefficients of variation for ED50 and Emax were
40% and 56%, respectively. Ethnicity was a statistically significant covariate (p < 0.05). AA and white
patients reached 82.4% and 91.9% of predicted FEV1, respectively (p ⴝ 0.0004); and absolute
improvement in percentage of predicted FEV1 was 16.6% in AA patients vs 26.7% in white patients
(p < 0.0003). There were no baseline characteristic differences between AA and white patients.
Nebulized albuterol increased FEV >
200 mL in 21% of participants. Heart rate and BP were
unchanged from baseline after maximal albuterol doses.
Conclusions: Our model predicts that 180 g of albuterol by MDI produces a 14.4% increase in
percentage of predicted FEV1 over baseline (11.7% in AA patients, and 17.5% in white patients).
Emax varies widely between asthmatic patients. AA patients are less responsive to maximal doses of
inhaled albuterol than white patients.
(CHEST 2008; 134:981–989)
Key words: African American; albuterol; asthma; bronchodilator; cumulative dose of albuterol required to bring about 50%
of maximum effect of albuterol; ethnicity; maximum effect of albuterol; metered-dose inhaler; nebulizer; pharmacodynamic
model; white race
Abbreviations: ED ⫽
cumulative dose of albuterol required to bring about 50% of maximum effect of albuterol; Emax ⫽ maximum effect of albuterol; ␥ ⫽ Hill coefficient that describes the steepness of the dose/response relation; ICS ⫽ inhaled corticosteroids; MDI ⫽ metered-dose inhaler; PPK/PD ⫽ population pharmacokinetic/pharmacodynamic; baseline percentage of predicted FEV1; Rmax ⫽ maximum percentage of predicted FEV1 reached after albuterol administration; SABA ⫽ short-acting ␤2-agonist Inhaled short-acting ␤2-agonists (SABAs) are the been associated with significant interpatient variabil-
most potent bronchodilators used today to treat ity in response.3–9 Many studies3–12 have character- acute symptoms of asthma1; and albuterol, a partial ized the SABA dose to bronchodilator response ␤2-agonist, is the most frequently prescribed asthma relationship under controlled conditions. However, medication in the United States.2 Although univer- few studies have explored the magnitude and sources sally used for acute asthma symptoms, SABAs have of bronchodilator response variability, and no studies CHEST / 134 / 5 / NOVEMBER, 2008 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
Dose by MDI
Cumulative Dose by
MDI + Nebulizer
Figure 1. Number of participants who received each cumulative dose of albuterol. After baselinespirometry, participants received 180 g of albuterol and then 90 g every 15 min until maximum improvement or 540 g was administered; all then received 2.5 mg of nebulized albuterol.
have characterized the dose to bronchodilator re- Materials and Methods sponse relationship using population pharmacoki-netic/pharmacodynamic (PPK/PD) modeling.
In a patient-care setting, the purpose of PPK/PD modeling is to gain a better understanding of the Participants of any ethnicity 8 to 65 years old with a well- defined history of physician-diagnosed asthma; a baseline pre- quantitative guidelines for dosage individualization bronchodilator FEV1 of 40% to 80% predicted for age, height, and optimization. Additionally, PPK/PD modeling and gender15,16; who denied oral corticosteroid use, emergency allows one to identify and quantify fixed and random department visits, or hospitalizations within the previous 3 sources of variability that characterize the dose (or months; who were nonsmokers or had ⬍ 5–pack-year history with concentration) vs response relationship in the target no smoking in the previous year; and who had a normal physicalexamination and no confounding diseases were selected. Partic- population to be treated with the drug.13 ipants had to withhold inhaled SABAs or inhaled anticholinergic American Thoracic Society guidelines state that an drugs for 8 h, oral antihistamines for 5 days, theophylline for 24 h, and cromolyn, nedocromil, and inhaled corticosteroids (ICS) for 1 of 12 to 15% above baseline measured 15 min following inhalation of 100 to 400 2 h prior to the study. Inhaled salmeterol and formoterol and g of a SABA, such as albuterol, by metered-dose leukotriene modifiers were not available in the United Stateswhen this study was conducted. Participants were recruited from inhaler (MDI) "suggest a significant bronchodilata- our asthma research clinic database or newspaper advertise- tion."14 Additionally, this measurement is a criterion ments. The study was approved by our local Institutional Review used to diagnose asthma.1 However, it is not clear if Board, and written informed consent was obtained.
these dosing recommendations will achieve maximalbronchodilator response in patients.
Study Design and Drug Administration In the present study, we characterized the albu- terol dose to bronchodilator response relationship in This was an open-label study conducted over 1 to 2 h for each participant on a single day. After we obtained baseline spirome- 81 children and adults with moderate-to-severe per- try, heart rate, and BP measurements, participants received two sistent asthma using a population pharmacodynamic inhalations of albuterol (90 g per inhalation) from an MDI approach. The purpose was to obtain estimates of the attached to a holding chamber (InspirEase; Schering-Plough pharmacodynamic parameters that characterize the Corporation; Kenilworth, NJ). Additional inhalations of 90 g albuterol dose/bronchodilator response curve, quan- through the holding chamber were administered every 15 min,with spirometry, heart rate, and BP measured immediately prior tify and identify sources of interpatient pharmacody- to each dose. When there was no further improvement in FEV1 namic variability, and determine the additional bron- (⬍ 100 mL change from the highest FEV1 obtained after the chodilator effect of a single dose of nebulized previous dose), each participant received a single 2.5-mg dose of albuterol after maximal dosing from an MDI.
nebulized albuterol. Final spirometry, heart rate, and BP mea-surements were obtained 15 min after nebulized albuterol. Thecumulative doses of albuterol administered from the MDI were *From the Center for Clinical Pediatric Pharmacology Research 180 g, 270 g, 360 g, 450 g, 540 g; and the cumulative (Drs. Blake and Lima), Nemours Children's Clinic, Jacksonville; doses from the MDI plus nebulizer were 270 g MDI plus 2,500 and Department of Pharmaceutics (Drs. Madabushi and Deren- g nebulized (2,770 g); 360 g MDI plus 2,500 g nebulized dorf), College of Pharmacy, University of Florida, Gainesville, FL.
All work was performed in the Center for Clinical Pediatric g); 450 g MDI plus 2,500 g nebulized (2,950 g); and Pharmacology Research, Nemours Children's Clinic, Jackson- 540 g MDI plus 2,500 g nebulized (3,040 g). The number of participants receiving each dose and the cumulative administered The authors have no conflicts of interest to report.
doses (MDI and MDI plus nebulized) are shown in Figure 1.
Manuscript received December 13, 2007; revision accepted May These doses represent the amount of drug administered to the patient from each device.
Reproduction of this article is prohibited without written permission Prior to the first dose of study drug, two actuations from the from the American College of Chest Physicians (www.chestjournal.
albuterol MDI were discharged into the holding chamber to prime the MDI and to neutralize the electrostatic charge present Correspondence to: Kathryn Blake, PharmD, Center for Clinical in the plastic holding chamber.17,18 The holding chamber was Pediatric Pharmacology Research, Nemours Children's Clinic, 807Childrens Way, Jacksonville, FL 32207; e-mail: [email protected] collapsed and expanded several times in a location away from the participant to remove any aerosolized albuterol from the interior Original Research Downloaded From: http://publications.chestnet.org/ on 10/07/2016
chamber of the InspirEase. For each single inhalation of albu- dicted FEV1 between whites and African Americans, and dura- terol from the MDI, including the initial two inhalations, partic- tion of asthma between whites and African Americans. The ipants were instructed to actuate the inhaler to release one dose proportion of whites vs African Americans who used ICS, the (90 g) of albuterol into the holding chamber, breathe in slowly proportion of whites vs African Americans who used regularly through the mouthpiece without sounding the reed (inhalation scheduled inhaled albuterol for daily asthma management, and rate of 0.3 L/s is not exceeded), and breath hold for 5 s.
the proportion of ICS users vs nonusers who reported regularly Participants were instructed to exhale into the chamber and scheduled inhaled albuterol therapy for daily asthma manage- inhale a second time followed by a 5-s breath hold.19 ment were compared by 2 analysis. Paired t tests (two-tailed) Albuterol for nebulization (inhalation solution 0.5%) was were used to test for differences in BP and heart rate after diluted with saline solution to a final volume of 3.5 mL. The maximal albuterol doses compared with baseline. A p value dose was administered by tidal breathing to nebulizer sputter- ⬍ 0.05 was considered significant.
ing after repeated tamping of the nebulizer bowl using an opensystem consisting of a nebulizer (Puritan-Bennett; OverlandPark, KS) connected to a mouthpiece by a T joint and driven by an air compressor (Medi-mist; Mountain Medical Equip-ment; Littleton, CO).
Spirometry (MultiSpiro; Irvine, CA) was performed with the participant standing and wearing a nose clip, and up to eight Of 107 asthmatics screened, 81 patients met the efforts were recorded after each dose to obtain the two highest inclusion criteria. Participant characteristics are pre- FEV1 measurements within 100 mL of each other; the highest sented in Table 1. Race and ethnicity were deter- FEV1 was recorded. Polgar reference equations were used fordetermining predicted FEV mined by self-report from the adults and by parental 1 values in girls and boys ⬍ 19 years of age; Knudson reference equations were used for men and report for children ⬍ 18 years old. Thirty-seven women ⱖ 19 years of age.15,16 BP and heart rate were measured percent of participants were ⬍ 20 years old, 40% with the participant seated (Dinamap BP monitor; Critikon, GE were 20 to 45 years old, and 23% were 46 to 65 years Healthcare; Bucks, UK).
old. Baseline FEV1 was from 60 to 80% of predictedin 68% of participants, classifying them as having Population Pharmacodynamic Analysis Population analysis was performed on the cumulative albuterol dose/response data.13 A sigmoid maximum effect of albuterol (Emax) model was used to describe the relationship betweenalbuterol dose and bronchodilator response as determined by the change in percentage of predicted FEV1 from baseline (R0).20 (Rmax ⫺ R0) ⫻ D␥/(ED50 17 (21.0)/12 (14.8) 27 (33.3)/5 (6.2) where D is cumulative albuterol dose, Rmax is the maximum 13 (16.0)/3 (3.7) percentage of predicted FEV1 reached after albuterol adminis- tration, ␥ is the Hill coefficient that describes the steepness of the Duration of asthma, % of patient's life dose/response relation, and ED50 is the cumulative dose of albuterol required to bring about 50% of Emax.
Emax ⫽ Rmax ⫺ R Baseline FVC, % of predicted Mean and between subject coefficient of variation values for Baseline FEV1, % of predicted population parameters were obtained by nonlinear mixed-effects Baseline FEF25–75, % of predicted modeling (NONMEM Project Group; San Francisco, CA). The between-participant variability was assumed to follow a log- ICS current users‡ normal distribution, while an additive error model was used to ICS not used currently or never used explain the random residual error. The method of estimation was Oral corticosteroid: current users (20 mg qod) first-order conditional estimation, which uses conditional esti- Dose of ICS (n ⫽ 45)§ mates of the random interindividual variability while estimating the population parameters.
21,22 The first-order conditional esti- mation method is applicable for nonlinear data and as the amount of data per individual increases.
Duration of ICS therapy (n ⫽ 45), yr Gender, ethnicity, age, years diagnosed with asthma, and current ICS use (yes/no) were incorporated into the model as covariates. A power function was used to test the influence of continuous covariates normalized to their median values for numerical stability on the model parameters. Categorical covari- *Data are presented as mean ⫾ SD or No. (%) unless otherwise ates that take numerical values were tested using a linear model.
forced expiratory flow, midexpiratory phase.
Two-sample t tests (two-tailed, unequal variance) were used to †There was one Hispanic patient in each age group and one other test for significant differences in baseline pulmonary function ethnicity in the 20-to 45-year age group.
(R0), Rmax, baseline percentage of predicted FEV1 between ‡ICS included beclomethasone, flunisolide, and triamcinolone.
users and nonusers of ICS, duration of asthma between users and §Low-, medium-, and high-dose levels as specified in National nonusers of ICS, absolute improvement in percentage of pre- Asthma Education and Prevention Program.1 CHEST / 134 / 5 / NOVEMBER, 2008 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
moderate persistent asthma.1 By patient report onthe day of the study visit, 26 patients (8 AfricanAmericans) stated that they used two inhalations ofalbuterol on a regular schedule either once daily(n ⫽ 5), twice daily (n ⫽ 5), three times daily(n ⫽ 8), or four times daily (n ⫽ 8) [African Ameri-cans vs whites, p ⫽ 0.40]. All other patients reportedusing albuterol at two inhalations on an as-neededbasis. Quantification of SABA use during the weekimmediately prior to the study day was not obtained.
Forty percent of participants were using low-doseICS, 14% were using medium-dose ICS, and 2%were using high-dose ICS; one pediatric patient wastreated with prednisone every other day.1 All partic-ipants had been using ICS for at least 3 months, butthe majority had used ICS for ⱕ 2 years. Clinicalcharacteristics were similar between users and non-users of ICS (baseline FEV Figure 2. Fitted dose/response after cumulative doses of albu- 1 percentage of predicted [p ⫽ 0.89]; duration of asthma [p ⫽ 0.89]; and fre- terol (solid line). Open circles represent individual patient re-sponses. Response is percentage of predicted FEV quency of SABA use [p ⫽ 0.48]). Thirty-two patients lative doses of albuterol administered from the MDI were 180 were using a theophylline product, and 1 patient was g, 270 g, 360 g, 450 g, and 540 g; and the cumulative using cromolyn sodium. Of these 32 patients, 21 doses from the MDI plus nebulizer were 2,770 g (270 g MDI plus 2,500 g nebulized); 2,860 g (360 g MDI plus 2,500 g patients were also using an ICS. All participants had nebulized); 2,950 g (450 g MDI plus 2,500 g nebulized); and long-standing asthma with an asthma diagnosis for 3,040 g (540 g MDI plus 2,500 g nebulized).
64%, 63%, and 56% of their lives in the age groups ⬍ 20 years, 20 to 45 years, and 46 to 65 years, whites and African Americans demonstrated no dif- ference in ED50, but Rmax was 91.9% of predictedFEV1 in whites and 82.4% of predicted in African Modeled Data Americans (p ⫽ 0.0004) [Fig 3]. Consistent with ourmodeled data of difference in Rmax between ethnic Population modeling of the albuterol dose/re- groups, whites had an absolute improvement in sponse relationship is shown in Figure 2. A Hill percentage of predicted FEV coefficient (␥) of 2 was found to best fit the data and 1 of 26.7% from base- line after receiving maximum albuterol doses had lowest objective function value. In preliminary compared with 16.6% in African Americans studies, several pharmacodynamic models were fit- (p ⬍ 0.0003). Using the modeled parameters, two ted to the albuterol dose vs FEV1 relationship. The inhalations of albuterol (180 g) would increase sigmoid Emax model with ␥ ⫽ 2 provided the best fit percentage of predicted FEV to the data. Subsequent analyses setting ␥ as a 1 by 11.7% in African Americans vs 17.5% in whites. Baseline percentage parameter resulted in unreasonable pharmacody- namic and variability estimates suggesting that fitting was not different between whites and African Americans (65.2 ⫾ 11.4% vs the sigmoid Emax model with four parameters re- 65.8 ⫾ 8.3%, respectively; p ⫽ 0.81), nor was du- sulted in overparameterization. Therefore, we set ration of asthma (p ⫽ 0.31) nor the proportion 2 and fit the model with thee parameters. The using ICS (p ⫽ 0.61).
modeled parameters, ED50 of 141 g and Emax of24.0%, predict that the standard of administeringtwo inhalations of albuterol (180 g) is sufficient to Table 2—Population Modeling of Albuterol
produce a 14.4% increase in percentage of predicted FEV1 from baseline and to reach 60.0% of Emax (Table 2). There were 40% and 56% variabilities associated with ED50 and Emax, respectively.
Incorporating gender, age, years diagnosed with asthma, and current ICS use (yes/no) as covariates 64.3% of predicted FEV1 87.6% of predicted FEV1 for R0, Rmax, and ED50 did not account for signifi- 24.0% of predicted FEV1 cant between-participant variability. Including eth- nicity as a covariate on Emax decreased the interpa- tient variability by 1% (p ⬍ 0.05). Modeled data for Residual error (SD) 3.2% of predicted FEV1 Original Research Downloaded From: http://publications.chestnet.org/ on 10/07/2016
Table 3—BP and Heart Rate at Baseline and After
Maximal Albuterol Doses*
After Maximal Albuterol Systolic BP, mm Hg† Diastolic BP, mm Hg‡ Heart rate, beats/min§ *Data are presented as mean ⫾ SD.
†p ⫽ 0.53.
‡p ⫽ 0.06.
§p ⫽ 0.13.
response to SABAs has been observed to be highlyvariable between patients.3–9 The results of thepresent study support these findings and extendthem to include quantification of the variability in Figure 3. Fitted dose/response after cumulative doses of albu- bronchodilator response using a pharmacodynamic terol in African Americans (solid line) and whites (dotted line).
population model. This is the first study to our knowl- Open triangles are individual patient responses for African edge to use population pharmacodynamic modeling to Americans. Open circles are individual patient responses forwhites. Response is percentage of predicted FEV characterize the dose/response relationship and vari- tive doses of albuterol administered from the MDI were 180 g, ability associated with bronchodilator response after 270 g, 360 g, 450 g, and 540 g; and the cumulative doses inhaled albuterol in physician-diagnosed asthmatic pa- from the MDI plus nebulizer were 2,770 g (270 g MDI plus 2,500 g nebulized); 2,860 g (360 g MDI plus 2,500 g tients with moderate-to-severe persistent disease. With nebulized); 2,950 g (450 g MDI plus 2,500 g nebulized); and an Emax of 24% of predicted FEV1 (absolute change 3,040 g (540 g MDI plus 2,500 g nebulized).
in percentage of predicted FEV1 over baseline) andan ED50 of 141 g (dose of albuterol that producedhalf-maximal bronchodilation, ie, 12% [0.5 ⫻ 24%]), Effect of Nebulized Albuterol After Maximum these modeled data predict that two inhalations of Doses From the MDI albuterol (180 g) would increase the percentage ofpredicted FEV All participants reached maximum improvement 1 by 14.4%. The results of this study cannot be applied to the management of acute exacerba- in FEV1 (⬍ 100 mL change from highest FEV1 tions of asthma, which may have a predominantly obtained after previous dose) after six inhalations or inflammatory component. Inflammation is known to less of albuterol from the MDI (Fig 2). The population- impair the response to inhaled ␤ modeled data in Figure 2 demonstrate that addition 2-agonists, which would result in different ␤ of nebulized albuterol to maximal doses from an MDI (from 2,770 to 3,040 g) does not further Patients were considered stable and enrolled in the increase bronchodilator response. However, nebu- study if they had not had an asthma exacerbation lized albuterol provided additional bronchodilation requiring treatment with oral steroids, emergency de- (ⱖ 200 mL)14 in 11 participants (21%) [mean ⫾ SD partment care, or hospitalization in the past 3 months improvement, 366.5 ⫾ 126.1 mL; range, 200 to 610 and were not having an acute worsening of their mL]. After receiving nebulized albuterol, six par- symptoms (albuterol use for acute symptom control ticipants had a fall in FEV ⬎ 100 mL (range, 3.3 was unchanged over previous days). It is likely that some patients would be considered as having poorlycontrolled but stable asthma based on their baseline Adverse Effects pulmonary function, lack of antiinflammatory therapy, There was no change from baseline in BP or heart and regularly scheduled use of inhaled albuterol. Ques- rate after maximal albuterol doses (Table 3). There tionnaires currently used to assess asthma stability such were no complaints of tremor.
as the Asthma Control Test, the Childhood AsthmaControl Test, the Asthma Control Questionnaire, andthe Asthma Therapy Assessment Questionnaire control index1 were not available at the time this study wasconducted.
Inhaled albuterol is the most extensively used Bronchodilator response in the present study was medication for patients with asthma. Bronchodilator extremely variable (Fig 2). Nevertheless, the results CHEST / 134 / 5 / NOVEMBER, 2008 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
of our study clearly show the typical pharmacologic study, the covariates of gender, ethnicity, age, years pattern for the bronchodilator response to albuterol diagnosed with asthma, and current ICS use (yes/no) (steep increase in response at low doses followed by did not further explain the variability observed. We flattening of the response curve at high doses). The were surprised that ICS use did not influence our between-subject coefficient of variation for R0 and findings because corticosteroids increase ␤-adrenergic Rmax was approximately 16%, and for Emax was expression and could affect ED50 and Emax.36 How- 56.2% (Table 2). The similar coefficient of variation ever, only a little over half of patients were using for R0 and Rmax compared with the large variability ICS, and 73% were using a low dose. There were no in Emax suggests that variability associated with significant differences between ICS users (including Emax is due to R0, ED50, and Rmax, and that the the pediatric patient on prednisone) and nonusers change from baseline (Emax) between individuals is for baseline FEV1 percentage of predicted nor du- highly variable. Thus, the Emax 56.2% coefficient of ration of asthma. In addition, a similar proportion of variation predicts that certain asthmatics may be ICS users and nonusers reported albuterol use on a particularly responsive to the bronchodilator effects regular schedule (two inhalations once to four times of albuterol and may experience relief of symptoms daily). Thus, there were not any obvious clinical with relatively low doses of inhaled albuterol. This differences between ICS users and nonusers that individual variation in bronchodilator responsiveness would be expected to influence the ED50 or Emax is clearly evident in Figure 2. However, the variabil- findings. It is possible that inclusion of participants ity in the ED50, although high (41%), is not clear with differing genotypes or haplotypes for genes in from the graph and indicates that the relationship the ␤2-receptor pathway could have contributed to between the dose of inhaled albuterol to achieve a variability.37–43 However, a limitation of our study is targeted reversibility is highly variable.
that we did not collect DNA.
The actual doses of albuterol delivered to the Additionally, we do not know the extent of prior lungs of the study participants would be lower inhaled SABA usage in the week immediately prior than the doses we used in the pharmacodynamic to the study day. Twenty-six patients reported regu- model for the MDI (90 g) and nebulizer (2,500 lar use of albuterol one to four times daily as part of g). Of the 100 g present in the valve of an their asthma self-management. Frequent use of in- albuterol MDI (90 g delivered from the mouth- haled SABAs and long-acting ␤2-agonists can induce piece of the actuator), only 25 to 40 g is delivered ␤2-receptor desensitization, causing patients to be- to the patient in an in vitro model when the MDI come less bronchodilator responsive to additional is attached to a holding chamber.25–27 Likewise, SABA doses.44–46 In addition, frequent use is con- only 400 to 500 g of a 2,500-g dose of albuterol sidered a marker of airways inflammation and in- inhalation solution placed in the nebulizer used in flammatory mediators impair ␤2-receptor activation this study is available for inhalation.28 As we did by ␤2-agonists.24,31 Thus, the variability in broncho- not measure the amount of drug available to the dilator response observed in this study could reflect patient from the devices, we chose to use the MDI dysfunction of the ␤2-receptor induced by overuse of and nebulizer doses most commonly recognized by albuterol and the presence of underlying airway inflammation in some patients.
Patients in this study had a wide range of baseline While patients included in our study had been FEV1 values (40 to 80% of predicted FEV1). Base- nonsmokers for at least the previous year, patients line FEV1 influences the bronchodilator response to with ⬍ 5–pack-year history were allowed to partici- inhaled ␤2-agonists such that larger doses are re- pate. Smoking is known to increase responsiveness to quired in patients with lower baseline values to reach albuterol and methacholine, and even former smok- maximum bronchodilation compared with patients ing increases the risk of having poorly controlled who have higher baseline values.29 Reasons for this asthma.47–49 It is possible that the inclusion of a mix phenomenon could include the presence of endoge- of former and never-smokers in our study could have nous functional antagonists acting at the ␤2-receptor, or contributed to the variability in bronchodilator desensitization of the ␤2-receptor due to either the action of inflammatory mediators at the receptor Our data demonstrate an ethnic difference in or from excessive exposure (due to overuse) to bronchodilator reversibility in white vs African- ␤2-agonist drugs.24,30,31 Baseline FEV1 was not in- American patients with moderate-to-severe, stable cluded as a covariate in our analysis because it is asthma. Ethnicity as a covariate accounted for only included as a parameter in the pharmacodynamic 1% of the variability in Emax (p ⬍ 0.05), but when bronchodilator response was stratified by ethnicity, Other studies5,7,8,35 have also noted significant differences became clinically important. White pa- interpatient variability in response. In the present tients achieved a 9.5% higher maximum percentage Original Research Downloaded From: http://publications.chestnet.org/ on 10/07/2016
of predicted FEV1 than African-American patients consistent with a study in hospitalized asthmatics in (91.9% vs 82.4%, p ⫽ 0.0004), and the pharmacody- which approximately seven inhalations of albuterol namic model predicts that African-American pa- produced maximal bronchodilation and the addition tients would increase percentage of predicted FEV1 of a single 5.0-mg dose of nebulized albuterol in- by 11.7%, compared with 17.5% for white patients creased FEV1 by only 44 ⫾ 8.7 mL.55 Examination after a standard dose of albuterol (two inhalations of of individual responses indicates that there are asth- 90 g from an MDI). There was no difference in matics who benefit with treatment by nebulizer baseline FEV1 nor duration of asthma to explain this following maximal MDI dosing (Fig 2). Further finding, and 50% of the African Americans were re- research is needed to identify which patients would ceiving ICS therapy. It is possible that there were require additional dosing by nebulization.
genetic differences between white and Africans- Both the asthma and COPD diagnosis and man- American patients in our study population that influ- agement guidelines recommend up to a 400-g dose enced response.41 Our data could have important of a short-acting inhaled bronchodilator to assess the clinical implications for ␤2-agonist treatment in African degree of bronchodilator response as an indicator of Americans, in which higher doses of albuterol oradditional or alternative drugs such as anticholinergics disease severity.1,56 Our findings do not alter this may be required for sufficient bronchodilation.
recommendation for asthmatics because we found Three previous studies34,50,51 compared broncho- that two to four inhalations of albuterol (as predicted dilator response to albuterol between white and by the ED50 of 141 g) could increase FEV1 African-American asthmatics. Our data are consis- percentage of predicted by 12% in patients with tent with Hardie et al,50 who found that maximum moderate-to-severe persistent disease. However, af- bronchodilation in mild asthmatics was lower in ter maximal bronchodilation was achieved by dosing African-American compared to white patients after with the MDI, 21% of our study patients had further multiple doses of albuterol by MDI following clinically relevant increases in FEV1 with a 2.5-mg methacholine-induced bronchoconstriction. Of the nebulized dose of albuterol. Therefore, our results other two studies,34,51 one was underpowered to suggest that if adequate bronchodilation is not detect a difference between ethnic groups, and the achieved with the MDI, administration of a nebu- other was conducted in emergency department lized dose may be warranted. Nebulized albuterol is patients (whose clinical features differ from stable known to cause palpitations, sinus tachycardia, anx- asthmatics), and patients were not dosed with iety, tremor, and increased BP.
albuterol to maximal bronchodilation. Differences A small number of participants had bronchocon- in response between other ethnic groups have striction after nebulized albuterol. The formulation been observed.52,53 of albuterol solution used at the time this study was The finding from our modeled data that 180 g of conducted contained 50 g of benzalkonium chlo- albuterol is sufficient to increase percentage of pre- ride per 2.5-mg dose. Inhaled benzalkonium chlo- dicted FEV1 14.4% from baseline and to reach ride administered in the absence of an SABA is 60.0% of Emax is supported by results from other known to induce bronchospasm in asthmatics.57,58 studies5,8,11 in which four inhalations (90 g per However, aside from case reports, there are no inhalation) or less achieve near-maximal bronchodi- controlled studies to indicate that the dose of ben- lation. Studies that found that larger doses were zalkonium chloride used in albuterol solutions for required to reach a maximum bronchodilator re- nebulization approved by the Food and Drug Ad- sponse included patients with severe bronchocon- ministration cause clinically relevant bronchocon- striction, which is known to shift the albuterol dose/ response curve to the right54 (larger doses needed to Our pharmacodynamic population model of albu- achieve the same effect), or demonstrated relatively terol bronchodilator response data is important to small incremental increases (⬍ 100 mL) in FEV1 at the practicing clinician because we found that the higher doses.7,9,11 majority of stable asthmatics with moderate-to-severe Nebulizer treatment is often used in patients with asthma having symptoms will achieve a 12% increase insufficient response to multiple inhalations of albu- in percentage of predicted FEV1 with two to four terol from an MDI. Our modeled population data inhalations of albuterol from their MDI. However, predict that nebulized albuterol does not add to the the maximum percentage of predicted FEV1 will bronchodilator effects from maximal albuterol dos- vary widely between patients with additional doses.
ing from an MDI as shown by the flat dose/response Importantly, the reduced bronchodilator response to curve for all cumulative doses, which include the albuterol in African-American asthmatics compared 2.5-mg nebulized albuterol dose (2,770 g, 2,860 g, to whites suggests that African Americans may require 2,950 g, 3,040 g) [Fig 1, 2]. These data are more aggressive treatment than whites to ensure the CHEST / 134 / 5 / NOVEMBER, 2008 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
bronchodilator and dose used will be effective in 20 Gabrielsson J, Weiner D. Pharmacodynamic concepts: phar- macokinetic and pharmacodynamic data analysis; conceptsand applications. Stockholm, Sweden: Swedish Pharmaceuti-cal Press, 1997; 172–250 21 Jonsson EN, Wade JR, Karlsson MO. Nonlinearity detection: advantages of nonlinear mixed-effects modeling. AAPS 1 National Asthma Education and Prevention Program. Expert PharmSci 2000; 2:E32 panel report 3: guidelines for the diagnosis and management 22 Beal SL, Scheiner LB. NONMEM users guide, NONMEM of asthma. Bethesda, MD: U.S. Department of Health and Project Group. San Francisco, CA: University of California at Human Services, Public Health Service, National Institutes of San Francisco, 1989 Health, National Heart, Lung, and Blood Institute, 2007; 23 Beal SL, Scheiner LB. NONMEM users guide. Part VII: publication 08 – 4051 Conditional estimation methods. San Francisco, CA: Univer- 2 Top 200 generic drugs by units 2005. Drug Topics Maga- sity of California at San Francisco, 1992 24 Shore SA, Moore PE. Regulation of ␤-adrenergic responses 3 Lehmann S, Bakke PS, Eide GE, et al. Bronchodilator in airway smooth muscle. Respir Physiol Neurobiol 2003; reversibility testing in an adult general population; the im- portance of smoking and anthropometrical variables on the 25 Barry PW, O'Callaghan C. Inhalational drug delivery from response to a ␤2-agonist. Pulm Pharmacol Ther 2006; 19: seven different spacer devices. Thorax 1996; 51:835– 840 26 Wilkes W, Fink J, Dhand R. Selecting an accessory device 4 Dales RE, Spitzer WO, Tousignant P, et al. Clinical interpre- with a metered-dose inhaler: variable influence of accessory tation of airway response to a bronchodilator: epidemiologic devices on fine particle dose, throat deposition, and drug considerations. Am Rev Respir Dis 1988; 138:317–320 delivery with asynchronous actuation from a metered-dose 5 Kradjan WA, Driesner NK, Abuan TH, et al. Effect of age on inhaler. J Aerosol Med 2001; 14:351–360 bronchodilator response. Chest 1992; 101:1545–1551 27 Proventil prescribing information [package insert]. Kenilworth, 6 Turner DJ, Landau LI, LeSouef PN. The effect of age on NJ: Schering-Plough Corporation, 2007 bronchodilator responsiveness. Pediatr Pulmonol 1993; 15: 28 Hess D, Fisher D, Williams P, et al. Medication nebulizer performance: effects of diluent volume, nebulizer flow, and 7 Chaieb J, Belcher N, Rees PJ. Maximum achievable bron- nebulizer brand. Chest 1996; 110:498 –505 chodilatation in asthma. Respir Med 1989; 83:497–502 29 Barnes PJ, Pride NB. Dose-response curves to inhaled 8 Hendeles L, Beaty R, Ahrens R, et al. Response to inhaled ␤-adrenoceptor agonists in normal and asthmatic subjects.
albuterol during nocturnal asthma. J Allergy Clin Immunol Br J Clin Pharmacol 1983; 15:677– 682 2004; 113:1058 –1062 30 Lemoine H, Overlack C, Kohl A, et al. Formoterol, fenoterol, 9 Lipworth BJ, Clark RA, Dhillon DP, et al. ␤-Adrenoceptor and salbutamol as partial agonists for relaxation of maximally responses to high doses of inhaled salbutamol in patients with contracted guinea pig tracheae: comparison of relaxation with bronchial asthma. Br J Clin Pharmacol 1988; 26:527–533 receptor binding. Lung 1992; 170:163–180 10 Fishwick D, Bradshaw L, Macdonald C, et al. Cumulative and 31 Nijkamp FP, Engels F, Henricks PA, et al. Mechanisms of single-dose design to assess the bronchodilator effects of ␤-adrenergic receptor regulation in lungs and its implications ␤2-agonists in individuals with asthma. Am J Respir Crit Care for physiological responses. Physiol Rev 1992; 72:323–367 Med 2001; 163:474 – 477 32 Lima JJ, Krukemyer JJ, Boudoulas H. Drug- or hormone- 11 Lotvall J, Palmqvist M, Arvidsson P, et al. The therapeutic induced adaptation: model of adrenergic hypersensitivity.
ratio of R-albuterol is comparable with that of RS-albuterol J Pharmacokinet Biopharm 1989; 17:347–364 in asthmatic patients. J Allergy Clin Immunol 2001; 108: 33 Lalonde RL, Straka RJ, Pieper JA, et al. Propranolol phar- macodynamic modeling using unbound and total concentra- 12 Blake KV, Hoppe M, Harman E, et al. Relative amount of tions in healthy volunteers. J Pharmacokinet Biopharm 1987; albuterol delivered to lung receptors from a metered-dose inhaler and nebulizer solution: bioassay by histamine bron- 34 Lima JJ, Mohamed MH, Self TH, et al. Importance of choprovocation. Chest 1992; 101:309 –315 ␤(2)adrenergic receptor genotype, gender and race on 13 Ette EI, Williams PJ. Population pharmacokinetics: I. Back- albuterol-evoked bronchodilation in asthmatics. Pulm Phar- ground, concepts, and models. Ann Pharmacother 2004; macol Ther 2000; 13:127–134 35 Tinkelman DG, Avner SE, Cooper DM. Assessing broncho- 14 Pellegrino R, Viegi G, Brusasco V, et al. Interpretative dilator responsiveness. J Allergy Clin Immunol 1977; 59:109–114 strategies for lung function tests. Eur Respir J 2005; 36 Barnes PJ. ␤-Adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995; 152:838 – 860 15 Polgar G, Promadhat V. Standard values: pulmonary function 37 Martinez FD, Graves PE, Baldini M, et al. Association testing in children; techniques and standards. Philadelphia, between genetic polymorphisms of the ␤2-adrenoceptor and PA: WB Saunders, 1971; 87–212 response to albuterol in children with and without a history of 16 Knudson RJ, Lebowitz MD, Holberg CJ, et al. Changes in the wheezing. J Clin Invest 1997; 100:3184 –3188 normal maximal expiratory flow-volume curve with growth 38 Lima JJ, Thomason DB, Mohamed MH, et al. Impact of and aging. Am Rev Respir Dis 1983; 127:725–734 genetic polymorphisms of the ␤2-adrenergic receptor on 17 Blake KV, Harman E, Hendeles L. Evaluation of a generic albuterol bronchodilator pharmacodynamics. Clin Pharmacol albuterol metered-dose inhaler: importance of priming the Ther 1999; 65:519 –525 MDI. Ann Allergy 1992; 68:169 –174 39 Small KM, Brown KM, Theiss CT, et al. An Ile to Met 18 Kenyon CJ, Thorsson L, Borgstrom L, et al. The effects of polymorphism in the catalytic domain of adenylyl cyclase type static charge in spacer devices on glucocorticosteroid aerosol 9 confers reduced ␤2-adrenergic receptor stimulation. Phar- deposition in asthmatic patients. Eur Respir J 1998; 11:606–610 macogenetics 2003; 13:535–541 19 InspirEase prescribing information [package insert]. Ken- 40 Tantisira KG, Small KM, Litonjua AA, et al. Molecular ilworth, NJ: Schering-Plough Corporation, 2007 properties and pharmacogenetics of a polymorphism of ad- Original Research Downloaded From: http://publications.chestnet.org/ on 10/07/2016
enylyl cyclase type 9 in asthma: interaction between beta- ness: FEV(1) and symptom differences in whites and African agonist and corticosteroid pathways. Hum Mol Genet 2005; Americans with mild asthma. J Asthma 2007; 44:621– 628 51 El Ekiaby A, Brianas L, Skowronski ME, et al. Impact of race 41 Hawkins GA, Tantisira K, Meyers DA, et al. Sequence, on the severity of acute episodes of asthma and adrenergic haplotype, and association analysis of ADR␤2 in a multiethnic responsiveness. Am J Respir Crit Care Med 2006; 174:508–513 asthma case-control study. Am J Respir Crit Care Med 2006; 52 Choudhry S, Ung N, Avila PC, et al. Pharmacogenetic differences in response to albuterol between Puerto Ricans 42 Drysdale CM, McGraw DW, Stack CB, et al. Complex and Mexicans with asthma. Am J Respir Crit Care Med 2005; promoter and coding region ␤2-adrenergic receptor haplo- types alter receptor expression and predict in vivo respon- 53 Naqvi M, Thyne S, Choudhry S, et al. Ethnic-specific differ- siveness. Proc Natl Acad Sci U S A 2000; 97:10483–10488 ences in bronchodilator responsiveness among African Amer- 43 Silverman EK, Kwiatkowski DJ, Sylvia JS, et al. Family-based icans, Puerto Ricans, and Mexicans with asthma. J Asthma association analysis of ␤2-adrenergic receptor polymorphisms 2007; 44:639 – 648 in the Childhood Asthma Management Program. J Allergy 54 Kelly HW, Murphy S. ␤-Adrenergic agonists for acute, severe Clin Immunol 2003; 112:870 – 876 asthma. Ann Pharmacother 1992; 26:81–91 44 Hancox RJ, Aldridge RE, Cowan JO, et al. Tolerance to 55 Tarala RA, Madsen BW, Paterson JW. Comparative efficacy ␤-agonists during acute bronchoconstriction. Eur Respir J of salbutamol by pressurized aerosol and wet nebulizer in 1999; 14:283–287 acute asthma. Br J Clin Pharmacol 1980; 10:393–397 45 Haney S, Hancox RJ. Tolerance to bronchodilation during 56 Global Initiative for Chronic Obstructive Lung Disease.
treatment with long-acting ␤-agonists: a randomised con- Global Strategy for the Diagnosis, Management, and Preven- trolled trial. Respir Res 2005; 6:107 tion of Chronic Obstructive Pulmonary Disease. Bethesda, 46 van der Woude HJ, Winter TH, Aalbers R. Decreased MD: National Institutes of Health, National Heart, Lung, and bronchodilating effect of salbutamol in relieving methacho- Blood Institute, and the World Heath Organization, 2007 line induced moderate to severe bronchoconstriction during 57 Asmus MJ, Sherman J, Hendeles L. Bronchoconstrictor high dose treatment with long acting ␤2 agonists. Thorax additives in bronchodilator solutions. J Allergy Clin Immunol 2001; 56:529 –535 1999; 104:S53–S60 47 Boskabady MH, Farhadi H. Relation of airway responsiveness 58 Beasley R, Fishwick D, Miles JF, et al. Preservatives in to salbutamol and to methacholine in smokers. Med Sci nebulizer solutions: risks without benefit. Pharmacotherapy Monit 2005; 11:CR344 –CR350 1998; 18:130 –139 48 Pedersen SE, Bateman ED, Bousquet J, et al. Determinants 59 Ponder RD, Wray BB. A case report: sensitivity to benzalko- of response to fluticasone propionate and salmeterol/flutica- nium chloride. J Asthma 1993; 30:229 –231 sone propionate combination in the Gaining Optimal Asthma 60 Spooner LM, Olin JL. Paradoxical bronchoconstriction with Control study. J Allergy Clin Immunol 2007; 120:1036 –1042 albuterol administered by metered-dose inhaler and nebu- 49 Boulet LP, Lemiere C, Archambault F, et al. Smoking and lizer solution. Ann Pharmacother 2005; 39:1924 –1927 asthma: clinical and radiologic features, lung function, and 61 Boucher M, Roy MT, Henderson J. Possible association of airway inflammation. Chest 2006; 129:661– 668 benzalkonium chloride in nebulizer solutions with respiratory 50 Hardie GE, Brown JK, Gold WM. Adrenergic responsive- arrest. Ann Pharmacother 1992; 26:772–774 CHEST / 134 / 5 / NOVEMBER, 2008 Downloaded From: http://publications.chestnet.org/ on 10/07/2016
Malawi HIV and AIDS Monitoring and Evaluation Report 2005-2006 Estimated Population based HIV prevalence per Region Acknowledgements The National AIDS Commission (NAC) is grateful to the following organizations for providing data used to compile this report; all CBOs that reported to district assemblies in the 2005-6 Financial Year; NGOs, FBOs, public sector and private sector institutions that submitted reports to NAC, and District Assemblies during the 2005-2006 Financial Year; District AIDS Coordinators and numerous individuals that assisted in data abstraction from data source institutions, namely: Mr. J. Ghobede (Population Services International) Mrs. Veronica Chirwa, Mr James Gondwe and Mr. J. Zingeni (Ministry of Health, John Snow Incorporated Project); Mr. Chris Moyo and Mr. Naphini (Ministry of Health, HMIS); Dr Felix Salaniponi (Ministry of Health, TB Control Programme); Mr George Bello (Ministry of Health-CHSU); Dr. Eric Schouten (Ministry of Health, HIV Co-ordinator); Professor Tony Harries (Ministry of Health, HIV and AIDS Unit), Tupochele Mtila and Felistas Sibweza (Banja la Mtsogolo), Mrs Kanyuka and Mr. Derick Zanera (National Statistics Office); Mr. Wellington Limbe and Mr Tapson Ndundu (Malawi AIDS Counselling and Rehabilitation Organisation); Mr. D. Runganaikaloo (National AIDS Commission- Financial Management Agency); HIV Sentinel Surveillance Technical Working Group; Dr Kalanda (MASAF); National Health Accounts and HIV Resource Tracking Technical Working Group; and, the Malawi Demographic and Health Survey Steering Committee,