- Email: [email protected]
Effect of Different Albuterol Dosing Regimens in the Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease
GENERAL CLINICAL INVESTIGATION/BRIEF REPORT
Effect of Different Albuterol Dosing Regimens in the Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease I
From the Department of Emergency Medicine, MetroHealth Medical Center, Department of Surgery, Case Western Reserve University, Cleveland, Ohio. Receivedfor publication October 25, 1995. Revision received March 15, 1996, and July 15, 1996. Acceptedfor publicationJuly 26, i996. Presented at the Societyfor Academic Emergency Medicine Annual Meeting, Washington DC, October 1992. Copyright © by the American College of Emergency Physicians.
CharlesL Emerman,MD Rita K Cydulka,MD
I
I
Study objective: Tocompare hourly administration of albuterol with more frequent administration of a higher cumulative dose in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD). Methods: Participants in this pilot study were patients older than 50 years who presented to the emergency department with an acute exacerbation of COPD.After initial assessment and spirometry, all patients received nebulized aerosols every 20 minutes. Patients were randomly assigned to receive either albuterol (2.5 rag) every 60 minutes for two doses, interspersed with saline aerosols every 20 minutes; or albuterol (2.5 rag) every 20 minutes for 2 hours. Patients were assessed with spirometry after 60 and 120 minutes. No other medications were administered during the course of this study. Results: Eighty-six patients were enrolled in the study. No statistically significant difference was found between groups in mean 1-second forced expiratory volume (FEV1)at study initiation, 1 hour, or 2 hours or in the interval changes in mean FEV1. There was, however, almost twice as much improvement in FEV~in the higherdose group. Group hospitalization rates were similar. There were more side effects in the higher-dose group (45% versus 24%, P<.05). Among 32 patients with a pretreatment FEV1 less than 20% of predicted, there was a significantly greater interval improvement in FEV1 at both 1 hour and 2 hours. Conclusion: This study failed to demonstrate a statistically significant advantage to use of a higher cumulative dose of albuterol in patients with acute exacerbation of COPD, possibly because of type II statistical error. There may be an advantage to more frequent dosing, particularly in patients with initially severe bronchospasm, although at the expense of more frequent side effects. [Emerman CL, Cydulka RK: Effect of different albuterol dosing regimens in the treatment of acute exacerbation of chronic obstructive pulmonary disease. Ann EmergMed Apri11997;29: 474-478.]
47 4
ANNALS OF EMERGENCY MEDICINE
29:4 APRIL 1997
ALBUTEROL
Emerman & Cy,dulkea
nil
INTRODUCTION
Previous studies have established a log-linear increase in pulmonary function, as measured by 1-second forced expiratory volume (FEV~), with increasing doses of albuterol for patients with stable chronic obstructive pulmonary disease (COPD). 1 However, the optimal dose of ~-agonists to administer during acute exacerbation of COPD has not been established. 2 The National Asthma Education and Prevention Program has recommended that adults with acute asthma receive aerosolized 13-agonists every 20 to 30 minutes. 3 In part, these recommendations were based on a previous study that suggested asthma patients who received metaproterenol every 20 minutes had greater improvement in pulmonary function than those who received hourly administration of ~-agonists. 4 Other studies have not demonstrated that more frequent administration of atbuterol leads to a greater improvement in pulmonary function in asthmatic adults. 5 Although aerosolized albuterol is routinely used in the management of COPD, higher doses can lead to increases in heart rate and decreases in serum potassium levels. 6 There is little objective information to guide the administration of albuteroI for patients presenting to the emergency department with acute exacerbation of COPD. The purpose of this pilot study was to compare hourly administration of albuterol with more frequent administration at a higher cumulative dose. MATERIALS AND METHODS
This study was conducted from January 1993 to December 1994 in the ED of MetroHealth Medical Center, a large, urban, county-owned teaching institution. During times when one of the investigators or research nurses was present, patients older than 50 years who presented to the ED with complaints of dyspnea were enrolled in the study if they had a previously established diagnosis of COPD as determined by their primary physician or if they gave a history consistent with chronic bronchitis (ie, sputum production for 3 months of the year for at least 2 years), r Each patient's medical record was reviewed to verify the onset of episodes of wheezing and shortness of breath after the age of 45 years. Patients who denied a prior diagnosis of COPD and who did not have a history consistent with chronic bronchitis were excluded from this study; patients with history of both asthma and COPD were included. Patients were excluded if they had clinical evidence of decompensated congestive heart failure or pneumonia, if they had a history of lung cancer or previous lung surgery, or if they were too ill to perform spirometry
APRIL 1997 29:4 ANNALS 0F EMERGENCYMEDICINE
III
On arrival of the patient at the ED, spirometry was performed with the patient seated and wearing nose clips. A computerized, Fleisch pneumotachygraph-type spirometer (SpiroScan 1000; Brentwood Instruments) was used. Three forced vital capacity maneuvers were obtained, and the highest FEV~ was used for analysis. The spirometer was calibrated at least three times a week with the use of a 3-L syringe. Spirometry was performed by one of two trained research nurses or by one of the investigators. After informed consent was obtained, blood was drawn for CBC, theophylline level, serum potassium, and room air arterial blood gas determinations. An anteroposterior chest radiograph was obtained on all patients at bedside. All patients received nasal oxygen, 3 L/minute, adjusted on the basis of the pulse oximetry and the arterial blood gas results. Therapy was initiated with albuterol, 2.5 n'@ by air-driven nebulizer. Patients were enrolled by a predetermined block randomization scheme. The medication was contained in coded vials prepared in advance by the hospital pharmacy so that patients, treating physicians, and investigators were blinded to the treatments contained in the aerosols administered at 20, 40, 80, and 100 minutes. The drug administered at the onset of the study and at 60 minutes was from openTable 1.
Pretreatment vatues fo~" control and experime~taI groups (mean+_SD, except as noted).
Parameters Age (years) Sex (M/F) Cigarette use (pack-years) Arterial Po2 (ram Hg) Arterial Pcoz (ram Hg) Leukocyte count (cells/mL 3) Theophylline level
Control Group {n=45)
Experimental Group (n=41)
Probability Value
652_+7.4 19/26 63.4_+364
62.5_+8.7 23/18 58.2.+30.5
NS NS NS
68.3.+16.3
712_+16.7
NS
45.4.+1Z8
43.1_+9.9
NS
10,089-+3,257
NS
7.0-+6.4
6.5.+9.6
NS
4.3_+.6
4.2-+.4
NS
24.5+11.7
24.9-+11.2
NS
93 68 53 20
90 59 68 29
NS NS NS NS
9,668+_3,478
(rag/L)
Potassium level (mEq/L) FEV1 (% of predicted normal value) Medication use (%) J3-Agonists Theophylline Ipratroprium Prednisone
475
ALBUTEROL Emerman & Cydulka
label stock because both groups received the same treatment (albuterol, 2.5 rag) at those times. The experimental group received albuterol, 2.5 rag, by aerosol every 20 minutes, for a total of six doses; the control group received two doses of aerosolized albuterol spaced 60 minutes apart, with saline aerosol administered at the other treatment times. Patients did not receive theophylline, corticosteroids, or any other medications during the course of the study. Corticosteroids were not administered because our previous work has found that they do not alter the ED course for patients with acute exacerbation of COPD. All medications were administered by one of the investigators or by a research nurse. Spirometry was obtained at 60 minutes and at 120 minutes. A repeat serum potassium level was obtained at the end of treatment. After 2 hours, the study was terminated and patients were questioned about the appearance of albuterol side effects, including palpitations, headache, tremor, nausea, and vomiting. Any further treatment was at the discretion of the treating physician. In most cases, the decision to admit or discharge the patient from the ED was made at the termination of the study, by the treating physician.
RESULTS
Eighty-six patients, 42 men and 44 women, were enrolled in the study; the average age was 63.9+8.1 years. Seventysix patients had a history of COPD alone, and 10 patients gave a history of both COPD and asthma. Ninety-three percent had a history of current or past cigarette use. The demographic data for the experimental and control groups are listed in Table 10 along with initial laboratory and FEV~ values. There were no differences between the experimental and control groups in any of the parameters.
FEV1 (% of Predicted Normal Value
Figure. Change in pulmonary function with treatment.
The target outcome was change in spirometry at 120 minutes. The secondary outcomes were occurrence of side effects, hospitalization rate, and change in spirometry at 60 minutes. Data were analyzed using Student's t test for continuous variables and the Z2 test for categorical data. Data are expressed as the mean + SD. Unless otherwise noted, the FEV1 is denoted as a percentage of the predicted normal value. This study was approved by the hospital's Human Investigation Committee. The SAS statistical program was used for data analysis.
60 •
Experimental
o
Control
50
40
30-
20-
10Before Treatment
1 Hour
2 Hours
Change in FEV1 With Treatment
47 6
ANNALS QE EMERGENCY MEDICINE 29:4
APRIL 1997
ALBUTEROL Emerman & Qvdulka
I
I
There was a significant increase in pulmonary function with treatment in both groups (Figure). The results of treatment are reported in Table 2. After 2 hours, the FEV 1 (as percentage of predicted normal value) was no different in the control group compared with the experimental group (95% confidence interval [CI], -4.04 to 9.44). The percentage change in the absolute value of FEV~ from pretreatment to 2 hours posttreatment in the experimental group was almost double that in the control group (P=.09; 95% CI, -2.0 to 30.2). Repeated-measures ANOVA confirmed that there was no significant difference in the change in FEV 1 with time between the two groups. The hospitalization rate for patients in each groups was the same; the 95% CI for the difference in rates was -18% to 21%. Side effects consistent with albuterol treatment were more common in the experimental group. The 95% CI for the difference in percent with side effects was 21% to 42%. There was no difference in the posttreatment potassium level between the groups. We then ana]yzed the effects of the higher-dose albuterol regimen in those patients with very severe airway obstruction (pretreatment FEVs<20% of predicted normal). This threshold was chosen after examination of the data for an optimal cutpoint. In these 32 very obstructed patients (18 in the control group and 14 in the experimental group), the experimental treatment led to a greater improvement in pulmonary function than did hourly treatment. After 2 hours, the percentage increase in pulmona U function was 5.7_+22.3 in the control group and 38.8_+52.4 in the experimental group (P<.05). Repeated-measures ANOVA confirmed that there was a significant difference between the changes in FEVx achieved in these severely obstructed patients in the two groups (P<.05). The hospitalization rate was 83% in the control group for these sicker patients and 71% in the experimental group (P=NS). Among these more severely obstructed patients, 30% of the experimental group experienced side effects, compared with 22% of the control group
admission rate between the two groups. On the other hand, McDermott 5 compared treatment with albuterol every 20 minutes versus hourly albuteroI in asthmatic adults. There was no difference in the measures of pulmonary function between the two groups, although the highe>dose group had a higher heart rate. To our knowledge, no other studies have demonstrated an advantage to more frequent doses of albuterol in a large group of adult asthmatic patients. We found greater improvement in pulmonary function among those severely obstructed patients who were given albuterol more frequently and in a higher cumulative dose. Because of the study design, the effects of more frequent nebulization cannot be differentiated from those of the higher cumulative dose. Two studies have compared continuous versus intermittent administration of albuterolS,9; both demonstrated a modest advantage to continuous administration. This study underscores the importance of tailoring therapy to the patient, on the basis of severity of initial presentation. The resuks are consistent with those of Idris et ai ~°, who found a correlation between the number of [~agonist treatments needed and the severity of initial presentation. Colacone et al n found that approximately 14% of their asthmatic patients required higher doses of albuterol to receive maximal response, although they did not con> pare patients in terms of presenting FEVt. This study is subject to several limitations. First, we did not follow patients beyond 2 hours. It is possible that an advantage to more frequent administration of albuteroI would have been revealed had we followed patients for a longer period or contacted patients to determine the re]apse rate. Second, other patient characteristics, such as baseline Table 2.
Results with treatment (mean+__SD,except as noted).
(P=.IO). Parameters
DISCUSSION
The optimal dose for treating patients with airway obstruction remains a topic of study; there is little information about patients wJ.th COPD and conflicting information for asthmatic adults. Nelson et a]~ compared patients given metaprotereno], 5 rag, either every 20 minutes or every hour. The patients receiving the higher cumulative dose had a higher FEV 1 compared with those given hourly metaprotereno], although this difference did not reach statistical significance, and there was no difference in the hospital
APRIL 1997
29:4
ANNALS OF EMERGENCY MEDICINE
FEV~ at 60 minutes (% of predicted normal} FEV~at 120 minutes (% of predicted normal} % Change in FEV1 at 120 minutes compared with baseline Hospitalization rate
(%)
Potassium level (mEq/L) Side effects (%)
Control Group (n=45)
Experimental Group (n=41)
27.7_+16.0
312_+15.2
NS
28.9_+15.7
31.6_+15.7
NS
15.1_+36.2
29,2_+35.9
.09
69
69
NS
4.1_+.05
3,9_+.5
.09
24
45
<,05
Probability Value
477
ALBUTEROL gmerman & Cydulka
pulmonary function tests, may further characterize those patients who require higher cumulative doses of albuterol. A larger stud> using additional data from the patients during a quiescent period, could help assess those characteristics. In this study, we used the FEV 1 rather than the peak expiratory flow rate (PEFR) to gauge improvement in pulmonary function. There is recent evidence that the PEFR overestimates lung function, compared with the FEV1, m both asthmatic subjects and patients with COPD. 12,13 Our study is limited by the small sample size. A larger study might have shown a statistically significant advantage to the higher-dose treatment. There is no particular rationale to limiting the dose of albuterol to 2.5 mg every 20 minutes. Even higher doses of albuterol may elicit a response in patients with mild to moderate airway obstruction. In asthmatic patients, very high doses of albuterol (24 rag/hour) have been employed, although with some occurrence of cardiac stimulation. 6 In our data set, there was an advantage to use of a higher cumulative dose albuterol in patients with more severe airway obstruction. This finding was based on a post hoc analysis and therefore requires verification. Finally, the distinction between the diagnosis of COPD and that of asthma in older patients is difficult on occasion. Our study is limited by reliance on the clinical histories provided by the patients and the accuracy of the diagnoses made by their physicians. We did not find a statistically significant advantage to administration of a higher cumulative dose of albuterol in patients with acute exacerbation of COPD, possibly because of type II statistical error. There may be an advantage to more frequent dosing, particularly in patients with severe obstruction, although at the expense of a higher incidence of side effects. Additional studies are required to determine the optimal doses of albuterol for patients with acute exacerbations of COPD.
7. Standardsfor the diagnosisand care of patients with chronic obstructive pulmonarydisease (COPD}and asthma.Am RoyRaspirDis 1987;134:225-243. 8. RudnitskyGS, Eberlein RS, Schoffstal[JM, et al: Comparisonof intermittent and continuously nebulized albuterol for treatment of asthma in an urban emergencydepartment.Ann EmergMad 1993;22:1842-1846. 9. Lin RY, Sauter D, NewmanT, et ah Continuousversus intermittent albuterol nebulization in the treatment of acute asthma.Ann EmargMed1993;22:1847-1853. 16. Idris AH, McDermott MF, RaucciJC, et ah Emergencydepartmenttreatment of severe asthma: Metered-doseinhaler plus holding chamberis equivabnt in effectivenessto nebulizer. Chest1993;103:865-872. 11. ColaconeA, Afgab M, Wolkove N, eta(: A comparisonof aibuterol administered by metered dose inhaler {and holding chamber)or wet nebulizer in acute asthma. Chest1993;164:835-841. 12. EmermanCL, CyduIkeRK: Use of peekexpiratoryflow rate in emergencydepartmentevaluation of acute exacerbationof COP& Ann EmergMad 1996;27:159-189. 13. Silverman R, Gallagher EJ, Scharf S: Lackof agreementbetween FEV~and peakexpiratory flow rate in acute asthma.Acad EmergMad 1996;3:467.
Reprint no. 47/1/77732 Address for reprints: CharlesL Emerman,MD Departmentof EmergencyMedicine $1-203 MetrOHealthMedical Center 2500 MetroHealthDrive Cleveland,Ohio44109
REFERENCES 1. VathenenAS, Britton JR, EbdenP, et at: High-doseinhaled albuterol in severechronic airflow limitation. Am RevRespirDis 1988;138:850-855. 2. Kuhl DA, Agiri OA, Mauro L8: Betaoagonistsin tile treatment of acute exacerbationof COPD. Ann Pharmacother1994;28:1379-1388. 3. National Asthma EducationProgramExpertPanel Report; Guidelinesfor the diagnosis and managementof asthm& PediatrAsthmaAllergy Immunol1991;5:138-168. 4. Nelson MS, NofstadterA, ParkerJ, et ah Frequencyof inhaled metaproterenolin the treatment of acute asthma exacerbation.Ann EmergMad 1990;19:21-25. 5. McElermottM: Comparisonof two dosing regimens of 13-adrenergicsin acute asthma, in Murphy S (ed): Proceedingsof First National Conferenceon As~hmaManagement.Washington DC: National Heart, Lung, and Blood institute, 1992:55. 6. Lin RY, Smith AJ, HergenroederP: High serum albuterol levels and tachycardia in adult asthmatics treated with high-dosecontinuouslyaeroselizedalbuteroh Chest1993;103:221-225.
478
ANNALS OE EMERGENCY MEDICINE
29:4
APRIL 1997
Effect of Different Albuterol Dosing Regimens in the Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease I
From the Department of Emergency Medicine, MetroHealth Medical Center, Department of Surgery, Case Western Reserve University, Cleveland, Ohio. Receivedfor publication October 25, 1995. Revision received March 15, 1996, and July 15, 1996. Acceptedfor publicationJuly 26, i996. Presented at the Societyfor Academic Emergency Medicine Annual Meeting, Washington DC, October 1992. Copyright © by the American College of Emergency Physicians.
CharlesL Emerman,MD Rita K Cydulka,MD
I
I
Study objective: Tocompare hourly administration of albuterol with more frequent administration of a higher cumulative dose in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD). Methods: Participants in this pilot study were patients older than 50 years who presented to the emergency department with an acute exacerbation of COPD.After initial assessment and spirometry, all patients received nebulized aerosols every 20 minutes. Patients were randomly assigned to receive either albuterol (2.5 rag) every 60 minutes for two doses, interspersed with saline aerosols every 20 minutes; or albuterol (2.5 rag) every 20 minutes for 2 hours. Patients were assessed with spirometry after 60 and 120 minutes. No other medications were administered during the course of this study. Results: Eighty-six patients were enrolled in the study. No statistically significant difference was found between groups in mean 1-second forced expiratory volume (FEV1)at study initiation, 1 hour, or 2 hours or in the interval changes in mean FEV1. There was, however, almost twice as much improvement in FEV~in the higherdose group. Group hospitalization rates were similar. There were more side effects in the higher-dose group (45% versus 24%, P<.05). Among 32 patients with a pretreatment FEV1 less than 20% of predicted, there was a significantly greater interval improvement in FEV1 at both 1 hour and 2 hours. Conclusion: This study failed to demonstrate a statistically significant advantage to use of a higher cumulative dose of albuterol in patients with acute exacerbation of COPD, possibly because of type II statistical error. There may be an advantage to more frequent dosing, particularly in patients with initially severe bronchospasm, although at the expense of more frequent side effects. [Emerman CL, Cydulka RK: Effect of different albuterol dosing regimens in the treatment of acute exacerbation of chronic obstructive pulmonary disease. Ann EmergMed Apri11997;29: 474-478.]
47 4
ANNALS OF EMERGENCY MEDICINE
29:4 APRIL 1997
ALBUTEROL
Emerman & Cy,dulkea
nil
INTRODUCTION
Previous studies have established a log-linear increase in pulmonary function, as measured by 1-second forced expiratory volume (FEV~), with increasing doses of albuterol for patients with stable chronic obstructive pulmonary disease (COPD). 1 However, the optimal dose of ~-agonists to administer during acute exacerbation of COPD has not been established. 2 The National Asthma Education and Prevention Program has recommended that adults with acute asthma receive aerosolized 13-agonists every 20 to 30 minutes. 3 In part, these recommendations were based on a previous study that suggested asthma patients who received metaproterenol every 20 minutes had greater improvement in pulmonary function than those who received hourly administration of ~-agonists. 4 Other studies have not demonstrated that more frequent administration of atbuterol leads to a greater improvement in pulmonary function in asthmatic adults. 5 Although aerosolized albuterol is routinely used in the management of COPD, higher doses can lead to increases in heart rate and decreases in serum potassium levels. 6 There is little objective information to guide the administration of albuteroI for patients presenting to the emergency department with acute exacerbation of COPD. The purpose of this pilot study was to compare hourly administration of albuterol with more frequent administration at a higher cumulative dose. MATERIALS AND METHODS
This study was conducted from January 1993 to December 1994 in the ED of MetroHealth Medical Center, a large, urban, county-owned teaching institution. During times when one of the investigators or research nurses was present, patients older than 50 years who presented to the ED with complaints of dyspnea were enrolled in the study if they had a previously established diagnosis of COPD as determined by their primary physician or if they gave a history consistent with chronic bronchitis (ie, sputum production for 3 months of the year for at least 2 years), r Each patient's medical record was reviewed to verify the onset of episodes of wheezing and shortness of breath after the age of 45 years. Patients who denied a prior diagnosis of COPD and who did not have a history consistent with chronic bronchitis were excluded from this study; patients with history of both asthma and COPD were included. Patients were excluded if they had clinical evidence of decompensated congestive heart failure or pneumonia, if they had a history of lung cancer or previous lung surgery, or if they were too ill to perform spirometry
APRIL 1997 29:4 ANNALS 0F EMERGENCYMEDICINE
III
On arrival of the patient at the ED, spirometry was performed with the patient seated and wearing nose clips. A computerized, Fleisch pneumotachygraph-type spirometer (SpiroScan 1000; Brentwood Instruments) was used. Three forced vital capacity maneuvers were obtained, and the highest FEV~ was used for analysis. The spirometer was calibrated at least three times a week with the use of a 3-L syringe. Spirometry was performed by one of two trained research nurses or by one of the investigators. After informed consent was obtained, blood was drawn for CBC, theophylline level, serum potassium, and room air arterial blood gas determinations. An anteroposterior chest radiograph was obtained on all patients at bedside. All patients received nasal oxygen, 3 L/minute, adjusted on the basis of the pulse oximetry and the arterial blood gas results. Therapy was initiated with albuterol, 2.5 n'@ by air-driven nebulizer. Patients were enrolled by a predetermined block randomization scheme. The medication was contained in coded vials prepared in advance by the hospital pharmacy so that patients, treating physicians, and investigators were blinded to the treatments contained in the aerosols administered at 20, 40, 80, and 100 minutes. The drug administered at the onset of the study and at 60 minutes was from openTable 1.
Pretreatment vatues fo~" control and experime~taI groups (mean+_SD, except as noted).
Parameters Age (years) Sex (M/F) Cigarette use (pack-years) Arterial Po2 (ram Hg) Arterial Pcoz (ram Hg) Leukocyte count (cells/mL 3) Theophylline level
Control Group {n=45)
Experimental Group (n=41)
Probability Value
652_+7.4 19/26 63.4_+364
62.5_+8.7 23/18 58.2.+30.5
NS NS NS
68.3.+16.3
712_+16.7
NS
45.4.+1Z8
43.1_+9.9
NS
10,089-+3,257
NS
7.0-+6.4
6.5.+9.6
NS
4.3_+.6
4.2-+.4
NS
24.5+11.7
24.9-+11.2
NS
93 68 53 20
90 59 68 29
NS NS NS NS
9,668+_3,478
(rag/L)
Potassium level (mEq/L) FEV1 (% of predicted normal value) Medication use (%) J3-Agonists Theophylline Ipratroprium Prednisone
475
ALBUTEROL Emerman & Cydulka
label stock because both groups received the same treatment (albuterol, 2.5 rag) at those times. The experimental group received albuterol, 2.5 rag, by aerosol every 20 minutes, for a total of six doses; the control group received two doses of aerosolized albuterol spaced 60 minutes apart, with saline aerosol administered at the other treatment times. Patients did not receive theophylline, corticosteroids, or any other medications during the course of the study. Corticosteroids were not administered because our previous work has found that they do not alter the ED course for patients with acute exacerbation of COPD. All medications were administered by one of the investigators or by a research nurse. Spirometry was obtained at 60 minutes and at 120 minutes. A repeat serum potassium level was obtained at the end of treatment. After 2 hours, the study was terminated and patients were questioned about the appearance of albuterol side effects, including palpitations, headache, tremor, nausea, and vomiting. Any further treatment was at the discretion of the treating physician. In most cases, the decision to admit or discharge the patient from the ED was made at the termination of the study, by the treating physician.
RESULTS
Eighty-six patients, 42 men and 44 women, were enrolled in the study; the average age was 63.9+8.1 years. Seventysix patients had a history of COPD alone, and 10 patients gave a history of both COPD and asthma. Ninety-three percent had a history of current or past cigarette use. The demographic data for the experimental and control groups are listed in Table 10 along with initial laboratory and FEV~ values. There were no differences between the experimental and control groups in any of the parameters.
FEV1 (% of Predicted Normal Value
Figure. Change in pulmonary function with treatment.
The target outcome was change in spirometry at 120 minutes. The secondary outcomes were occurrence of side effects, hospitalization rate, and change in spirometry at 60 minutes. Data were analyzed using Student's t test for continuous variables and the Z2 test for categorical data. Data are expressed as the mean + SD. Unless otherwise noted, the FEV1 is denoted as a percentage of the predicted normal value. This study was approved by the hospital's Human Investigation Committee. The SAS statistical program was used for data analysis.
60 •
Experimental
o
Control
50
40
30-
20-
10Before Treatment
1 Hour
2 Hours
Change in FEV1 With Treatment
47 6
ANNALS QE EMERGENCY MEDICINE 29:4
APRIL 1997
ALBUTEROL Emerman & Qvdulka
I
I
There was a significant increase in pulmonary function with treatment in both groups (Figure). The results of treatment are reported in Table 2. After 2 hours, the FEV 1 (as percentage of predicted normal value) was no different in the control group compared with the experimental group (95% confidence interval [CI], -4.04 to 9.44). The percentage change in the absolute value of FEV~ from pretreatment to 2 hours posttreatment in the experimental group was almost double that in the control group (P=.09; 95% CI, -2.0 to 30.2). Repeated-measures ANOVA confirmed that there was no significant difference in the change in FEV 1 with time between the two groups. The hospitalization rate for patients in each groups was the same; the 95% CI for the difference in rates was -18% to 21%. Side effects consistent with albuterol treatment were more common in the experimental group. The 95% CI for the difference in percent with side effects was 21% to 42%. There was no difference in the posttreatment potassium level between the groups. We then ana]yzed the effects of the higher-dose albuterol regimen in those patients with very severe airway obstruction (pretreatment FEVs<20% of predicted normal). This threshold was chosen after examination of the data for an optimal cutpoint. In these 32 very obstructed patients (18 in the control group and 14 in the experimental group), the experimental treatment led to a greater improvement in pulmonary function than did hourly treatment. After 2 hours, the percentage increase in pulmona U function was 5.7_+22.3 in the control group and 38.8_+52.4 in the experimental group (P<.05). Repeated-measures ANOVA confirmed that there was a significant difference between the changes in FEVx achieved in these severely obstructed patients in the two groups (P<.05). The hospitalization rate was 83% in the control group for these sicker patients and 71% in the experimental group (P=NS). Among these more severely obstructed patients, 30% of the experimental group experienced side effects, compared with 22% of the control group
admission rate between the two groups. On the other hand, McDermott 5 compared treatment with albuterol every 20 minutes versus hourly albuteroI in asthmatic adults. There was no difference in the measures of pulmonary function between the two groups, although the highe>dose group had a higher heart rate. To our knowledge, no other studies have demonstrated an advantage to more frequent doses of albuterol in a large group of adult asthmatic patients. We found greater improvement in pulmonary function among those severely obstructed patients who were given albuterol more frequently and in a higher cumulative dose. Because of the study design, the effects of more frequent nebulization cannot be differentiated from those of the higher cumulative dose. Two studies have compared continuous versus intermittent administration of albuterolS,9; both demonstrated a modest advantage to continuous administration. This study underscores the importance of tailoring therapy to the patient, on the basis of severity of initial presentation. The resuks are consistent with those of Idris et ai ~°, who found a correlation between the number of [~agonist treatments needed and the severity of initial presentation. Colacone et al n found that approximately 14% of their asthmatic patients required higher doses of albuterol to receive maximal response, although they did not con> pare patients in terms of presenting FEVt. This study is subject to several limitations. First, we did not follow patients beyond 2 hours. It is possible that an advantage to more frequent administration of albuteroI would have been revealed had we followed patients for a longer period or contacted patients to determine the re]apse rate. Second, other patient characteristics, such as baseline Table 2.
Results with treatment (mean+__SD,except as noted).
(P=.IO). Parameters
DISCUSSION
The optimal dose for treating patients with airway obstruction remains a topic of study; there is little information about patients wJ.th COPD and conflicting information for asthmatic adults. Nelson et a]~ compared patients given metaprotereno], 5 rag, either every 20 minutes or every hour. The patients receiving the higher cumulative dose had a higher FEV 1 compared with those given hourly metaprotereno], although this difference did not reach statistical significance, and there was no difference in the hospital
APRIL 1997
29:4
ANNALS OF EMERGENCY MEDICINE
FEV~ at 60 minutes (% of predicted normal} FEV~at 120 minutes (% of predicted normal} % Change in FEV1 at 120 minutes compared with baseline Hospitalization rate
(%)
Potassium level (mEq/L) Side effects (%)
Control Group (n=45)
Experimental Group (n=41)
27.7_+16.0
312_+15.2
NS
28.9_+15.7
31.6_+15.7
NS
15.1_+36.2
29,2_+35.9
.09
69
69
NS
4.1_+.05
3,9_+.5
.09
24
45
<,05
Probability Value
477
ALBUTEROL gmerman & Cydulka
pulmonary function tests, may further characterize those patients who require higher cumulative doses of albuterol. A larger stud> using additional data from the patients during a quiescent period, could help assess those characteristics. In this study, we used the FEV 1 rather than the peak expiratory flow rate (PEFR) to gauge improvement in pulmonary function. There is recent evidence that the PEFR overestimates lung function, compared with the FEV1, m both asthmatic subjects and patients with COPD. 12,13 Our study is limited by the small sample size. A larger study might have shown a statistically significant advantage to the higher-dose treatment. There is no particular rationale to limiting the dose of albuterol to 2.5 mg every 20 minutes. Even higher doses of albuterol may elicit a response in patients with mild to moderate airway obstruction. In asthmatic patients, very high doses of albuterol (24 rag/hour) have been employed, although with some occurrence of cardiac stimulation. 6 In our data set, there was an advantage to use of a higher cumulative dose albuterol in patients with more severe airway obstruction. This finding was based on a post hoc analysis and therefore requires verification. Finally, the distinction between the diagnosis of COPD and that of asthma in older patients is difficult on occasion. Our study is limited by reliance on the clinical histories provided by the patients and the accuracy of the diagnoses made by their physicians. We did not find a statistically significant advantage to administration of a higher cumulative dose of albuterol in patients with acute exacerbation of COPD, possibly because of type II statistical error. There may be an advantage to more frequent dosing, particularly in patients with severe obstruction, although at the expense of a higher incidence of side effects. Additional studies are required to determine the optimal doses of albuterol for patients with acute exacerbations of COPD.
7. Standardsfor the diagnosisand care of patients with chronic obstructive pulmonarydisease (COPD}and asthma.Am RoyRaspirDis 1987;134:225-243. 8. RudnitskyGS, Eberlein RS, Schoffstal[JM, et al: Comparisonof intermittent and continuously nebulized albuterol for treatment of asthma in an urban emergencydepartment.Ann EmergMad 1993;22:1842-1846. 9. Lin RY, Sauter D, NewmanT, et ah Continuousversus intermittent albuterol nebulization in the treatment of acute asthma.Ann EmargMed1993;22:1847-1853. 16. Idris AH, McDermott MF, RaucciJC, et ah Emergencydepartmenttreatment of severe asthma: Metered-doseinhaler plus holding chamberis equivabnt in effectivenessto nebulizer. Chest1993;103:865-872. 11. ColaconeA, Afgab M, Wolkove N, eta(: A comparisonof aibuterol administered by metered dose inhaler {and holding chamber)or wet nebulizer in acute asthma. Chest1993;164:835-841. 12. EmermanCL, CyduIkeRK: Use of peekexpiratoryflow rate in emergencydepartmentevaluation of acute exacerbationof COP& Ann EmergMad 1996;27:159-189. 13. Silverman R, Gallagher EJ, Scharf S: Lackof agreementbetween FEV~and peakexpiratory flow rate in acute asthma.Acad EmergMad 1996;3:467.
Reprint no. 47/1/77732 Address for reprints: CharlesL Emerman,MD Departmentof EmergencyMedicine $1-203 MetrOHealthMedical Center 2500 MetroHealthDrive Cleveland,Ohio44109
REFERENCES 1. VathenenAS, Britton JR, EbdenP, et at: High-doseinhaled albuterol in severechronic airflow limitation. Am RevRespirDis 1988;138:850-855. 2. Kuhl DA, Agiri OA, Mauro L8: Betaoagonistsin tile treatment of acute exacerbationof COPD. Ann Pharmacother1994;28:1379-1388. 3. National Asthma EducationProgramExpertPanel Report; Guidelinesfor the diagnosis and managementof asthm& PediatrAsthmaAllergy Immunol1991;5:138-168. 4. Nelson MS, NofstadterA, ParkerJ, et ah Frequencyof inhaled metaproterenolin the treatment of acute asthma exacerbation.Ann EmergMad 1990;19:21-25. 5. McElermottM: Comparisonof two dosing regimens of 13-adrenergicsin acute asthma, in Murphy S (ed): Proceedingsof First National Conferenceon As~hmaManagement.Washington DC: National Heart, Lung, and Blood institute, 1992:55. 6. Lin RY, Smith AJ, HergenroederP: High serum albuterol levels and tachycardia in adult asthmatics treated with high-dosecontinuouslyaeroselizedalbuteroh Chest1993;103:221-225.
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