Home nebulizer use among patients with cystic fibrosis

H

Home nebulizer use among patients with cystic fibrosis

Margaret Rosenfeld, MD, MPH, Julia Emerson, MD, MPH, Susan Astley, PhD, Pam Joy, RN, Judy WilliamsWarren, RN, MPH, Thomas A. Standaert, PhD, Darlene L. Yim, MS, Donna Crist, BS, MaryJane Thykkuttathil, BS, Mary Torrence, DVM, PhD, Stacey FitzSimmons, PhD, and Bonnie Ramsey, MD

Objective: To describe current patterns of home nebulizer use among patients with cystic fibrosis. Study design: A population-based survey of home nebulizer practices among 227 patients with cystic fibrosis using nebulizers from 1993 to 1994 (Objective 1), and a prospective study of “typical” home use, including testing of performance and bacterial cultures in nebulizers after use, completed by 36 subjects (Objective 2). Results: Objective 1: 85% of subjects reported using jet and 8% ultrasonic nebulizers (categories not mutually exclusive); 15% used unknown brands. Most jet nebulizers were disposable models, which were used for > 14 days by more than half the subjects. Mixing of medications in a single treatment (other than cromolyn and a bronchodilator) was reported by 28% of patients. Objective 2: no apparent deterioration in aerosol particle size or output rate of returned nebulizers compared with new units was observed. Staphylococcus aureus was cultured from 55% and Pseudomonas aeruginosa from 35% of returned nebulizers. Concordance between nebulizer and sputum cultures was poor. Conclusions: Although not generally tested for reusability, disposable nebulizers are generally used by patients for long periods. Medication mixing is common, although its effects on aerosol properties are unknown. Cystic fibrosis respiratory pathogens are frequently isolated from used nebulizers. Patient guidelines for home nebulizer use need to be established. (J Pediatr 1998;132:125-31) Delivery of medications by the inhaled route is an essential component of therapy for cystic fibrosis because it allows application of high concentrations of drug to the respiratory tract with minimal systemic absorption. Aerosolized bronchodilators, an-

tibiotics, antiinflammatory agents, and DNase are in widespread use among patients with CF.1 Some are available by metered-dose inhaler; however, inhaled antibiotics and DNase can only be delivered by nebulizer. The young age of many

From the Department of Pediatrics, University of Washington School of Medicine and Cystic Fibrosis Center, Children’s Hospital and Medical Center, Seattle; Department of Epidemiology, University of Washington School of Public Health, Seattle; Epidemiology Team, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Rockville, Maryland; and Medical Department, Cystic Fibrosis Foundation, Bethesda, Maryland. Funded by a grant from the Food and Drug Administration (no. 223-94-6012) and grants from the Cystic Fibrosis Foundation, LeRoy Matthews Physician Scientist Award (MR). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services or the U.S. Food and Drug Administration, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or Food and Drug Administration. Submitted for publication Sept. 18, 1996; accepted Apr. 2, 1997. Reprint requests: Margaret Rosenfeld, MD, MPH, Division of Pulmonary Medicine, Children’s Hospital and Medical Center, 4800 Sandpoint Way, Seattle, WA 98105. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/83078

patients with CF makes effective coordination of a metered-dose inhaler difficult.2 Thus nebulizers are a mainstay of aerosol delivery in patients with CF. Use of nebulizers is likely to increase as novel therapies such as uridine 5´-triphosphate, antiproteases, and gene therapy become available for clinical use.3 The dose of drug actually delivered to the lung from a nebulizer is difficult to control and measure. The delivered dose is governed by the complex interaction of factors related to nebulizer design and operating conditions, drug formulation, and patient characteristics.3 Even in the laboratory setting under standardized operating conditions, a wide intrabrand and interbrand variability exists in nebulizer efficiency.4-6 No standardized patient use guidelines for home nebulizers are available. The Food and Drug Administration does not require testing of disposable jet nebulizers for reusability. However, patients report use of these units for long periods. Repeated use of nebulizers is a recognized source of nosocomial pneumonia.7-10 Hospitals have developed strict protocols for nebulizer cleaning. Although it is likely that bacterial contamination is equally prevalent with domiciliary nebulizers, no published standard cleaning criteria are available. CF CFF FDA

Cystic fibrosis Cystic Fibrosis Foundation Food and Drug Administration

To assess the safety and efficacy of home nebulizers used by patients with CF and to establish patient use guidelines, it is necessary to first ascertain 125

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current use patterns. We therefore conducted: (1) a population-based survey of prescriptive patterns and home nebulizer use practices among patients with CF who used nebulized medications from 1993 to 1994 and (2) a prospective study of “typical” home use, including the bacterial colonization and functional status of jet nebulizers returned after completion of use.

METHODS Subject Selection and Enrollment Twelve Cystic Fibrosis Foundation–accredited care centers, equally distributed among four geographic regions in the United States, were randomly selected to participate in two simultaneous studies of home nebulizer use practices. These studies consisted of a retrospective survey (Objective 1) and a prospective, diarybased investigation (Objective 2). Centers were eligible for study participation if they had a patient population of more than 200 with at least 60 patients eligible for enrollment from April 1, 1995, to June 30, 1995. Patient eligibility criteria included: (1) age > 3 years, (2) CF diagnosis confirmed by sweat chloride level ≥ 60 mEq/dl11 or evidence of two copies of mutations associated with CF,12 (3) enrollment in the CFF Patient Registry during 1993 and 1994, (4) CF center visits at least every 6 months during 1993 and 1994, and (5) use of aerosolized medication for at least 3 months in both 1993 and 1994. An additional criterion for Objective 2 was current use of a jet nebulizer. Each subject was enrolled in only one of the two studies. A list of all patients at each participating center fulfilling eligibility criteria 1 through 4 was generated from the CFF Patient Registry (Bethesda, Md.); eligible patients were identified if criterion 5 was satisfied. The identity of all subjects was protected by use of a research code. Forty eligible subjects at each center were randomly selected for enrollment into Objective 1, and 20 were selected for Objective 2. A randomized, blocked selection process was used, balanced on 126

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age and gender for each center. Eligible subjects at each center were recruited to participate on the basis of this list until 20 patients were enrolled in Objective 1 and 5 were enrolled in Objective 2. The study was approved by the institutional review board at each center.

Objective 1: Retrospective Survey of Nebulizer Use A standardized questionnaire was completed for each subject regarding nebulizer practices in 1993 and 1994. Interviews were conducted in person or by telephone, and medical records were reviewed as necessary to complete the questionnaires. Information collected included nebulizer and compressor type, aerosol medications prescribed, frequency of aerosol treatments, duration of use of nebulizer units, and cleaning and maintenance practices. Responses to each question were selected from among preestablished categories. Because some patients use different nebulizers for each medication prescribed, subjects were allowed to specify the use of more than one nebulizer type. Use of bronchodilators and cromolyn were not ascertained separately.

Objective 2: Prospective Investigation of Nebulizer Use Subjects were issued a nebulizer of the type they routinely used and instructed to use it at home in their usual fashion. No information on cleaning or maintenance of the nebulizer was provided. Nebulizers were chosen from among the five most commonly used types at the participating centers: (1) Pari LC Jet (Richmond, Va.), (2) Hudson T Up-Draft II (Temecula, Calif.), (3) Marquest Acorn II (Englewood, Colo.), (4) DeVilbiss MicroMist (Somerset, Pa.) , and (5) Baxter Misty-Neb (Round Lake, Ill.). The Pari LC is a durable unit (manufacturer’s recommended length of use, 6 to 12 months), whereas all other models are disposable (single patient use). No more than one subject at each center was selected to use the Pari LC, which served as a durable nebulizer control with which to compare the disposable

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units. Patients were instructed to use the nebulizer until they determined it should be replaced on the basis of their usual criteria. Duration of use was limited to 60 days, although subjects were unaware of this time limit at study initiation. Patients completed a standardized diary entry on a daily basis, documenting the number of treatments and type of cleaning performed. Immediately on termination of use, subjects were instructed to mail nebulizers directly to the central laboratory, without cleaning the units before mailing.

Microbiology On the basis of a pilot study to determine the packaging method that would maximize bacterial yield after 72 hours (the maximum shipping period), nebulizers were mailed in a presupplied sterile cup filled with nonbacteriostatic saline solution and sealed in an airtight bag to prevent desiccation. At the central laboratory, samples were cultured onto the following selective media: MacConkey agar, mannitol salt agar, and Pseudocel (Cetrimide). The media and mailing conditions were designed to maximize growth of the pathogens most commonly isolated from the sputum of patients with CF: Pseudomonas aeruginosa and Staphylococcus aureus. Results of a sputum culture from within 6 months of the nebulizer culture for each study subject were obtained from participating centers.

Nebulizer Performance The performance characteristics of returned nebulizers were tested by nebulization of 5 ml of 0.9% physiologic saline solution (7 ml for the Pari LC) with a Pulmo-Aide compressor (DeVilbiss, Somerset, Pa.). Nebulization was performed in triplicate before and after cleaning the nebulizers in a soap solution with 5% bleach. Measurements obtained included time period of aerosol production, output (in milliliters per minute), mass median aerodynamic diameter, respirable fraction, and the percent of aerosol mass contained in particles in the respirable range (1 to 6 µm). Mass median aerodynamic diameter and respirable fraction

THE JOURNAL OF PEDIATRICS Volume 132, Number 1 were determined with a laser diffraction particle size analyzer (Mastersizer X; Malvern, Southborough, Mass.). Output was measured by gravimetric determinations of fluid content over the period of aerosol production. Performance of the returned nebulizers was compared with that of new units of the same nebulizer models.

Statistical Analysis Demographic and clinical characteristics of Objective 1 subjects were retrieved from the CFF Registry (1994 data) by use of a research code to protect patient identity. Forced expiratory volume in 1 second was expressed as a percent of predicted for height and gender, calculated by using a modified Knudson equation.13 Height and weight percentiles for age and gender were based on National Center for Health Statistics reference curves.14,15 Duration of nebulizer use was categorized on the survey form as < 3 months, 3 to 6 months, and > 6 months per year. Duration of nebulizer use for Objective 2 subjects was computed as the total number of days from initial to final use. Means were compared by using twosample t tests and proportions with the chi-squared test. Median time to discontinuation of nebulizer use among Objective 2 study subjects was generated by means of a Kaplan-Meier estimate. The kappa statistic was computed as a measure of agreement of nebulizer and sputum cultures beyond that expected caused by chance. A value of 1 indicates complete agreement, 0 indicates chance agreement, and values greater or less than 0 indicate agreement greater or less than that expected by chance.16 All statistical analyses were performed with STATA software (Release 4.0, 1995; StataCorp, College Station, Texas).

RESULTS Objective 1 The 227 subjects who completed the survey were compared with all patients in the 1994 CFF Registry, which includes ~80% of patients diagnosed with

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Table I. Comparison of survey subjects to Cystic Fibrosis Foundation Registry subjects in 1994

Characteristic Age on 12/31/94, mean (SD) Race, % Caucasian Gender, % male FEV1, % predicted, mean (SD) Weight, % <5th percentile for age Height, % <5th percentile for age Respiratory culture,‡ % P. aeruginosa positive % Hospitalized储 % Using DNase

Study subjects* (n = 227)

Registry subjects* (n = 19,517)

16.7 (10.0)† 97.8 46.3† 70.0 (28.9) 24.8 20.8 74.7§

15.3 (10.6) 96.2 53.7 72.2 (28.7) 26.3 20.6 59.6

49.3§ 66.5§

35.8 41.0

*Number of subjects analyzed varies between characteristics because of missing data. The lowest sample sizes are those for FEV1: study sample, n = 198; registry, n = 13,636. Two sample t tests were used to compare means, and chi-squared test was used to compare proportions. †p value ≤ 0.05 for comparison of means or proportions. ‡From sputum, throat swabs, and bronchoscopy. §p value ≤ 0.005 for comparison of proportions. 储Percent hospitalized for CF-related reasons at a Cystic Fibrosis Foundation–accredited center in 1994.

Table II. Nebulizers used among survey subjects (n = 227)

Nebulizer brand*

Nebulizer type

No. of subjects (%) reporting use†

Hudson Marquest DeVilbiss

Jet, disposable Jet, disposable Jet, durable and disposable Jet, disposable Jet, durable Ultrasonic — —

87 (38) 87 (38) 28 (12)

Baxter Pari DeVilbiss Other‡ Unknown§

28 (12) 26 (11) 18 (8) 36 (16) 41 (18)

*Subjects were able to indicate manufacturer but not model. †Subjects could indicate more than one type of nebulizer. Percent of total subjects (n = 227) is indicated in parentheses. ‡Includes Hospitak, Inspirator, Invacan, Medic-Aid, Pro-Mist, Rain Drop, Salter, and Twin Jet. §Subjects could not recall nebulizer brand name.

CF in the United States (Table I).17 As expected, the inclusion criterion of long-term nebulizer use selected more severely ill subjects. Study subjects were more likely to be hospitalized in the past year and to be colonized with P. aeruginosa than the Registry population as a whole. They were also slightly older, included a higher proportion of female subjects, and were more often prescribed DNase in 1994. The nebulizer brands used by survey subjects are reported in Table II. Subjects reported manufacturers but not models.

Of the 194 (85%) patients for whom the nebulizer brand was known, 18 (9%) used ultrasonic nebulizers and 192 (99%) used jet nebulizers. Among the jet nebulizer brands, subjects were not always able to distinguish disposable from durable models. Thus the exact proportion of subjects using disposable nebulizers could not be calculated. However, a minimum of 161 (71% of all survey subjects) used disposable nebulizers (produced by Hudson, Marquest, or Baxter). Only 11% of subjects used the Pari LC, the only exclusively durable jet nebulizer. 127

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Table III. Duration of nebulizer use among survey subjects by type of medication administered

Duration of use Medication

Total No. of subjects (%)*

Length of use

Subjects using disposable only† N (%)

Subjects using durable only† N (%)

Bronchodilators

203 (89)

<14 days 15-60 days >60 days Unknown

36 (31) 38 (33) 36 (31) 5 (4) (n = 115)

0 0 7 (100) 0 (n = 7)

Tobramycin

108 (48)

<14 days 15-60 days >60 days Unknown

28 (54) 12 (23) 12 (23) 0 (n = 52)

0 0 3 (75) 1 (25) (n = 4)

DNase

162 (71)

<14 days 15-60 days >60 days Unknown

56 (48) 37 (32) 18 (16) 5 (4) (n = 116)

0 3 (13) 18 (78) 2 (9) (n = 23)

*Subjects frequently were prescribed more than one inhaled medication. †Subjects exclusively using those brands known to be disposable (Hudson, Marquest, Baxter) compared with those subjects exclusively using the durable Pari LC.

Table IV. Cleaning methods used by study subjects

Survey study (n = 227)

Prospective study (n = 36)

No. of methods used

No. of subjects (%)

No. of subjects (%)

Never cleaned One method Two methods Three or more methods

5 (2) 96 (42) 105 (46) 21 (9)

3 (8) 16 (44) 8 (22) 9 (25)

Cleaning method

Tap water rinse Vinegar soak Hand wash with soap Dishwasher Other methods‡

No. of subjects (%) using method*

Percentage using daily

No. of subjects (%) using method*

Ratio of days cleaned to days used†

118 (52) 102 (45) 95 (42) 7 (3) 58 (26)

83 29 64 29 66

22 (61) 14 (39) 12 (33) 4 (11) 10 (28)

0.78 0.28 0.31 0.14 0.95

*Patients could indicate more than one method. †Median values for the ratio of number of days cleaning method was used to number of days nebulizer was used. ‡Includes commercial products (e.g., disinfectants or bleach) and hot or boiling water.

The most widely used disposable jet nebulizers were those FDA approved for use with DNase, the Hudson and Marquest. The most commonly prescribed aerosol medications are shown in Table III. 128

Tobramycin was the most frequently prescribed aminoglycoside (n = 108, 48%), with less frequent use of gentamicin (n = 32, 14%). The only other antibiotic reported was colistin (n = 11, 5%).

Acetylcysteine use was reported by 33 subjects (15%). Co-administration of medications was reported by 64 subjects (28%); the two most common combinations were bronchodilators with an

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Table V. Performance of returned nebulizers

MMAD* (microns)

Respirable fraction†

Output (ml/min)

Nebulizer brand

N

Mean (SD)

% Baseline‡

Mean (SD)

% Baseline‡

Mean (SD)

% Baseline‡

Baxter DeVilbiss Hudson Marquest Pari LC

4 1 9 15 3

5.9 (0.4) 5.6 (—) 5.1 (0.3) 5.3 (0.3) 4.6 (0.1)

101 107 103 100 104

44.5 (3.7) 48.1 (—) 49.8 (2.4) 48.1 (3.1) 57.3 (1.8)

94 90 94 97 98

0.20 (0.02) 0.16 (—) 0.22 (0.03) 0.15 (0.01) 0.47 (0.02)

113 109 125§ 115§ 136§

*Mass median aerodynamic diameter. †Percent of aerosol mass contained in particle range of 1 to 6 µm. ‡Ratio of mean value for returned nebulizers divided by the mean value for unused nebulizers, multiplied by 100. §p < 0.001 comparing means for returned and unused nebulizers.

aminoglycoside (n = 34) and bronchodilators with acetylcysteine (n = 27). Consistent with label recommendations, DNase was never reported to be combined with other medications. Sequential administration of medications with the same nebulizer was reported by 67 subjects (30%), of whom 27 did not clean their nebulizers between medications. Duration of nebulizer use is examined in Table III. Regardless of medication nebulized, subjects used disposable units for long periods. Of subjects using disposable nebulizers for bronchodilator administration, 64% reported duration of use > 2 weeks. For tobramycin and DNase, the corresponding proportions were 46% and 48%, respectively. Subjects used a wide variety of criteria for replacing their nebulizers. Less than half (n = 93, 41%) replaced their nebulizers according to a regular schedule. Others used visual and auditory cues to determine the need for replacement, such as leaking, cracked parts, increasing duration of treatments, or change in sound quality. Most subjects used one or more cleaning methods on a regular basis (Table IV), although a few (n = 5, 2%) never cleaned their units. Tap water rinse was used most frequently, often in combination with a second method used more intermittently, such as vinegar soak or hand-washing with soap.

Objective 2 Of 47 subjects enrolled, 36 (77%) completed the study; 11 subjects failed to re-

turn their diaries and nebulizers to the coordinating center. Five of the subjects waited > 2 weeks to mail their nebulizers, so their units were not cultured; therefore, 31 subjects were available for the microbiologic analyses. Subjects had a mean age of 18.7 years (SD, 9.3; range, 7 to 45 years) and included 20 female subjects (56%). The types of medications prescribed were similar to those among Objective 1 participants. Bronchodilators or cromolyn were used by 22 subjects (61%), DNase by 17 (47%), and antibiotics by 3 (8%). The long duration of disposable nebulizer use seen among Objective 1 participants was also confirmed. For the 33 subjects using disposable nebulizers, the median length of use was 38 days (range, 3 to 82 days), and 73% of subjects used their units > 14 days. The duration of use for the three subjects using the durable Pari LC ranged from 34 to 60 days. Mean total number of treatments administered was 55 (SD, 51) for disposable nebulizers compared with 122 (SD, 57) for durable nebulizers. Duration of use would have been longer if the study had not imposed a 60-day upper limit. Cleaning methods and frequency were similar to those used by Objective 1 participants. Of the nebulizers cultured after home use, 17 (55%) were positive for S. aureus, 11 (35%) for P. aeruginosa, and 6 (19%) for Klebsiella species. A wide variety of other organisms was also cultured from returned nebulizers, includ-

ing enteric gram-negative bacilli, nonfermentative gram-negative bacilli found widely in the environment, skin colonizers, and organisms from animal saliva. The total number of treatments administered did not differ significantly when nebulizers that had positive and negative cultures for S. aureus, P. aeruginosa, or Klebsiella species were compared. Sputum cultures were available for 26 subjects. The median time interval between nebulizer and sputum cultures was 55 days (range, 6 to 150 days). The concordance between sputum and nebulizer cultures was poor. For P. aeruginosa, both sources were positive in 8 cases, sputum alone was positive in 17 cases, and nebulizer alone was positive in 1 case (kappa = –0.08, p = 0.92). For S. aureus, both sputum and nebulizer were positive in 1 case, sputum alone was positive in 1 case, nebulizer alone was positive in 13 cases, and both sources were negative in 11 cases (kappa = –0.01, p = 0.54). The performance of returned nebulizers is evaluated in Table V. Four of the returned nebulizers could not be tested because of missing or broken parts, leaving 32 nebulizers for testing. These units showed no evidence of decline in function compared with unused units. Mean particle size and proportion of output in the respirable size range (respirable fraction) were similar to those of new units. The output in milliliters per minute was increased significantly in the Hudson, Marquest, and Pari LC nebulizers (p < 0.001) 129

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DISCUSSION In our survey we found that most patients with CF used jet rather than ultrasonic nebulizers. Jet nebulizers are less expensive and cumbersome than ultrasonic units, but the pressure injection molding process by which they are manufactured may introduce more interunit variability in aerosol output characteristics than the solid-state design of ultrasonic units.18 Most subjects used disposable, rather than durable, nebulizers and for long periods. One might expect the performance of disposable nebulizers to deteriorate with repeated use. We found that the aerosol particle size and output rate of nebulizers tested after typical home use were comparable to those of unused units. The reason for the slightly increased output of some returned nebulizers compared with new units is unknown but was also seen in a previous study of changes in nebulizer output with repeated use.19 We would not advocate repeated use of disposable units. The sample size was small, and only a limited number of brands were tested. We are currently completing a systematic investigation of nebulizer output characteristics with repeated use. Although no FDA-approved antibiotic formulation exists for aerosol delivery, two thirds of subjects reported use of inhaled antibiotics. Although tobramycin is available in both intravenous and intrathecal preparations (Eli Lilly, Indianapolis, Ind.), gentamicin is only available in an intravenous formulation (Schering Corp, Palo Alto, Calif.). The intravenous formulations of gentamicin and tobramycin both contain preservatives, such as methyl and propyl paraben, sodium bisulfite, and ethylenediaminetetraacetic acid, which may cause bronchoconstriction when administered by aerosol.20,21 The intrathecal tobramycin preparation (a dry powder) is preservative-free. A few patients reported using inhaled colistin, which has been reported to cause acute bronchoconstriction.22 The effects of co-administration of medications on aerosol output and bioactivity are poorly understood. Nonetheless, a quarter of patients reported mixing of medications other than a bronchodilator and cromolyn, and another 130

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12% nebulized two medications sequentially without cleaning the nebulizer between medications. A potential risk of home nebulizer therapy is microbial colonization or infection of the respiratory tract from contaminated units. Nebulizers have long been recognized as a source of organisms causing nosocomial pneumonias in intensive care units,7-9 particularly gram negative bacilli such as P. aeruginosa. Bacterial contamination of domiciliary nebulizers has been evaluated in few studies; all showed high rates of bacterial contamination.23-26 Wexler et al.23 recovered gram negative bacilli from throat cultures obtained immediately after nebulization in 25% (5 of 20) of children with asthma undergoing routine nebulization at home or in a day care center. In a point-prevalence home survey of 36 patients with CF, Pitchford et al.26 found 9 to have contaminated inhalation equipment. Concordance between sputum and equipment isolate was demonstrated in one patient. The current study also demonstrated a high prevalance of CF pathogens cultured from nebulizers after “typical” home use. In the hospital setting strict guidelines for nebulizer cleaning practices have effectively reduced the rate of microbial contamination and nosocomial pneumonias.27-29 The most common cleaning method in this study, tap water rinse, may not effectively sterilize medical equipment contaminated by gram-negative bacilli.30,31 Acetic acid solution (white vinegar) and quaternary ammonium compounds (bleach), routinely recommended by home care companies for disinfection of hand-held nebulizers, also may not adequately sterilize these units.32 Where they exist, standards and guidelines appear to have a significant impact on use patterns. The FDA has approved the Hudson, Marquest, and Pari LC nebulizers for administration of DNase; 80% of patients prescribed DNase reported using one of these models. In summary, the consequences of longterm use of disposable nebulizers and of medication mixing remain poorly understood. More extensive investigation of nebulizer performance after repeated use, maintenance practices that maximize performance, and effects of medication mix-

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ing on aerosol characteristics and bioactivity is needed. The potential for respiratory colonization by microbial nebulizer contaminants also needs to be further explored. On the basis of these studies, standards for nebulizer replacement, maintenance, cleaning, and medication mixing need to be developed. We thank Tanya Desloover for assistance in manuscript preparation.

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13. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983; 127:725-34. 14. Najjar MF, Rowland M. Anthropometric reference data and prevalence of overweight, United States, 1976-80. Washington: National Center for Health Statistics: Vital and Health Statistics; 1987. Series II. No. 238, pp. 87-1688. 15. Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979;32:607-29. 16. Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley and Sons; 1981. 17. FitzSimmons S. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1-9. 18. Dennis JH, Hendrick DJ. Design characteristics for drug nebulizers. J Med Engin Tech 1992;16:63-8. 19. Merkus PJFM, vanEssen-Zandvliet EEM, Parlevliet E, Borsboom G, Sterk PJ, Kerrebijn KF, et al. Changes of nebulizer

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26. Pitchford KC, Corey M, Highsmith AK, Perlman R, Bannatyne R, Gold R, et al. Pseudomonas species contamination of cystic fibrosis patients’ home inhalation equipment. J Pediatr 1987;111:212-6. 27. CDC guidelines for the prevention and control of nosocomial infections. Am J Infect Control 1983;11:26-7. 28. Morris AH. Nebulizer contamination in a burn unit. Am Rev Respir Dis 1973;107:802-8. 29. Craven DE, Lichtenberg DA, Goularte TA, Make BJ, McCabe WR. Contaminated medication nebulizers in mechanical ventilator circuits: source of bacterial aerosols. Am J Med 1984;77:834-8. 30. Lavallee DJ, Lapierre NM, Henwood PK, Pivik JR, Best M, Springthorpe VS, et al. Catheter cleaning or re-use in intermittent catheterization: new light on an old problem. Sci Nursing 1995;12:10-2. 31. Kurtz JJ, VanZandt K, Burns J. Comparison study of home catheter cleaning methods. Rehab Nursing 1995;20:212-4. 32. Chatburn RL, Kallstrom TJ, Bajaksouzian S. A comparison of acetic acid with a quaternary ammonium compound for disinfection of hand-held nebulizers. Respir Care 1988;33:179-87.

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