Disposable Jet Nebulizers· How Reliable Are They? Gregory F. Alvine, M.D.; lbt Rodgers, R.R.T.; Karen M. Fitzsimmons, B.S. ; and Richard C. Ahrens, M.D.t
We studied the frequency of malfunction, variability in rate of nebulization, and effect of this variability on aerosol particle size of eight disposable jet nebulizer models produced by six manufacturers. Four of eight models showed visual signs of malfunction, including spraying of large, individually visible droplets, lealdng of nebulizer solution, and air leaks that completely prevented nebulization. Variability of nebulization rate within specific models ranged from 57 to 129 percent. The model with the largest variability of nebulization rate was also associated with an unacceptably large variability in particle size. In
contrast, two models with smaller variability in nebulization rate had greater consistency of particle size. These results indicate poor quality control by some manufacturers in the disposable nebulizer industry. The data suggest that purchasing agents should consider reliability as weD as cost before selecting a specific nebulizer model and that their evaluation should include physical testing of multiple units of each model under consideration. (Chat 1992; 101:316-19) I-AM--M-D-=-ae-rod-yDllIIUC-'-mas-s-m-edian'--diame--te-r-'
J
to-unit Variability in rate of nebulization was determined for each model of nebulizer studied (100 X [highest rate -lowest rate)llowest rate). Visual signs of malfunction were recorded . Based on variation in rates of nebulization, we chose three models for further study in the second phase. One model selected had the largest unit-to-unit variability in rate of nebulization (model 3), while the other two models (models 1 and 2) showed relatively less unit-to-unit variation. Six nebulizers of each of these models, representing the entire range of nebulization rates for that model, were studied for particle size characterization. Three milliliters of normal saline solution was placed in each nebulizer, and airRow was again maintained at 6 Umin throughout the I-min sampling period. Uranine, 0.1 percent (Ruorescein sodium; Fisher Scientific, Fairlawn, NJ), was employed as a tracer. Aerosol particle size was determined by .using a 2 Umin, seven-stage Cascade Impactor
et nebulizers remain important tools for the delivery of aerosolized medications in the treatment of many acute and chronic respiratory diseases, such as bronchitis, asthma, and cystic fibrosis.I" Hospitals spend many dollars annually for disposable jet nebulizers and often choose the most competitively priced unit. Observation of aerosol nebulization rates during clinical use of jet nebulizers at the University ofIowa Hospitals (Iowa City) suggested that many of them For editorial comment see page 298 were malfunctioning. To better assess this problem, we studied the reliability of some commonly used nebulizers by examining the frequency of individual unit malfunction, unit-to-unit variability of nebulization rate, and the effect of nebulization rate on aerosol particle size . Eight different models of nebulizers supplied by six manufacturers were evaluated in a two-phase study. METHODS
In the first phase, we evaluated 12 units of each of the jet nebulizer models for visual signs of malfunction and for rate of nebulization (Table 1). After placing 3 ml of normal saline solution in each nebulizer, we weighed the nebulizer, and air Row through the nebulizer was set at a constant rate of 6 Umin. Every minute for the first 3 min of each trial , the nebulizer was weighed. Nebulization rates (expressed in milliliters per minute) were calculated from weight differences. Nebulization continued until the nebulizer ceased to produce any aerosol (4 to 16 min). The mean rate of nebulization over the first 3 min of operation was calculated for each nebulizer tested. From these data, the percentage of unit-From the College of Med icine, University ofIowa,lowa City (Drs. A1vine and Ahrens and Ms. Fitzsimmons); and Yuma Regional Medical Center, Yuma, Ariz (Ms. Rodgers). t Associate Professor, Department of Pediatrics. Manuscript received March 26; revision accepted June 3.
316
Table l-Eoaluotion ofEight Moclela ofJet Nebuliz.erajor
Vaaual Signa ofMalfunctionand NebulUation &tea (Phaae 1)
Rate of Nebulization, mVmin Malfunction by Visual Inspection
0112 0112 0112 121121I12t 12112t 7/11§
Median
Range
% Variability
0.194 0.202 0.238 0.242 0.207
0.261-0 .152 0.262-0 .162 0.293-0 .128 0.311-0.197 0.250-0.152
71.7 61.7 128.9 57.8
64.5
515'
·Functioned well only when held at 45" angle . tOne nebulizer would not produce aerosol. Results are from remaining units . *A11 nebulizers leaked from a screw top joint. §Air was bubbled through the saline solution rather than being forced through the jet. 'Large individually visible droplets sprayed out the top ; therefore, nebulization was discontinued. Malfunctions were so serious for the last three nebulizers that rate of nebulization could not be meaningfully estimated. Dispo8abIe Jet Nebulzenl (AMne 8t aI)
(Intox Products, Albuquerque, NM).· Aerosol was sampled isokinetically at the mouth of the nebulizer. Uranine deposited on each stage was eluted with 0.1 moVL phosphate buffer (pH 8). The uranine was quantified by using an MPF-2A 8uorescent spectrophotometer (Perkin-Elmer, Norwallc, CI'). Aerodyuamic mass median diameter (AMMD) was determined graphically from log probability plots of cumulative percentage deposited on each stage vs the estimated cutoff diameter of that stage .··· The AMMD is defined such that for each nebulizer, AMMD was plotted against minute rate of nebulization of that particular nebulizer as previously determined. These results were analyzed by using linear regression to determine the relationship between AMMD and minute nebulization rate. RESULTS
In phase 1, four of the eight models tested showed visual signs of malfunction (Table 1). Model 8 had large, individually visible droplets spraying out the top of each of five units tested. Model 7 had air bubbling through the saline solution rather than being forced through the jet, such that nebulization did not occur at all in seven of the 11 nebulizers. Model 6 had saline solution leaking from a screw top joint in each of 12 units tested. Finally, model 4 functioned adequately if held at approximately a 45° angle, but all units tested sprayed large individually visible droplets out the top if used in the recommended vertical position. Median rates of nebulization for models without visible signs of malfunction ranged from 0.194 to 0.242 mVmin. Unit-to-unit variability ranged from 57.8 to 128.9 percent. In phase 2, the three models selected functioned appropriately throughout the testing. For model 3, the model with the largest variation in rate of nebulization, the rate of nebulization correlated with AMMD (Fig 1). Units with the highest rates of nebulization had larger AMMDs. For models 1 and 2, those with a 8
8
2 R.0.27
,."11 5
i
-e
.. 3
2 +--.---.--r--.--...--.----.-.......-.., 0.1
0 .0
0 .3
0.2
Rate or Nebulization (ml/min) FIGURE 2. Rate of nebulization plotted against AMMD for nebulizer
1 (little unit-to-unit variation in rate of nebulization). Data points
represent individual nebulizers. A significant relationship did not exist between rate of nebulization and particle size .
smaller unit-to-unit variation in nebulization rates, the rate of nebulization did not correlate with AMMD (Figs 2 and 3). DISCUSSION
These results indicate a deficiency of quality control or design on the part of some manufacturers in the disposable nebulizer industry. Half of the models tested showed such serious visual signs of malfunction that the rate of clinically useful aerosol output could not be determined. For the model with the largest unit-to-unit variability in rate of nebulization, particle 8 2 R-ll.03 p -0.75
2
R .0.7 p .0.003
5
5
..
.. o
o o
o
o
3
0
2
2
1+--._--.--.---1101,--...----.--.--_._---. 0.1 0 .0 0 .2 0 .3 Rate or Nebulization (ml/min) FIGURE 1. Rate of nebulization plotted against AMMD for nebulizer 3 (large unit-to-unit variation in rate of nebulization). Data points represent individual nebulizers. A significant relationship existed between rate of nebulization and particle size.
0+--...----.--,.--.--...--.----.-.......-.., 0 .0
0 .1
0 .2
0 .3
Rate or Nebulization (m1/mln) FIGURE 3. Rate of nebulization plotted against AMMD for nebulizer 2 (little unit-to-unit variation in rate of nebulization). Data points represent individual nebulizers. A significant relationship did not exist between rate of nebulization and particle size. CHEST I 101 121 FEBRUARY, 1992
317
size varied over a wide range and appeared to correlate with rate of nebulization. Unit-to-unit variability in this model was greater than twice that of the model with the least variability. These findings suggest that better quality control on the part of some manufacturers could improve the performance and reliability of their jet nebulizers. Many factors may affect the nebulization rate and particle size distribution of a nebulizer. Among these are flow rate, initial volume of liquid, surface tension and composition of the liquid, humidity, and structural differences between models such as bafBe design and jet orifice size. 7.9 Our study was conducted with flow rate, initial volume, and aerosol solution composition held constant. A dry compressed air source was used. Although not specifically evaluated, we postulate that the jet orifice contributed most to the variability in nebulization rate and particle size. Since disposable jet nebulizers are made of molded plastic, it may be difficult to keep the tiny jet orifice symmetrical and constant from unit to unit. This consistency, however, is critical because a smaller jet orifice produces smaller particles. 9 Frequent malfunction and a wide unit-to-unit variability in nebulization rate may decrease drug delivery and thus have an impact on clinical efficacy of nebulization treatment. Large, individually visible droplets spraying out the units obviously will not reach the targeted lung tissue . Similarly, drug solution leaking from a nebulizer screw top joint will not benefit the patient. The wide variability in nebulization rates found with some models might be considered a mere annoyance. However, in our study the model with the widest unit-to-unit variability (model 3) also was associated with an unacceptably wide variation in particle size (AMMO). Particle size is an important factor in determining the quantity and deposition site of inhaled drug. 10 Unit-to-unit and model-to-model variation in nebulization rate and particle size may be one of the factors that leads to inconsistencies in the medical literature concerning the efficacy of drug delivery by jet nebulizer. For example, estimates of the relative efficacy (milligram for milligram) of using a metered-
dose inhaler or jet nebulizer to deliver albuterol for relief of asthmatic bronchospasm range from 1:1 to 1:12.5,11·14 Studies showing the jet nebulizer to be up to 12.5 times less effective than the metered-dose inhaler may well have inadvertently chosen a nebulizer model with a high frequency of malfunction or a model which delivered aerosol with characteristics unsuitable for pulmonary drug delivery. Other seemingly minor details of the nebulizer system used such as airflow rate, volume of solution placed in the nebulizer, and tubing attached to the nebulizer may also have adversely affected pulmonary drug delivery. 15 We believe that future articles documenting the efficacy of drugs delivered by jet nebulizer should include detailed information on the model of nebulizer used, the total volume and concentration of drug solution placed in the nebulizer, the airflow rate through the nebulizer, the "plumbing" used to deliver drug from the nebulizer to the patient, and the nebulization rate and aerosol characteristics of the specific nebulizer units actually used in the study. Ideally, a nebulizer chosen for clinical use should have reliable and consistent clinical effects from unit to unit. Of the nebulizers studied, we found some models without visible malfunctions (models 1, 2, and 3) and some with a relatively low unit-to-unit variability (models 1, 2, 4, and 5). The nebulizer models having both of these characteristics (models 1 and 2) also showed a more consistent AMMO than the model with the widest unit-to-unit variability (model 3) and therefore should yield consistent clinical efficacy. Disposable jet nebulizers are purchased in large quantities by hospitals throughout the nation. The University of Iowa Hospitals and Clinics, for example, purchased more than 14,000 disposable nebulizers during the 1987-1988 fiscal year at a cost of $12,100. Cost remains a factor in choosing a disposable nebulizer. However, it is also important to purchase a model that will function consistently. Our study demonstrates that consistent, reliable function cannot automatically be assumed for a specific nebulizer simply because it has reached the market. Recently, Hollie et al l 6 drew similar conclusions from a study of the DeVilbiss 646 jet nebulizer. Unfortunately, there is currently no
Table 2-Probability of Identifying at Lean One Malfunctioning Nebulizer Unit Given the Number of [}nita Tened and the "true" Frequency ofMalfunctioning UW* No. of Units Tested Frequency of Malfunction , % 50 30
20 10 5
8
9
10
11
12
13
14
15
16
20
0.996 0.942 0.833 0.570 0.367
0.998 0.960 0.866 0.613 0.370
0.999 0.972 0.893 0.651 0.401
1.0 0.980 0.914 0.686 0.431
1.0 0.986 0.931 0.718 0.460
1.0 0.990 0.945 0.746 0.487
1.0 0.993 0.956 0.771 0.512
1.0 0.995 0.965 0.794 0.537
1.0 0.997 0.972 0.815 0.560
1.0 0.999 0.988 0.878 0.642
.·Based on binomial distribution.,.
318
DisposlIbIe Jet Nebulizenl (AMne 8t III)
readily available source of unbiased information regarding the quality and reliability of available nebulizers. Ideally, an independent testing laboratory should be set up to characterize the aerosol produced by, and the quality control of, commercially available nebulizers. In the absence of this, those making purchasing decisions might consider the following simple procedures to better assess nebulizers. First, a specific number of units of a disposable jet nebulizer being considered for purchase should be operated in accordance with usual clinical procedures and carefully examined for visual signs of malfunction. We chose to test 12 units because this would give us a 93 percent chance of detecting at least one malfunctioning unit if the "true" frequency of malfunctioning units was one in five (20 percent). If malfunctioning units are identified, a lack of reliability must be suspected. If a larger number of units had been tested, it is an even lower frequency of malfunction would have been detected (Table 2).17 Second, using a top-loading scale capable of measurement to 0.01 g, rate of nebulization should be measured over a 3-min period (gram weight loss/minute = milliliter of solution nebulized/minute). From this Information, median rate of nebulization and unit-to-unit variability can be assessed . We suggest that the median rate of nebulization should be at least 0.2 mllmin, and unit-to-unit variability in the rate of nebulization should be less than 75 percent. Nebulizers failing to meet these specifications should be considered unacceptable. We believe that the 1 to 2 h requ ired to perform the tests outlined herein are well justified considering the critical importance of reliable drug delivery to hospitalized patients receiving inhaled medication . APPENDIX
Designation in Article
Nebulizer Models Investigated" Manufacturer
Model No.
1 2
Baxter, Valencia,CA Puritan-Bennett, Overland Park, KS
3 4 5 6 7 8
Intec Medical, Bluesprings, MO Intec Medical, Bluesprings, MO Hospitak, Lindenhurst, NY Hudson, Temecula, CA Baxter, Valencia,CA AVA Corporationt
00214 001140 (Raindrop) 2016 3017 Up-Mist Up-Draft II 008120 AVA-neb
REFERENCES
1 Miller WF. Aerosol therapy in acute and chronic respiratory disease . Arch Intern Med 1973; 131:148-55 2 Johnson ~E . Principles of nebulizer-delivered drug therapy for asthma, Am J Hosp Pharm 1989; 46:1845-55 3 Hodson M, Penketh A, Batten JC . Aerosol carbenicillin and gentamicin treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis. Lancet 1981; 2:137-39 4 Steinkamp GS, Tummler B, Gappa M, Albus A, Potel J, Doring G, et al. Long-term tobramycin aerosol therapy in cystic fibrosis. Pediatr Pulmonoll989; 6:91-8 5 Hinds WC. Acceleration and curvilinear particle motion. In: Aerosol technology: properties, behavior and measurement of airborne particles. New York: John Wiley & Sons Inc, 1982:11925 6 Hinds WC. Particle size statistics. In: Aerosol technology: properties, behavior and measurement of airborne particles. New York: John Wiley & Sons Inc, 1982:77-83 7 Clay MM, Pavia D, Newman SF, Clark SW Factors inHuencing the size distribution of aerosols from jet nebulizers. Thorax 1983; 38:755-59 8 Mercer TT. Production of therapeutic aerosols: principles and techniques . Chest 1981; 80:813-17 9 Lourenco RY, Cotromanes E . Clinical aerosols: I. characterization of aerosols and their diagnostic uses. Arch Intern Med 1982; 142:2163-71 10 Lippman M, Albert RE. The effect of particle size on the regional deposition of inhaled aerosols in the respiratory tract. Am Indust Hyg Assoc J 1969; 30:257-75 11 Mestitz H, Copland JM, McDonald CF. Comparison of outpatient nebulized vs metered dose inhaler terbutaline in chronic airflow obstruction . Chest 1989; 96:1237-40 12 Weber RW, Petty WE, Nelson HS. Aerosolized terbutaline in asthmatics. J Allergy Clin Immunoll979; 63:116-21 13 Harrison BA, Pierce RJ. Comparison of wet and dry aerosol salbutamoI. Aust N Z J Med 1983; 13:29-33 14 Colacone A, AfilaloM, Wolkove N, Kreisman H. Dose response to inhaled salbutamol administered by metered dose inhaler or wet nebulizer in the treatment of acute asthma [abstract) . Am Rev Respir Dis 1991; 143:A650 15 Hess D, Homey D, SnyderT. Medication-delivery performance of eight small-volume, hand-held nebulizers : effects of diluent volume, gas f1owrate, and nebulizer model. Respir Care 1989; 34:717-23 16 Hollie MC, Malone RA, Skufca RM, Nelson HS. Extreme variability in aerosol output of the DeVilbiss 646 jet nebulizer [abstract No. 30). Presented at the American College of Allergy meeting, San Francisco, November 1990 17 Dixon WI, Massey FJ. Introduction to statistical analysis. 3rd ed . New York: McGraw-Hill, 1983: 245
"Nebulizer units tested at the time experimental work in this study was performed mayor may not be representative ofthose produced under current practices. We strongly urge readers to perform the ir own evaluations of nebulizer models they intend to purchase as described in the Discussion section of this manuscript rather than considering data presented here to be either an endorsement or condemnation of specific nebulizer models. tThe AVA Corporation has been acquired by the Hudson Oxygen Company.
CHEST I 101 121 FEBRUARY, 1992
319
We studied the frequency of malfunction, variability in rate of nebulization, and effect of this variability on aerosol particle size of eight disposable jet nebulizer models produced by six manufacturers. Four of eight models showed visual signs of malfunction, including spraying of large, individually visible droplets, lealdng of nebulizer solution, and air leaks that completely prevented nebulization. Variability of nebulization rate within specific models ranged from 57 to 129 percent. The model with the largest variability of nebulization rate was also associated with an unacceptably large variability in particle size. In
contrast, two models with smaller variability in nebulization rate had greater consistency of particle size. These results indicate poor quality control by some manufacturers in the disposable nebulizer industry. The data suggest that purchasing agents should consider reliability as weD as cost before selecting a specific nebulizer model and that their evaluation should include physical testing of multiple units of each model under consideration. (Chat 1992; 101:316-19) I-AM--M-D-=-ae-rod-yDllIIUC-'-mas-s-m-edian'--diame--te-r-'
J
to-unit Variability in rate of nebulization was determined for each model of nebulizer studied (100 X [highest rate -lowest rate)llowest rate). Visual signs of malfunction were recorded . Based on variation in rates of nebulization, we chose three models for further study in the second phase. One model selected had the largest unit-to-unit variability in rate of nebulization (model 3), while the other two models (models 1 and 2) showed relatively less unit-to-unit variation. Six nebulizers of each of these models, representing the entire range of nebulization rates for that model, were studied for particle size characterization. Three milliliters of normal saline solution was placed in each nebulizer, and airRow was again maintained at 6 Umin throughout the I-min sampling period. Uranine, 0.1 percent (Ruorescein sodium; Fisher Scientific, Fairlawn, NJ), was employed as a tracer. Aerosol particle size was determined by .using a 2 Umin, seven-stage Cascade Impactor
et nebulizers remain important tools for the delivery of aerosolized medications in the treatment of many acute and chronic respiratory diseases, such as bronchitis, asthma, and cystic fibrosis.I" Hospitals spend many dollars annually for disposable jet nebulizers and often choose the most competitively priced unit. Observation of aerosol nebulization rates during clinical use of jet nebulizers at the University ofIowa Hospitals (Iowa City) suggested that many of them For editorial comment see page 298 were malfunctioning. To better assess this problem, we studied the reliability of some commonly used nebulizers by examining the frequency of individual unit malfunction, unit-to-unit variability of nebulization rate, and the effect of nebulization rate on aerosol particle size . Eight different models of nebulizers supplied by six manufacturers were evaluated in a two-phase study. METHODS
In the first phase, we evaluated 12 units of each of the jet nebulizer models for visual signs of malfunction and for rate of nebulization (Table 1). After placing 3 ml of normal saline solution in each nebulizer, we weighed the nebulizer, and air Row through the nebulizer was set at a constant rate of 6 Umin. Every minute for the first 3 min of each trial , the nebulizer was weighed. Nebulization rates (expressed in milliliters per minute) were calculated from weight differences. Nebulization continued until the nebulizer ceased to produce any aerosol (4 to 16 min). The mean rate of nebulization over the first 3 min of operation was calculated for each nebulizer tested. From these data, the percentage of unit-From the College of Med icine, University ofIowa,lowa City (Drs. A1vine and Ahrens and Ms. Fitzsimmons); and Yuma Regional Medical Center, Yuma, Ariz (Ms. Rodgers). t Associate Professor, Department of Pediatrics. Manuscript received March 26; revision accepted June 3.
316
Table l-Eoaluotion ofEight Moclela ofJet Nebuliz.erajor
Vaaual Signa ofMalfunctionand NebulUation &tea (Phaae 1)
Rate of Nebulization, mVmin Malfunction by Visual Inspection
0112 0112 0112 121121I12t 12112t 7/11§
Median
Range
% Variability
0.194 0.202 0.238 0.242 0.207
0.261-0 .152 0.262-0 .162 0.293-0 .128 0.311-0.197 0.250-0.152
71.7 61.7 128.9 57.8
64.5
515'
·Functioned well only when held at 45" angle . tOne nebulizer would not produce aerosol. Results are from remaining units . *A11 nebulizers leaked from a screw top joint. §Air was bubbled through the saline solution rather than being forced through the jet. 'Large individually visible droplets sprayed out the top ; therefore, nebulization was discontinued. Malfunctions were so serious for the last three nebulizers that rate of nebulization could not be meaningfully estimated. Dispo8abIe Jet Nebulzenl (AMne 8t aI)
(Intox Products, Albuquerque, NM).· Aerosol was sampled isokinetically at the mouth of the nebulizer. Uranine deposited on each stage was eluted with 0.1 moVL phosphate buffer (pH 8). The uranine was quantified by using an MPF-2A 8uorescent spectrophotometer (Perkin-Elmer, Norwallc, CI'). Aerodyuamic mass median diameter (AMMD) was determined graphically from log probability plots of cumulative percentage deposited on each stage vs the estimated cutoff diameter of that stage .··· The AMMD is defined such that for each nebulizer, AMMD was plotted against minute rate of nebulization of that particular nebulizer as previously determined. These results were analyzed by using linear regression to determine the relationship between AMMD and minute nebulization rate. RESULTS
In phase 1, four of the eight models tested showed visual signs of malfunction (Table 1). Model 8 had large, individually visible droplets spraying out the top of each of five units tested. Model 7 had air bubbling through the saline solution rather than being forced through the jet, such that nebulization did not occur at all in seven of the 11 nebulizers. Model 6 had saline solution leaking from a screw top joint in each of 12 units tested. Finally, model 4 functioned adequately if held at approximately a 45° angle, but all units tested sprayed large individually visible droplets out the top if used in the recommended vertical position. Median rates of nebulization for models without visible signs of malfunction ranged from 0.194 to 0.242 mVmin. Unit-to-unit variability ranged from 57.8 to 128.9 percent. In phase 2, the three models selected functioned appropriately throughout the testing. For model 3, the model with the largest variation in rate of nebulization, the rate of nebulization correlated with AMMD (Fig 1). Units with the highest rates of nebulization had larger AMMDs. For models 1 and 2, those with a 8
8
2 R.0.27
,."11 5
i
-e
.. 3
2 +--.---.--r--.--...--.----.-.......-.., 0.1
0 .0
0 .3
0.2
Rate or Nebulization (ml/min) FIGURE 2. Rate of nebulization plotted against AMMD for nebulizer
1 (little unit-to-unit variation in rate of nebulization). Data points
represent individual nebulizers. A significant relationship did not exist between rate of nebulization and particle size .
smaller unit-to-unit variation in nebulization rates, the rate of nebulization did not correlate with AMMD (Figs 2 and 3). DISCUSSION
These results indicate a deficiency of quality control or design on the part of some manufacturers in the disposable nebulizer industry. Half of the models tested showed such serious visual signs of malfunction that the rate of clinically useful aerosol output could not be determined. For the model with the largest unit-to-unit variability in rate of nebulization, particle 8 2 R-ll.03 p -0.75
2
R .0.7 p .0.003
5
5
..
.. o
o o
o
o
3
0
2
2
1+--._--.--.---1101,--...----.--.--_._---. 0.1 0 .0 0 .2 0 .3 Rate or Nebulization (ml/min) FIGURE 1. Rate of nebulization plotted against AMMD for nebulizer 3 (large unit-to-unit variation in rate of nebulization). Data points represent individual nebulizers. A significant relationship existed between rate of nebulization and particle size.
0+--...----.--,.--.--...--.----.-.......-.., 0 .0
0 .1
0 .2
0 .3
Rate or Nebulization (m1/mln) FIGURE 3. Rate of nebulization plotted against AMMD for nebulizer 2 (little unit-to-unit variation in rate of nebulization). Data points represent individual nebulizers. A significant relationship did not exist between rate of nebulization and particle size. CHEST I 101 121 FEBRUARY, 1992
317
size varied over a wide range and appeared to correlate with rate of nebulization. Unit-to-unit variability in this model was greater than twice that of the model with the least variability. These findings suggest that better quality control on the part of some manufacturers could improve the performance and reliability of their jet nebulizers. Many factors may affect the nebulization rate and particle size distribution of a nebulizer. Among these are flow rate, initial volume of liquid, surface tension and composition of the liquid, humidity, and structural differences between models such as bafBe design and jet orifice size. 7.9 Our study was conducted with flow rate, initial volume, and aerosol solution composition held constant. A dry compressed air source was used. Although not specifically evaluated, we postulate that the jet orifice contributed most to the variability in nebulization rate and particle size. Since disposable jet nebulizers are made of molded plastic, it may be difficult to keep the tiny jet orifice symmetrical and constant from unit to unit. This consistency, however, is critical because a smaller jet orifice produces smaller particles. 9 Frequent malfunction and a wide unit-to-unit variability in nebulization rate may decrease drug delivery and thus have an impact on clinical efficacy of nebulization treatment. Large, individually visible droplets spraying out the units obviously will not reach the targeted lung tissue . Similarly, drug solution leaking from a nebulizer screw top joint will not benefit the patient. The wide variability in nebulization rates found with some models might be considered a mere annoyance. However, in our study the model with the widest unit-to-unit variability (model 3) also was associated with an unacceptably wide variation in particle size (AMMO). Particle size is an important factor in determining the quantity and deposition site of inhaled drug. 10 Unit-to-unit and model-to-model variation in nebulization rate and particle size may be one of the factors that leads to inconsistencies in the medical literature concerning the efficacy of drug delivery by jet nebulizer. For example, estimates of the relative efficacy (milligram for milligram) of using a metered-
dose inhaler or jet nebulizer to deliver albuterol for relief of asthmatic bronchospasm range from 1:1 to 1:12.5,11·14 Studies showing the jet nebulizer to be up to 12.5 times less effective than the metered-dose inhaler may well have inadvertently chosen a nebulizer model with a high frequency of malfunction or a model which delivered aerosol with characteristics unsuitable for pulmonary drug delivery. Other seemingly minor details of the nebulizer system used such as airflow rate, volume of solution placed in the nebulizer, and tubing attached to the nebulizer may also have adversely affected pulmonary drug delivery. 15 We believe that future articles documenting the efficacy of drugs delivered by jet nebulizer should include detailed information on the model of nebulizer used, the total volume and concentration of drug solution placed in the nebulizer, the airflow rate through the nebulizer, the "plumbing" used to deliver drug from the nebulizer to the patient, and the nebulization rate and aerosol characteristics of the specific nebulizer units actually used in the study. Ideally, a nebulizer chosen for clinical use should have reliable and consistent clinical effects from unit to unit. Of the nebulizers studied, we found some models without visible malfunctions (models 1, 2, and 3) and some with a relatively low unit-to-unit variability (models 1, 2, 4, and 5). The nebulizer models having both of these characteristics (models 1 and 2) also showed a more consistent AMMO than the model with the widest unit-to-unit variability (model 3) and therefore should yield consistent clinical efficacy. Disposable jet nebulizers are purchased in large quantities by hospitals throughout the nation. The University of Iowa Hospitals and Clinics, for example, purchased more than 14,000 disposable nebulizers during the 1987-1988 fiscal year at a cost of $12,100. Cost remains a factor in choosing a disposable nebulizer. However, it is also important to purchase a model that will function consistently. Our study demonstrates that consistent, reliable function cannot automatically be assumed for a specific nebulizer simply because it has reached the market. Recently, Hollie et al l 6 drew similar conclusions from a study of the DeVilbiss 646 jet nebulizer. Unfortunately, there is currently no
Table 2-Probability of Identifying at Lean One Malfunctioning Nebulizer Unit Given the Number of [}nita Tened and the "true" Frequency ofMalfunctioning UW* No. of Units Tested Frequency of Malfunction , % 50 30
20 10 5
8
9
10
11
12
13
14
15
16
20
0.996 0.942 0.833 0.570 0.367
0.998 0.960 0.866 0.613 0.370
0.999 0.972 0.893 0.651 0.401
1.0 0.980 0.914 0.686 0.431
1.0 0.986 0.931 0.718 0.460
1.0 0.990 0.945 0.746 0.487
1.0 0.993 0.956 0.771 0.512
1.0 0.995 0.965 0.794 0.537
1.0 0.997 0.972 0.815 0.560
1.0 0.999 0.988 0.878 0.642
.·Based on binomial distribution.,.
318
DisposlIbIe Jet Nebulizenl (AMne 8t III)
readily available source of unbiased information regarding the quality and reliability of available nebulizers. Ideally, an independent testing laboratory should be set up to characterize the aerosol produced by, and the quality control of, commercially available nebulizers. In the absence of this, those making purchasing decisions might consider the following simple procedures to better assess nebulizers. First, a specific number of units of a disposable jet nebulizer being considered for purchase should be operated in accordance with usual clinical procedures and carefully examined for visual signs of malfunction. We chose to test 12 units because this would give us a 93 percent chance of detecting at least one malfunctioning unit if the "true" frequency of malfunctioning units was one in five (20 percent). If malfunctioning units are identified, a lack of reliability must be suspected. If a larger number of units had been tested, it is an even lower frequency of malfunction would have been detected (Table 2).17 Second, using a top-loading scale capable of measurement to 0.01 g, rate of nebulization should be measured over a 3-min period (gram weight loss/minute = milliliter of solution nebulized/minute). From this Information, median rate of nebulization and unit-to-unit variability can be assessed . We suggest that the median rate of nebulization should be at least 0.2 mllmin, and unit-to-unit variability in the rate of nebulization should be less than 75 percent. Nebulizers failing to meet these specifications should be considered unacceptable. We believe that the 1 to 2 h requ ired to perform the tests outlined herein are well justified considering the critical importance of reliable drug delivery to hospitalized patients receiving inhaled medication . APPENDIX
Designation in Article
Nebulizer Models Investigated" Manufacturer
Model No.
1 2
Baxter, Valencia,CA Puritan-Bennett, Overland Park, KS
3 4 5 6 7 8
Intec Medical, Bluesprings, MO Intec Medical, Bluesprings, MO Hospitak, Lindenhurst, NY Hudson, Temecula, CA Baxter, Valencia,CA AVA Corporationt
00214 001140 (Raindrop) 2016 3017 Up-Mist Up-Draft II 008120 AVA-neb
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"Nebulizer units tested at the time experimental work in this study was performed mayor may not be representative ofthose produced under current practices. We strongly urge readers to perform the ir own evaluations of nebulizer models they intend to purchase as described in the Discussion section of this manuscript rather than considering data presented here to be either an endorsement or condemnation of specific nebulizer models. tThe AVA Corporation has been acquired by the Hudson Oxygen Company.
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