Dosing Efficiency and Particle-size Characteristics of Pressurized Metered-dose Inhaler Aerosols in Narrow Catheters

1r r r i

laboratory and animal investigations Dosing Efficiency and Particlesize Characteristics of Pressurized Metereddose Inhaler Aerosols in Narrow Catheters* Robert H . Taylor; M . B . ; ] e m l d Lerman, M.D.; Carole Chambers; and Myrna Dolovich, I? Eng.

An experimental in oitm model was used to determine the effects of intraluminal catheter diameter and length on the delivered dose and particle-size characteristics of salbutamol (albuterol)aerosol delivered by metered dose inhaler (MDI)(Ventolin, 100 pg per puff).The dose of aerosolized drug that exited a 16-cm-longtracheal tube with an inner diameter (ID) of 6 mm was compared with that from 4 catheters of differing diameters and lengths that were inserted individually into the tracheal tube. The salbutamol MDI canister was actuated ten times into each delivery system, and the efRuent aerosol was trapped onto a filter. The filtrate was dissolved in methanol, and the salbutamol concentration was determined using high-performance liquid chromatography. For the 3 22-cm-long catheters, the delivered dose (mean SD)of salbutamol per actuation for the %-standard wire gauge (SWG)catheter was 97.5*3.9 pg, which was similar to that for the 19-SWG catheter (102.3k2.5 pg) but was significantly less than that for the 14-SWG catheter (108.224.2 pg) (p<0.05). These delivered doses exceeded those of the 6.0-mm-ID tracheal tube alone (2.33 0.76 pg) and the 13-cm-long19-SWGcatheter

*

*

delivery of bronchodilator drug therapy by Themetered dose inhaler (MDI) has received wide-

spread interest in the recent 1iterature.l The application of this technique to intubated patients is based For editorial comment see page 657

on several studies in which the dose of fenoterol delivered with an MDI and a spacer device exceeded that delivered with a jet nebulizefl and in two studies in which MDI salbutamol (albuterol) attenuated histamine-induced bronchoconstriction during halothane anesthesia in dogs3 and reduced both peak airway pressure and auto-PEEP in adult humans with COPD during mechanical ~entilation.~ In the latter study, -

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*Fmm the Department of Anaesthesia and the Research Institute, The Hospital for Sick Children, University of Toronto, Tomnto, Canada (Drs. 'Igylor and Lerman); and the Department of Medicine, St. Jose h i Hospital, McMaster University, Hamilton, Canada (Mses. ~Ramixrsand Dolovich). Presented in part at the Annud Meeting, American Society of Anesthesiologists, Las Vegas, October 1990. Supported by a grant from Glaxo Canada, Inc. Reprint requests: Dr. Lerman, Department of Anesthesia, Hospital for Sick Children, T w a t o , Ontario, C a d M5G 1x8

920

*

(2.17 0.29 pg) (p<0.001). In a second experiment using a cascade impactor, the distribution of aerosol particle diameters that exited the 6mm-ID tracheal tube was compared with that exiting a 13-cm-long19-SWGcatheter that extended halfway down the tracheal tube and with that exiting a 22-cm-long 19-SWG catheter inserted into the distal end of the 6mm-ID tracheal tube. The mass median aerodynamic diameter (mean SD) of the salbutamol aerosols delivered thmugh both the 6.0-mm-ID tracheal tube (1.1 0.1 pm) and that of the 13-cm-long lQSWG catheter (1.2fO.2 pm) were significantly less than that delivered through the 22-cm-long 19-SWG catheter (2.0k0.1 pm) (p<0.05). The authors conclude that delivery of respirable aerosol can occur through narrow catheters that function as extended nozzles for MDIs. Optimal dosing will be obtained when the catheter extends the full length of the (Chest 1993; 103:920-24) tracheal tube.

*

*

GSD =geometric standard deviation; ID = inner diameter; MDI =metered dose inhaler; MMAD =mass median aerodynamic diameter; SWG =standard wire gauge

salbutamol was delivered by MDI through a short catheter placed partway down the tracheal tube. The delivery of MDI aerosol through tracheal tubes depends on several factors, including the diameter of the tube and the pattern of gas f l o ~ .Previous ~ , ~ studies determined that under o~timalconditions., onlv, a small fraction of the discharged MDI aerosol actually reached the tracheobronchial tree.2,59 Donna et a15 suggested that although the fraction of drug delivered to the trachea may be small, the tube may act as a spacer device, in which large nonrespirable particles are deposited and smaller respirable particles (0.95 to 1.15 pm) enter the lung. Recently, we found that the fraction of aerosolized drug that enters the trachea may be increased tenfold by actuating the aerosol into a narrow intraluminal catheter that delivered the aerosol to the distal end of the tube, rather than actuating it directly into the tracheal tube.10 In the present study, we investigated the effects of the length and diameter of distally placed intraluminal catheters on the delivered dose and particle-sue characteristics of salbutamol MDI aerosol. PressurizedMetereddose Inhaler Aerosols in Narrow Calheters (Taylor et el)

An in oitw experimental model was used to study the dose of salbutamol MDI aerosol delivered through a l k m - l o n g tracheal tube with a 6.0-mm internal diameter (ID). The apparatus consisted of the following three components connected in series (Fig 1, a): (1) a swivel actuator (Intec 742275, Cardiac Pacemakers, St. Paul, Minn) attached to the proximal end of the tracheal tube; (2) a 6.0mm-ID tracheal tube (ConcordlPortex, Keene, NH) with a curve similar to that of a tube in the trachea; and (3) a %pm mesh filter inserted inside a 3-ml syringe barrel that was placed over the distal end of the tracheal tube to collect the aerosol. Ten actuations of a well-shaken salbutamol MDI canister were discharged every 30 s through the swivel actuator into a continuous flow of dry air at 30 Umin being drawn through the tracheal tube. The syringe barrel and filter were then placed into a 10-ml test tube containing 5 ml of methanol. This procedure was repeated three times using clean apparatus for each run. The apparatus used to study the delivered dose of salbutamol through catheters was similar to that mentioned above except that an elbow connector with LuerLok attachment, through which the catheter was inserted, replaced the swivel actuator (Fig 1, b, c). Three subsequent experiments were performed. In the first, a 14standard wire gauge (SWG) catheter 13 cm in length was positioned in the tracheal tube so that the distal end of the catheter was approximately halfway down the tracheal tube (Fig 1, b). In the second experiment, 22-, 1 4 , and l 4 S W G catheters, each 22 cm in length with IDS of 0.40, 0.70, and 1.60 mm, respectively, were inserted individually into the tracheal tube with the distal end of the catheter positioned at the distal tip of the tracheal tube (Fig 1, c). The k m difference in length between the catheters and the tracheal tube was required to accommodate the length of the elbow connector (Fig 1, c). The LuerLok connector at the proximal end of each catheter was shortened by 4 mm to facilitate the seating of the MDI valve stem against the inner wall ledge of the LuerLok connector. The MDI was discharged 10 times through the apparatus, and the contents exiting the system were collected on 20-mesh filters. The syringe barrel and filter were placed into a 10-ml test tube containing 5 ml of methanol. Each study was repeated three times with new components. The salbutamol dose was determined for each test tube using reversed-phase high performance liquid chromatography with amperometric detection." The value obtained for each experiment was divided by the number of puffs used to obtain the dose in micrograms per puff. In the third study, the particle-size distribution of aerosol exiting a 6-mm-ID tracheal tube with the swivel actuator was measured and compared with that exiting 14SWG catheters measuring 13 cm and 22 cm in length. The apparatus was similar to that shown in Figure 1, except that in this study the syring<er collection system was not used. The aerosol that exited the catheter andlor the tracheal tube was sampled under isokinetic flow conditions using a Mercer 1-L 7-stage cascade impactor.1aThe cutoff diameters of the impactor were 8.02, 4.79, 2.83, 1.69, 1.00, 0.60 and 0.35 pm. Wall suction was applied to the impactor sampling tube apparatus to provide a flow of 20 Umin. For each experiment, the salbutamol MDI aerosol was discharged 30 times, releasing one puff every minute. The residue collected on each stage of the impactor was dissolved in 3 ml of 0.1 moVL HCI, and the amount of dhutamol was determined using ultraviolet spectrophotometry (Pye Unicam model SP&4000 WAS) at an absorbance wavelength of 276 nm. The percentage of deposition of salbutamol on each stage was calculated as the salbutamol dose on that stage times 100 divided by the total dose sample by the impactor. To determine the mass median aerodynamic diameter (MMAD) (ie, the diameter at 50 percent of the accumulated deposition), the cumulative deposition data were plotted against stage cutoff diameter on logarithmic probability

Swivel Actuator 30 U m ~ n

Ebow mnndor 6mmTub

Syringr ud filler

FIGURE 1. a: Schematic diagram of the appratus used to determine the delivery dose through a swivel actuator and 6-mm-ID tracheal tube. b: Apparatus used to determine the delivery dose through a catheter placed partway (13 cm) down a 6-mm-ID tracheal tube. c: Apparatus used to determine the delivery dose through a catheter placed distally (22 cm) in a 6-mm-ID tracheal tube.

paper. The geometric standard deviation (GSD) was calculated as the size at 84 percent accumulated deposition divided by the MMAD, or alternatively, as the MMAD divided by the size at 16 percent deposition. Statistical Andysis

Statistical significance of p<0.05 was accepted. The delivered doses and aerosol particle sizes for the 6-mm-ID tracheal tube; the 22-cm-long 22-, 19-, and 14-SWG catheters; and the 13-em-long 14SWG catheter were compared using one-way analysis of variance and the Newman-Keuls test. CHEST 1 103 1 3 / MARCH. 1993

Table 1-Dose of SaZbutamol D e h d to the P %tious D e k e t y Systems* -

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h for

Delivered Dose per Actuation, p g

Delivery System Tracheal tube, 6.0-mm I D Catheters 19-SWG, 13-cm-long 22-SWG, 22-cm-long 19-SWG, 22-cm-long 14-SWG, 22-cm-long

2.33 2 0 . 7 6 t 2.17 2 0 . 2 9 t 97.523.9 102.3 2 2 . 5 108.224.24

*Data are expressed as mean k SD. tp<0.001 compared with all 22-cm-long catheters. Sp<0.05 compared with 22-SWG 22-cm-long catheter.

The delivered dose (mean SD) per puff of salbutamol MDI aerosol through a 6.0-mm-ID tracheal tube and swivel actuator (2.33? 0.76 pg) did not differ significantly from that through a 13-cm-long 19-SWG catheter (2.17+0.29 pg) placed inside the 6-mm-ID tracheal tube. The delivered dose (meankSD) of salbutamol per actuation (100 pg) was greater for all 3 22-cm-long catheters compared with that for the 6.0cm-ID tracheal tube with swivel actuator alone or for the 13-cm-long 19-SWG catheter (Table 1). When the three 22-cm-long catheters were compared, the delivered dose for the 22-SWG catheter (97.5 + 3.9 pg) was similar to that for the 19-SWG catheter (102.3f2.5 pg) but was significantly less than that for a 14-SWG catheter (108.2? 4.2 pg) (pC0.05). The MMAD (mean? SD) of salbutamol aerosol exiting the 6.0-mm-ID tracheal tube alone (1.1 f O . l pm) and that for the 13-cm-long 19-SWG catheter placed within the tracheal tube (1.2f0.2 pm) were less than that for the 22-cm-long 19-SWC catheter (2.0 f 0.1 pm) (p<0.05) (Table 2). The GSD for a 6.0mm-ID tube (4.42 1.0) and that for a 13cm-long catheter (4.5a 0.4) were greater than that for a 22cmlong catheter (2.9 f 0.1) (p< 0.01). The values for the percentage of particles in the aerosol within the respirable range (ie, <3 pm aerodynamic diameter) were 74.0k0.8 percent, 73.1f3.7 percent, and 64.92 1.8 percent for the 6-mm-ID tracheal tube, the Table 2- Particle Size of S a l b u t u m d MDZ Aerosol as Measured by a Cascade Impactor*

Delivery System

MMAD, pm

GSD

Particles < 3 pm in Diameter, %

Tracheal tube, 6.0-mm I D Catheters 19-SWG, l k m - l o n g lQSWG, 22-cm-long

1.1 2 0 . 1

4.4k 1.0

74.020.8

1.220.2 2.0+0.lt

4.520.4 2.920.lt

73.123.7 64.9k 1.8$

*Data are expressed as mean 2 SD. tp
13-cm-long 19-SWG catheter, and the 22cm-long 19SWG catheter, respectively ('Table 2). Using the drug dose delivered to the cascade impactor via the 22-cm-long 19-SWG catheter as the standard (100 percent), the percentage sampled from the tracheal tube alone or through the 13-cm-long 19SWB catheter were slightly less (882 6.6 percent and 68.7 a 27.1 percent, respectively). The dose of salbutamol delivered through a short catheter (19 SWG, 13 cm in length) positioned approximately halfway into the tracheal tube was no greater than that delivered through a 6-mm-ID tracheal tube and swivel actuator alone. This confirms the results of Crogan and Bishop: who reported a similar net weight gain of 3 percent for an MDI aerosol delivered through a 6.0-mm-ID tracheal tube and a swivel actuator, and is within the range reported by Fuller et all3 for delivery of radiolabeled fenoterol MDI through a swivel adapter to intubated patients. This indicates that a large fraction of MDI aerosol is deposited within the tracheal tube with both of these delivery systems. Fernandez et a14 used a delivery system similar to the short catheter used in this study. Based on our results, a short catheter (13 cm in length) placed halfway down a tracheal tube is not an efficient system for delivering MDI aerosol drugs. With such a system, we believe most of the aerosol exits the catheter but then rains out onto the wall of the tube before reaching the trachea. Thus, the improvement in the respiratory function of the patients in the study by Fernandez et a' is particularly interesting since the delivered dose might only have been 2 to 5 pg for each actuation. The results from our study demonstrate that the dose of MDI salbutamol delivered through a catheter that is positioned with its distal end at the tip of the tracheal tube is optimal (93 to 113 pg per actuation). Among the three diameters of catheters studied, the delivered dose through even the narrowest (22-SWG) catheter, (97.5 pg) still represents a large dose, approximately equivalent to 10 puffs, given the efficiencies for both intubated (5.5 percent per p@ and nonintubated patients (10 pecent per p a . ' The catheter delivery system represented a 30- to 40-fold increase over the dose delivered through a 6.0-mmID tracheal tube with a swivel actuator alone.= To explain the dramatic increase in delivery of aerosol through a catheter, we hypothesized that the catheter might be considered an extension of the actuator nozzle. If this were true, we then speculated that the dimensions of the catheters might affect the delivery of aerosol: that is, the diameter, the length, and therefore the volume of the catheter. The volume released from the metering chamber in a Ventolin Regsurized Metered-doseInhaler Aemsds in N a m Cathetem (Taylor et el)

canister is 65 p1, while the volumes of 14-, 19-, and 22-SWG catheters 22 cm in length are 442, 84.7, and 27.7 p1, respectively. Despite a 15-fold variation in the volume of the catheters, all 3 catheters accommodate the volume of the discharged MDI metering chamber contents without incurring significant drug deposition within the catheter. The resistance of the catheter to aerosol flow is inversely related to the radius of the catheter to the fourth power. Despite a fourfold difference in the radius of the catheters (from 0.2 mm for a 22-SWG catheter to 0.8 mm for a 14SWG catheter) and a corresponding 256-fold variation in the resistance of these catheters, delivery varies less than 10 percent between the narrowest and the widest catheters. Using a formulation fluid density of 1.37 g d m l , a viscosity of 0.3047 centipoise, and a velocity of 26.8 d s , we estimated that the flow Reynold's number for Ventolin aerosol through the 19SWG catheter exceeded 80,000, indicating turbulent flow. Thus, the resistance to flow through catheters in this range of diameters would not be expected to affect the dose of aerosol delivered. Although we speculated that both the volume and the diameter of these intraluminal catheters might affect the delivery of aerosol, the results of this study support the notion that while the catheter may be considered an extension of the actuator nozzle, neither the volume nor the diameter of these catheters is crucial to the efficient delivery of aerosol through a full-length catheter. The use of a catheter system to deliver salbutamol by MDI aerosol will deliver the full metered dose of salbutamol to the tracheobronchial tree. An excessive number of actuations of the canister could theoretically deliver an overdose of salbutamol, which may produce cardiovascular and electrolyte disturbances." However, Bohn et all5have shown that intravenous infusions of salbutamol up to 4 pgkg-I min-I were associated with only a 25 percent increase in heart rate in asthmatic children treated in an intensive care unit without adverse side effects. Aerosols delivered by MDI consist of two constituents in addition to the drug: surfactant and chlorofluorocarbon (Freon)propellants. The surfactant, a nonvolatile component of the aerosol, is dissolved in the propellant mixture and maintains the drug particles in suspension. Each ~ u f of f Ventolin contains approximately 10 pg of the surfactant oleic acid, corresponding to 10 percent of the total amount of sdbutamol in each puff. Freon propellants evaporate very rapidly aftet actuation of the MDI16and have not been shown to cause adverse effects in adults in doses up to 24 puffs." Inhaled oleic acid has not been reported to produce lung injury. However, until studies confirm the safety of this technique, we recommend caution when using intraluminal catheters to deliver MDI aerosol drugs because of the very high fraction of

delivered dose of the MDI constituents. Using a distally placed catheter to deliver pressurized aerosols appears to be the most efficient delivery system. Thus, for those intubated patients who require more than two puffs of an MID aerosol to affect an improvement, a more predictable dose of drug may be administered by MDI delivery through an intraluminal catheter with fewer actuations. However, the efficiency of aerosol delivery systems depends not only on the total mass of drug delivered, but also on the quality of the aerosol produced and the patient's lung function. Aerosol particles with MMADs of 1 to 5 pm have been shown to reach the conducting airways.I8The MMAD of salbutamol aerosol delivered through a distally placed 19-SWG catheter (2.0 pm), although larger than that delivered through the tracheal tube alone or the tube with an intraluminal 13cm-long 19-SWG catheter, indicates that the majority of particles will be deposited in the peripheral airways. Furthermore, although the GSDs are large, the percentage of respirable particles less than 5 pm in diameter is approximately 80 percent and that for particles less than 3 pm is between 65 and 75 percent. This suggests that with the catheter delivery system, a large fraction of respirable particles will reach the peripheral airways. Further in vim studies are required to validate the deposition pattern of MDI aerosol delivered through intraluminal catheters. In summary, we have found that a substantially greater dose of salbutamol by MDI is delivered through a catheter placed distally inside a tracheal tube than is delivered through a tracheal tube with a swivel actuator or a catheter partly inserted into the tracheal tube, and that the aerosol produced by this system is a fine, highly respirable aerosol that should be delivered to the conducting airways. In oioo studies are indicated to determine the dose delivered to the lung using this delivery system and to determine the risk of side effects. ACKNOWLEDGMENTS:The authors thank theTherapeutic Drug Monitoring Laboratory at the Hospital for Sick Children, Toronto, for the HPLC analysis and Glaxo Canada, Inc for providing the salbutamol. 1 Newhouse M, Dolovich M . Aerosol therapy: nebulizer vs metered dose inhaler [editorial]. Chest 1987; 91:799-800 2 Fuller H, Dolovich M, Posmituck G, Wong Pack W, Newhouse MT. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Am Rev Respir Dis 1990; 141:440-44 3 Tobias JD, Hirschman CA. Abuterol attenuates bronchoconstriction during halothane anesthesia [abstract]. Anesthesiology 1989; 71:A1075 4 Fernandez A, Lazaro A, Garcia A, Aragon C, Cerda E. Bronchodilaton in patients with chronic obstructive pulmonary disease on mechanical ventilation. Am Rev Respir Dis 1990; 141:164-68 5 Donna E, Kim CS, Boszormenyi G, Marcial E, Gold M. Delivery efficiency of 3 metered dose inhaler aerosols and 2 CHEST 1 103 1 3 1 MARCH. 1993

923

gctrmtors via an endntracheal hlhe [abstract]. hnt.\t!it*\iol~nq? 1 W ; RkAR3A 6 Cmgm SJ, Bishop MJ. Deliwry &drn+* d n~rtrrrrldose aernsnjs given via endotmcheal h r h e s . htiertlit.sirrl~r~1989;

Aerosol Sci 1982; 13:1-7 13 Fuller H. I)olnvich M, Turpie F. Fbsmitadt C. N e w h M. Comparative efficiency of a e m l deposition to the lung fmm 4 devices used with metered dose inhalers (MDI)in meclianically m1m10 ventilated patrents [abstractJ.J Aerosol Med 1991: 4(snppl):R 14 Lipworth BJ, McDevitt DC, Struthers AD. Systemic p-adrp 7 N-an SF! M a D, Moren F, Sheahan NF. t:larke SIV Depsition of pressurized aerosols in human rerpiri~tll n tract. nowptor responses to dhatamol given hy m e t e d 4 m lnhaler alone and with ppsr shaped spacer attachment: comparisun of Thorax 1M1;36:52-5 8 Davis DS. Phm8~0kinetics of inhaled \r~lt\ht~cr-\. R~tgrad electrmardicwphic, hypoMaemic and haemdynamic PIT& Br J Clin Pharmaml 1989;27:U37-42 Med J 1975: 51:69-75 15 h h n D, killozhlian A, Jenkins J. Edmonds J, Barker G. 9 Kim CS, Eldridgr MA. Sackner MA. Otlrpharyngeal dt-poqition Intravenous sall111t;lmolin the treatment of status asthmaticus and delivery aspects of metereddose inhaler atm,rr~ls.Am Rev in children. Crit Care Med 19%: 12:1)92-Mi R q i r Dis 1W7; 135:157-64 10 Taylor RI1. Lrrmnn J. High &ciency delivery of ~ n l l ~ ~ i t a t i ~ ~16 ~ l Kim CS, Tn~jilloD. Swkner MA. Size aspects of metereddose with a metered-dose inhaler in narrow tracheal ~IIIH*\ and inhaler aemsolc Am Rw Respir Di5 1W5: 132:137-42 catlmters Anesthesiology 1990; 74:%043 17 Dollery CT,\Villiams FM, Draffan G11. Wise G, Sahpun H, P a t r r m JW. e t al. Arterial hlcnd levels of fltmmmrhns in 11 Tan YK, Soldin SJ. Determination dsalbntamol in human senlm asthmatic patients fhlliwving use of pressuri;red aenlsnls Clin reversed-phase high-perC~rmance liquid chrr~nutngr~ph! with ampen~mehicdetection.J Chromatrw 1984; 311:311-17 Phamml Ther 1973: 15:59-& I2 Corr I).&>ltrvich M, McCormark D, Ruffin R, olirriirirki G , 18 Sr*)tt WR, b u l k DB. Aerosol deposition dona the vertical axis of the lung. J Aertml Sci 1W: 16:32333 Newhouse hl. Designs and characteristicu of a ln>rtal*lrhwath actuatd. prticle size selective medical aerosol inhalcr. J

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XVII

Plan to Attend ACCP's

XVll World Congress on Diseases of the Chest