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Lung deposition and systemic bioavailability of different aerosol devices with and without humidification in mechanically ventilated patients
Heart & Lung xxx (2017) 1e4
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Lung deposition and systemic bioavailability of different aerosol devices with and without humidification in mechanically ventilated patients Islam O.F. Moustafa, BSc a, b, Mohammed R. A.-A. Ali, MSc c, Moataz Al Hallag, PhD d, Hoda Rabea, PhD a, James B. Fink, PhD e, Patricia Dailey, BSc f, Mohamed E.A. Abdelrahim, PhD a, g, * a
Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt Clinical Pharmacist Department, Saudi German Hospital SGH, Cairo, Egypt Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt d Critical Care Medicine, Critical Care, Faculty of Medicine, Cairo University, Egypt e Division Allied Health, Georgia State University, Atlanta, GA, USA f Medical Affairs/Clinical, Medical Science Liaison, Aerogen, Ltd., Galway, Ireland g Clinical Pharmacy Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 January 2017 Received in revised form 10 July 2017 Accepted 7 August 2017 Available online xxx
Background: During mechanical ventilation medical aerosol delivery has been reported to be upto two fold greater with dry inhaled gas than with heated humidity. Urine levels at 0.5 h post dose (URSAL0.5%) has been confirmed as an index of lung deposition and 24 h (URSAL24%) as index of systemic absorption. Our aim was to determine the effect of humidification and aerosol device type on drug delivery to ventilated patients using urine levels. Methods: In a randomized crossover design, 36 (18female) mechanically ventilated patients were assigned to one of three groups. Groups 1 and 2 received 5000 mg salbutamol using vibrating mesh (VM) and jet nebulizers (JN), respectively, while group 3 received 1600 mg (16 puffs) of salbutamol via metered dose inhaler with AeroChamber Vent (MDI-AV). All devices were placed in the inspiratory limb of ventilator downstream from the humidifier. Each subject received aerosol with and without humidity at >24 h intervals with >12 h washout periods between salbutamol doses. Patients voided urine 15 min before each study dose and urine samples were collected at 0.5 h post dosing and pooled for the next 24 h. Results: The MDI-AV and VM resulted in a higher percentage of urinary salbutamol levels compared to the JN (p < 0.05). Urine levels were similar between humidity and dry conditions. Conclusions: Our findings suggest that in-vitro reports overestimate the impact of dry vs. heated humidified conditions on the delivery of aerosol during invasive mechanical ventilation. Ó 2017 Elsevier Inc. All rights reserved.
Keywords: Vibrating mesh nebulizers MDI Spacer Non-invasive ventilation Urinary salbutamol Humidification
Inhaled aerosol delivery during conventional mechanical ventilation with dual limb circuits, has been reported to be 40e 80% greater with dry ambient inhaled gas than with heated humidity.1e3 For this reason, it has been suggested that clinicians should turn off the humidifier before starting aerosol delivery.
Studies have shown that there is no significant difference between aerosol delivery in dry and humidified conditions in a single limb non-invasive ventilation (NIV) bench model study4 and in automatic continuous positive airway pressure (Auto-CPAP) by patients’ study.5 However, this data cannot be extended to dual limb ventilation because of difference in aerosol generator positioning.
Location of study: Teaching Hospital of Faculty of Medicine, Faculty of Medicine, Beni-suef University, Beni-suef, Egypt and the Clinical Pharmacy Department, Faculty of Pharmacy, Beni-suef University, Beni-suef, Egypt (analysis). R&D Approval for patient study: Beni-suef Teaching Hospitals Research Ethics Committee approval number: FMBSU REC FWA#: FWA00015574. Author Disclosure Statement: No competing financial interests exist.
* Corresponding author. Department of Clinical Pharmacy, Faculty of Pharmacy, University of Ahram Canadian, Giza, Egypt. E-mail addresses: [email protected] (I.O.F. Moustafa), mohammedragab [email protected] (M.R.A.-A. Ali), [email protected] (M. Al Hallag), hoda_cp@ yahoo.com (H. Rabea), fi[email protected] (J.B. Fink), patriciaanndailey@ gmail.com (P. Dailey), [email protected] (M.E.A. Abdelrahim).
Introduction
0147-9563/$ e see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2017.08.004
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The debate of potential benefit of turning off the humidifier while delivering aerosol was addressed by Lin et al., reporting that turning off the humidifier for 20 min before aerosol delivery with MDI did not increase inhaled dose delivered to the ventilated patient. They attributed this to presence of condensate in the circuit that kept absolute humidity high despite reduced circuit temperature.6 More recently, Ari et al. demonstrated that in-vitro models simulating active exhaled humidity, more closely represent actual patient airway interactions, reducing differences in aerosol delivery between dry and humidified ventilator circuit, suggesting that models using passive or dry exhalation may overestimate total inhalable dose (TID) under dry conditions.7 Consequently, reports of better TID from aerosol delivered with dry versus heated humidified conditions might be due to failure of the models to simulate exhaled heat and humidity.7 The debate was furthered with reports of no difference of patients’ clinical status with changing humidity during aerosol delivery to ventilated patients.8 This suggests that a more reliable method is needed to determine the effect of humidity on aerosol delivery in the ventilated patient. Urine drug levels of salbutamol have been correlated to pulmonary delivery efficiency of inhaled medication.9,10 It has been previously shown that urinary salbutamol levels at 0.5 h post administration and cumulative over 24 h can be used as indices of the pulmonary deposition and systemic absorption of inhaled medication.9,10 The urinary drug level post aerosol administration has been used with other inhaled medications e.g. Sodium cromoglycate,11 Formatrol,12 Terbutaline,13 Tobramycin.14 The non-invasive urinary pharmacokinetic method has been used to compare delivery of a broad range of aerosol devices and administration methods: metered dose inhalers (MDI) to MDI with spacers15,16; investigate optimum inhalation technique17; compare dry powder inhalers (DPI) to MDIs18; determine the relative bioavailability of nebulized drug with prolonged administration19,20; and compare the use of highly resistant DPI in normal subjects to chronic obstructive lung disease (COPD) patients.21 In addition, urine levels have been used to study lung deposition and systemic absorption in critically ill patients e.g. during and following exacerbations.22,23 and during mechanical ventilation.24e27 Multiple data mining modelling studies have correlated urinary salbutamol method to in-vitro aerosol inhaled dose data.25,27,28 including mechanically ventilated patients.25,27 demonstrating that urinary salbutamol excreted at 0.5 h post dosing correlated to the fine particle dose (FPD) inhaled, and the mass median aerodynamic diameters (MMAD). They also showed that the urinary salbutamol excreted cumulatively collected over 24 h post dosing correlates to the total inhalable dose that reaches the patient. Consequently, urinary salbutamol method was proven to be a reliable method that can provide indices of lung deposition and systemic absorption. The aim of the present study was to determine the effect of humidification and type of inhalation device on aerosol delivery using salbutamol urine levels as indices of lung deposition and systemic absorption in mechanically ventilated patients. Materials and methods Study population This study was conducted in accordance with the amended Declaration of Helsinki. Local institutional review board (IRB) and independent ethics committees approved the protocol, with written informed consent obtained from all subjects. All subjects were recruited using hospital approved delayed consent procedure. Inclusion criteria was for subjects with a previous diagnosis of asthma or bronchospastic COPD that were admitted to the respiratory unit with an acute exacerbation, receiving invasive ventilation and prescribed to receive aerosol salbutamol. Subjects were excluded if they had taken part in a research study during the
previous 6 months, had known hypersensitivity to salbutamol, systolic blood pressure of <100 mmHg or severe renal impairment defined as Creatinine Clearance or eGFR of <20 mL min1. Study design and procedures We used the urinary salbutamol methodology previously reported by Hindle et al.9 to associate inhaled aerosol dose and urine levels of drug due to systemic absorption comparing three aerosol delivery methods during mechanical ventilation with and without heated humidification. In a randomized crossover design, asthmatic subjects receiving volume assisted control (V/AC) invasive mechanical ventilation using Bellavista 1000e Ventilator (Imtmedical, Buchs, Switzerland) and Ultramed endotracheal tube (cuffed) size 8 (Ultra For Medical Products Co., Cairo, Egypt) were randomly assigned to receive aerosol with a vibrating mesh nebulizer (VM; Aerogen Solo; Aerogen Ltd, Galway); a jet nebulizer (JN; Oxycare; Ceren Uretim A.S., Istanbol, Turkey); or a metered dose inhaler (Ventoline, GlaxoSmithKline, Egypt) with an AeroChamber Vent spacer (Trudell Medical International, Canada). Both VM and JN groups received 5000 mg of salbutamol respiratory solution (Farcolin, 5000 mg/mL; Pharco Pharmaceuticals, Egypt) with a dose volume of 2 mL. The metered dose inhaler with spacer (MDI-AV) group received 1600 mg (16 actuations at 100 mg per puff) of salbutamol. For each experiment the MDI was shaken well and primed with 2 actuation prior to use, with >30 s intervals between actuations. All devices were placed in the inspiratory limb of mechanical ventilation circuit (Int’air medical, Bresse, France) downstream from the humidifier (VH 2100 humidifier with humidifier chamber; Great Group Medical Co. (GGM), Changhua County, Taiwan). Subjects were randomized to receive aerosol during conventional mechanical ventilation with and without heated humidification at >24 h intervals with >12 h washout prior to each salbutamol dose. Salbutamol administration was withheld for at least 12 h prior dosing with salbutamol, with ipratropium bromide (Atrovent inhalation solution containing nominal dose of 25 mg mL1, Boehringer Ingelheim, Egypt) substituted during those periods. According to previous reports.21,24,26,29 using similar method, salbutamol was totally cleared from the urine after 24 h. Urine samples were collected 15 min before each study dose to establish baseline and again at 0.5 h (USAL0.5) after dose completion. Urine was then collected over the next 24 h (USAL24). All samples were measured and assayed for salbutamol using HPLC. Salbutamol was extracted from urine samples using solid phase extraction with Oasis MCX cartridge (Waters corporation, USA), with bambuterol hydrochloride added as an internal standard, and then injected into HPLC system.29 An ODS 5 mm, (4.6 250 mm, ZORBAX Eclipse) C-18 HPLC column with (4 mm 3 mm, Agilent, USA) C-18 (ODS) guard column was used. Mobile phase, acetonitrile: water containing 0.1% orthophosphoric acid (90:10, v/v), was pumped through columns at a flow of 1 mL min1 maintained at 25 C and photodiode array detection was set at 220 nm. Limit of detection and lower limit of quantification for salbutamol was 0.36 and 1.00 mg mL1, respectively. One way ANOVA with the application of the least significant difference (LSD) correction was used to determine differences between urinary salbutamol levels from the three inhalation methods with SPSS V17.0 (SPSS Inc., Chicago, USA). Independent T-test was used to determine difference between urinary salbutamol excretions at different humidity conditions (p < 0.05). Results 36 (18 females) consented subjects receiving mechanical ventilation were enrolled and randomly assigned to one of the three treatment groups. All subjects completed both study doses.
I.O.F. Moustafa et al. / Heart & Lung xxx (2017) 1e4
There was no significant difference between the studied subjects in age, weight and height in the 3 groups. The percentage of nominal or emitted dose assayed from excreted urine at 0.5 h and over 24 h post aerosol dosing from the inhalation devices at different humidification condition are shown in Table 1. Data are shown as 6 groups (12 results in each) representing each aerosol generator and humidity condition. Data are also shown in Table 2 as 3 aerosol generators groups (24 results in each group), regardless of the humidity condition. Subject anthropomorphic characteristics are shown in Table 2. Table 3 compares the 2 humidity conditions (36 results in each group), regardless of the aerosol generators used. MDI-AV resulted in a higher URSAL0.5% compared to the JN and VM (p < 0.001 and p ¼ 0.041, respectively). The VM resulted in significantly higherURSAL0.5% compared to JN (p ¼ 0.001). The URSAL24% was greater with the VM than the JN and MDI-AV (p ¼ 0.002 and 0.048, respectively). For each aerosol delivery device, USAL0.5% and USAL24% were similar with both dry and humid conditions. Discussion Similar to prior reports, we found a difference in drug delivery efficiency between devices.5,26,29 However, no significant difference was found between the two conditions of humidification. Ari et al.3 demonstrated similar inhaled dose efficiency of approximately 17% of nominal and emitted dose with both VM and MDI-AV with lower dose efficiency using the JN (3.6%) under heated humidified conditions. In the same paper, Ari and colleagues reported a higher inhaled dose with VM (30.2%), JN (9.7%) and MDI-AV (27.8%) under nonheated humidified conditions representing increases over humidified conditions of 79%, 62% and 169%, respectively. This was similar to reports by Fink et al.30 of inhaled dose of 16% with MDI-AV during heated humidified gas increasing to 30% with non-heated dry gas delivered through the ventilator. Many authors have demonstrated greater inhaled dose of aerosol during mechanical ventilation with dry gas, compared the heated humidity up to 170%.1e3,7 In a sole report showing increased aerosol delivery with dry gas in-vivo, Miller et al. compared aerosol delivery via nebulizer during mechanical ventilation with non-humidified and humidified gas, reporting a 2e3 fold greater sputum level of amikacin with non-humidified conditions.31 Based on these studies, some authors have suggested that the humidifier should be turned off prior to aerosol administration to optimize aerosol delivery to the ventilated patient. In contrast, we found no difference in urine levels at 0.5 and 24 h post administration. This may be explained in part by variances inherent to aspiration of sputum specimens which provides less homogenous sampling than systemic measurements such as urine. Many variables differentiate in-vitro vs. in-vivo delivery. In-vitro models collect aerosol on an absolute filter, where lungs exhale a greater proportion of inhaled aerosol resulting in method bias with the in-vitro model overestimating dose inhaled during mechanical ventilation. Fink and colleagues compared in-vivo and in-vitro estimates of exhaled albuterol during aerosol administration with MDI-AV under heated humidified conditions, demonstrating 4.8% Table 1 Salbutamol urine levels, as percent [mean (SD)] of dose, achieved after aerosol administration by JN, VM and MDI-AV during mechanical ventilation with (Humidity) and without (Dry) heated humidification.
URSAL0.5% URSAL24%
JN humidity
JN dry
VM humidity
VM dry
MDI-AV humidity
MDI-AV dry
0.7 (0.5) 6.2 (3.3)
0.9 (0.6) 6.6 (4.1)
1.7 (0.8) 10.1 (6.9)
1.8 (1.1) 10.5 (4.0)
2.0 (1.1) 7.8 (2.5)
2.5 (1.3) 8.0 (3.4)
3
Table 2 Anthropomorphic characteristics of the patients and salbutamol urine levels, as percent [mean (SD)] of dose, achieved after aerosol administration by JN, VM and MDI-AV during mechanical ventilation. Aerosol generator results
JN
VM
MDI-AV
Age (years) Weight (kg) Height (cm) URSAL0.5% URSAL24%
62.4 (8.5) 77.6 (13.9) 172.5 (8.7) 0.8 (0.5) 6.4 (3.6)
61.7 (9.0) 74.6 (7.8) 170.4 (7.3) 1.7 (1.0) 10.3 (5.5)
61.8 (9.5) 78.2 (10.6) 169.8 (9.8) 2.3 (1.2) 7.8 (2.9)
more of the emitted drug exhaled in-vivo than in-vitro, suggesting a corrected inhaled dose of 11% in-vivo which was consistent with previous scintigraphy deposition under similar ventilator conditions.32 The calculated lung dose with MDI-AV is similar to the 10e10.5% total salbutamol recovered from urine post treatment under both humidified and dry conditions. A partial explanation may lie in the role of exhaled humidity on the delivery of aerosol through an artificial airway. Patients exhale gas that has been actively heated and humidified in the lungs, while the commonly described bench model does not. Ari et al. have described the effects of providing active heated humidity to exhaled gas in their lung model, resulting in lower inhaled aerosol doses during administration of aerosol with dry gases than with standard passive exhalation.7 Their findings suggest that at least a portion of the difference between inhaled dose with heated humidified and dry gas may be due of the particulars of the model used, and how well it simulates patient aerosol interface.7 Even without active exhaled humidity, Lin et al. showed that switching off the humidifier for up to 30 min prior to administration of an MDI-AV did not result in greater aerosol delivery compared to administration with humidity.6 Our findings support the notion that aerosol administration with heated humidified gas does not result in up to a 3 fold increase in lung delivery with dry gas during mechanical ventilation. There was no significant difference in USAL0.5% as an index of lung deposition and USAL24% as an index of systemic absorption when inhalation methods were used in humidified or dry condition. Consequently, our findings suggest that turning off the humidifier may not improve aerosol delivery efficiency. Another important factor that supports our recommendation for aerosol delivery to ventilated patient under humidified conditions is that previous recommendation for switching off the humidifier may contribute to problems associated with administration of dry cold gas to the lungs such as; lung irritation, bronchospasm, and desiccation of secretions.33 These risks are even greater should the clinician fail to turn on the humidifier upon conclusion of aerosol administration. Consequently, based on our finding we would recommend not interrupting humidity during aerosol administration, especially after Moustafa et al. found no significant effect on patients’ clinical status with changing humidity during aerosol delivery to ventilated patient.8 The choice of aerosol delivery method has a greater impact than the effect of humidity. As previously shown, the VM and MDI-AV were more efficient than the JN.7,24,26,34,35 The VM resulted in highest USAL24% (p < 0.05) suggesting highest systemic absorption Table 3 Salbutamol urine levels, as percent [mean (SD)] of dose, achieved after aerosol administration during mechanical ventilation with (Humidity) and without (Dry) heated humidification. Condition results
Dry delivery
Humid delivery
URSAL0.5% URSAL24%
1.5 (1.0) 8.0 (4.8)
1.7 (1.2) 8.4 (4.1)
4
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at all conditions. Also, MDI-AV resulted in higher USAL0.5% (p < 0.05) suggesting highest lung deposition efficiency. The higher USAL24% of VM as an index of systemic absorption was due to the very small residual volume of VM compared to JN.7,24,34,36e38 and the spacer’s effect of MDI-AV in which most of the large aerosolized particles rained out.25,35,39 The higher USAL0.5% of MDI-AV maybe due to the distance of the MDI actuation in the AV spacer which allowed the MDI propellants to evaporate more and result in smaller MMAD that increased lung deposition compared to JN and VM.35,39 Limitations While the size of each group may have hidden some of the statistical differences between conditions, our range of ventilator parameters were similar across all groups. Further studies with a wider variety of ventilator parameters and patient conditions with a larger sample size may be of value. Conclusions In all conditions studied, the JN had the lowest USAL0.5% and USAL24%. MDI-AV had the highest USAL0.5% and VM had the highest USAL24%. The effect of heat and humidity on aerosol delivery was less than previously reported by in-vitro models using passive, non-humidified exhalation. The in-vivo urinary method demonstrated similarity of delivered aerosol dose to the lung with heated humidity and dry conditions in mechanically ventilated patients. References 1. Lange CF, Finlay WH. Overcoming the adverse effect of humidity in aerosol delivery via pressurized metered-dose inhalers during mechanical ventilation. Am J Respir Crit Care Med. 2000;161:1614e1618. 2. Ari A, Areabi H, Fink J. Evaluation of aerosol generator devices at 3 locations in humidified and non-humidified circuits during adult mechanical ventilation. Respir Care. 2010;55:837e844. 3. Ari A, Atalay OT, Harwood R, et al. Influence of nebulizer type, position, and bias flow on aerosol drug delivery in simulated pediatric and adult lung models during mechanical ventilation. Respir Care. 2010;55:845e851. 4. Saeed H, Mohsen M, Fink JB, et al. Fill volume, humidification and heat effects on aerosol delivery and fugitive emissions during noninvasive ventilation. J Drug Deliv Sci Technol. 2017;39:372e378. 5. Mohsen M, Elberry AE, Salah Eldin A, Hussein RR, Abdelrahim EM. Effects of heat and humidification on aerosol delivery during auto-CPAP noninvasive ventilation. Arch Pulmonol Respir Care. 2017;3:11e15. 6. Lin H-L, Fink JB, Zhou Y, Cheng Y-S. Influence of moisture accumulation in inline spacer on delivery of aerosol using metered-dose inhaler during mechanical ventilation. Respir Care. 2009;54:1336e1341. 7. Ari A, Harwood R, Sheard M, et al. Quantifying aerosol delivery in simulated spontaneously breathing patients with tracheostomy using different humidification systems with or without exhaled humidity. Respir Care. 2016;61:600e606. 8. Moustafa IOF, ElHansy MHE, Al Hallag M, et al. Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients. Pulm Pharmacol Ther. 2017;45:40e46. 9. Hindle M, Chrystyn H. Determination of the relative bioavailability of salbutamol to the lung following inhalation. Br J Clin Pharmacol. 1992;34:311e315. 10. Tomlinson HS, Corlett SA, Chrystyn H. Dose-response relationship and reproducibility of urinary salbutamol excretion during the first 30 min after an inhalation. Br J Clin Pharmacol. 2003;56:225e227. 11. Aswania OA, Corlett SA, Chrystyn H. Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion. Br J Clin Pharmacol. 1999;47:613e618. 12. Nadarassan DK, Chrystyn H, Clark BJ, Assi KH. Validation of high-performance liquid chromatography assay for quantification of formoterol in urine samples after inhalation using UV detection technique. J Chromatogr B Biomed Sci Appl. 2007;850:31e37. 13. Abdelrahim ME, Assi KH, Chrystyn H. Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion. Br J Clin Pharmacol. 2011;71:608e610.
14. Mashat M, Clark B, Assi K, Chrystyn H. Assessment of recent nebulizer delivery systems using urinary pharmacokinetics method and aerodynamic characteristics of TOBIÒ nebulized dose following inhalation. J Drug Deliv Sci Technol. 2017;39:428e434. 15. Hindle M, Chrystyn H, Newton DA. Relative bioavailability of salbutamol to the lung following inhalation using metered dose inhalation methods and spacer devices. Thorax. 1994;49:549e553. 16. Silkstone V, Corlett S, Chrystyn H. Relative lung and total systemic bioavailability following inhalation from a metered dose inhaler compared with a metered dose inhaler attached to a large volume plastic spacer and a jet nebuliser. Eur J Clin Pharmacol. 2002;57:781e786. 17. Hindle M, Newton DA, Chrystyn H. Investigations of an optimal inhaler technique with the use of urinary salbutamol excretion as a measure of relative bioavailability to the lung. Thorax. 1993;48:607e610. 18. Hindle M, Newton DA, Chrystyn H. Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary albuterol (salbutamol) assay technique. Chest. 1995;107:629e633. 19. Ismail NE, Chrystyn H. The relative bioavailability of salbutamol to the lungs from a U22 MicroAir nebuliser. J Pharm Pharmacol. 2004;56(supplement):S-39. 20. Silkstone VL, Chrystyn H, Tomlinson HS, Corlett SA. Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged. Br J Clin Pharmacol. 2000;50:281e284. 21. Abdelrahim ME. Emitted dose and lung deposition of inhaled terbutaline from turbuhaler at different conditions. Respir Med. 2010;104:682e689. 22. Mazhar S, Ismail N, Newton D, Chrystyn H. Relative lung deposition of salbutamol following inhalation from a spacer and a Sidestream jet nebuliser following an acute exacerbation. Brit J Clin Pharmacol. 2008;65:334e337. 23. Silkstone V, Dennis J, Pieron C, Chrystyn H. An investigation of in vitro/in vivo correlations for salbutamol nebulized by eight systems. J Aerosol Med. 2002;15: 251e259. 24. Abdelrahim M, Plant P, Chrystyn H. The relative lung and systemic bioavailability of terbutaline following nebulisation in non-invasively ventilated patients. Int J Pharm. 2011;420:313e318. 25. Hussein RRS, Ali AMA, Salem HF, et al. In vitro/in vivo correlation and modeling of emitted dose and lung deposition of inhaled salbutamol from metered dose inhalers with different types of spacers in noninvasively ventilated patients. Pharm Dev Technol. 2017;22:871e880. 26. Hassan A, Salah Eldin R, Abdelrahman MM, Abdelrahim ME. In-vitro/in-vivo comparison of inhaled salbutamol dose delivered by jet nebulizer, vibrating mesh nebulizer and metered dose inhaler with spacer during non-invasive ventilation. Exp Lung Res. 2017;43:19e28. 27. Rabea H, Ali AMA, Salah Eldin R, et al. Modelling of in-vitro and in-vivo performance of aerosol emitted from different vibrating mesh nebulisers in noninvasive ventilation circuit. Eur J Pharm Sci. 2017;97:182e191. 28. Ali AMA, Abdelrahim MEA. Modeling and optimization of terbutaline emitted from a dry powder inhaler and influence on systemic bioavailability using data mining technology. J Pharm Innov. 2014;9:38e47. 29. ElHansy MHE, Boules ME, El-Essawy AFM, et al. Inhaled salbutamol dose delivered by jet nebulizer, vibrating mesh nebulizer and metered dose inhaler with spacer during invasive mechanical ventilation. Pulm Pharmacol Ther. 2017;45:159e163. 30. Fink JB, Dhand R, Duarte AG, Jenne JW, Tobin MJ. Aerosol delivery from a metered-dose inhaler during mechanical ventilation. An in vitro model. Am J Respir Crit Care Med. 1996;154:382e387. 31. Miller DD, Amin MM, Palmer LB, Shah AR, Smaldone GC. Aerosol delivery and modern mechanical ventilation: in vitro/in vivo evaluation. Am J Respir Crit Care Med. 2003;168:1205e1209. 32. Fuller H, Dolovich M, Turpie F, Newhouse M. Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients. A study comparing four different actuator devices. Chest. 1994;105:214. 33. Branson RD, Gentile MA. Is humidification always necessary during noninvasive ventilation in the hospital? Respir Care. 2010;55:209e216. 34. Abdelrahim ME, Plant P, Chrystyn H. In-vitro characterisation of the nebulised dose during non-invasive ventilation. J Pharm Pharmacol. 2010;62:966e972. 35. Hassan A, Rabea H, Hussein RRS, et al. In-vitro characterization of the aerosolized dose during non-invasive automatic continuous positive airway pressure ventilation. Pulm Ther. 2016;2:115e126. 36. Saeed H, Elberry AA, Eldin AS, Rabea H, Abdelrahim MEA. Effect of nebulizer designs on aerosol delivery during non-invasive mechanical ventilation: a modeling study of in vitro data. 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Contents lists available at ScienceDirect
Heart & Lung journal homepage: www.heartandlung.org
Lung deposition and systemic bioavailability of different aerosol devices with and without humidification in mechanically ventilated patients Islam O.F. Moustafa, BSc a, b, Mohammed R. A.-A. Ali, MSc c, Moataz Al Hallag, PhD d, Hoda Rabea, PhD a, James B. Fink, PhD e, Patricia Dailey, BSc f, Mohamed E.A. Abdelrahim, PhD a, g, * a
Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt Clinical Pharmacist Department, Saudi German Hospital SGH, Cairo, Egypt Pharmacology and Toxicology Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt d Critical Care Medicine, Critical Care, Faculty of Medicine, Cairo University, Egypt e Division Allied Health, Georgia State University, Atlanta, GA, USA f Medical Affairs/Clinical, Medical Science Liaison, Aerogen, Ltd., Galway, Ireland g Clinical Pharmacy Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 January 2017 Received in revised form 10 July 2017 Accepted 7 August 2017 Available online xxx
Background: During mechanical ventilation medical aerosol delivery has been reported to be upto two fold greater with dry inhaled gas than with heated humidity. Urine levels at 0.5 h post dose (URSAL0.5%) has been confirmed as an index of lung deposition and 24 h (URSAL24%) as index of systemic absorption. Our aim was to determine the effect of humidification and aerosol device type on drug delivery to ventilated patients using urine levels. Methods: In a randomized crossover design, 36 (18female) mechanically ventilated patients were assigned to one of three groups. Groups 1 and 2 received 5000 mg salbutamol using vibrating mesh (VM) and jet nebulizers (JN), respectively, while group 3 received 1600 mg (16 puffs) of salbutamol via metered dose inhaler with AeroChamber Vent (MDI-AV). All devices were placed in the inspiratory limb of ventilator downstream from the humidifier. Each subject received aerosol with and without humidity at >24 h intervals with >12 h washout periods between salbutamol doses. Patients voided urine 15 min before each study dose and urine samples were collected at 0.5 h post dosing and pooled for the next 24 h. Results: The MDI-AV and VM resulted in a higher percentage of urinary salbutamol levels compared to the JN (p < 0.05). Urine levels were similar between humidity and dry conditions. Conclusions: Our findings suggest that in-vitro reports overestimate the impact of dry vs. heated humidified conditions on the delivery of aerosol during invasive mechanical ventilation. Ó 2017 Elsevier Inc. All rights reserved.
Keywords: Vibrating mesh nebulizers MDI Spacer Non-invasive ventilation Urinary salbutamol Humidification
Inhaled aerosol delivery during conventional mechanical ventilation with dual limb circuits, has been reported to be 40e 80% greater with dry ambient inhaled gas than with heated humidity.1e3 For this reason, it has been suggested that clinicians should turn off the humidifier before starting aerosol delivery.
Studies have shown that there is no significant difference between aerosol delivery in dry and humidified conditions in a single limb non-invasive ventilation (NIV) bench model study4 and in automatic continuous positive airway pressure (Auto-CPAP) by patients’ study.5 However, this data cannot be extended to dual limb ventilation because of difference in aerosol generator positioning.
Location of study: Teaching Hospital of Faculty of Medicine, Faculty of Medicine, Beni-suef University, Beni-suef, Egypt and the Clinical Pharmacy Department, Faculty of Pharmacy, Beni-suef University, Beni-suef, Egypt (analysis). R&D Approval for patient study: Beni-suef Teaching Hospitals Research Ethics Committee approval number: FMBSU REC FWA#: FWA00015574. Author Disclosure Statement: No competing financial interests exist.
* Corresponding author. Department of Clinical Pharmacy, Faculty of Pharmacy, University of Ahram Canadian, Giza, Egypt. E-mail addresses: [email protected] (I.O.F. Moustafa), mohammedragab [email protected] (M.R.A.-A. Ali), [email protected] (M. Al Hallag), hoda_cp@ yahoo.com (H. Rabea), fi[email protected] (J.B. Fink), patriciaanndailey@ gmail.com (P. Dailey), [email protected] (M.E.A. Abdelrahim).
Introduction
0147-9563/$ e see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.hrtlng.2017.08.004
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The debate of potential benefit of turning off the humidifier while delivering aerosol was addressed by Lin et al., reporting that turning off the humidifier for 20 min before aerosol delivery with MDI did not increase inhaled dose delivered to the ventilated patient. They attributed this to presence of condensate in the circuit that kept absolute humidity high despite reduced circuit temperature.6 More recently, Ari et al. demonstrated that in-vitro models simulating active exhaled humidity, more closely represent actual patient airway interactions, reducing differences in aerosol delivery between dry and humidified ventilator circuit, suggesting that models using passive or dry exhalation may overestimate total inhalable dose (TID) under dry conditions.7 Consequently, reports of better TID from aerosol delivered with dry versus heated humidified conditions might be due to failure of the models to simulate exhaled heat and humidity.7 The debate was furthered with reports of no difference of patients’ clinical status with changing humidity during aerosol delivery to ventilated patients.8 This suggests that a more reliable method is needed to determine the effect of humidity on aerosol delivery in the ventilated patient. Urine drug levels of salbutamol have been correlated to pulmonary delivery efficiency of inhaled medication.9,10 It has been previously shown that urinary salbutamol levels at 0.5 h post administration and cumulative over 24 h can be used as indices of the pulmonary deposition and systemic absorption of inhaled medication.9,10 The urinary drug level post aerosol administration has been used with other inhaled medications e.g. Sodium cromoglycate,11 Formatrol,12 Terbutaline,13 Tobramycin.14 The non-invasive urinary pharmacokinetic method has been used to compare delivery of a broad range of aerosol devices and administration methods: metered dose inhalers (MDI) to MDI with spacers15,16; investigate optimum inhalation technique17; compare dry powder inhalers (DPI) to MDIs18; determine the relative bioavailability of nebulized drug with prolonged administration19,20; and compare the use of highly resistant DPI in normal subjects to chronic obstructive lung disease (COPD) patients.21 In addition, urine levels have been used to study lung deposition and systemic absorption in critically ill patients e.g. during and following exacerbations.22,23 and during mechanical ventilation.24e27 Multiple data mining modelling studies have correlated urinary salbutamol method to in-vitro aerosol inhaled dose data.25,27,28 including mechanically ventilated patients.25,27 demonstrating that urinary salbutamol excreted at 0.5 h post dosing correlated to the fine particle dose (FPD) inhaled, and the mass median aerodynamic diameters (MMAD). They also showed that the urinary salbutamol excreted cumulatively collected over 24 h post dosing correlates to the total inhalable dose that reaches the patient. Consequently, urinary salbutamol method was proven to be a reliable method that can provide indices of lung deposition and systemic absorption. The aim of the present study was to determine the effect of humidification and type of inhalation device on aerosol delivery using salbutamol urine levels as indices of lung deposition and systemic absorption in mechanically ventilated patients. Materials and methods Study population This study was conducted in accordance with the amended Declaration of Helsinki. Local institutional review board (IRB) and independent ethics committees approved the protocol, with written informed consent obtained from all subjects. All subjects were recruited using hospital approved delayed consent procedure. Inclusion criteria was for subjects with a previous diagnosis of asthma or bronchospastic COPD that were admitted to the respiratory unit with an acute exacerbation, receiving invasive ventilation and prescribed to receive aerosol salbutamol. Subjects were excluded if they had taken part in a research study during the
previous 6 months, had known hypersensitivity to salbutamol, systolic blood pressure of <100 mmHg or severe renal impairment defined as Creatinine Clearance or eGFR of <20 mL min1. Study design and procedures We used the urinary salbutamol methodology previously reported by Hindle et al.9 to associate inhaled aerosol dose and urine levels of drug due to systemic absorption comparing three aerosol delivery methods during mechanical ventilation with and without heated humidification. In a randomized crossover design, asthmatic subjects receiving volume assisted control (V/AC) invasive mechanical ventilation using Bellavista 1000e Ventilator (Imtmedical, Buchs, Switzerland) and Ultramed endotracheal tube (cuffed) size 8 (Ultra For Medical Products Co., Cairo, Egypt) were randomly assigned to receive aerosol with a vibrating mesh nebulizer (VM; Aerogen Solo; Aerogen Ltd, Galway); a jet nebulizer (JN; Oxycare; Ceren Uretim A.S., Istanbol, Turkey); or a metered dose inhaler (Ventoline, GlaxoSmithKline, Egypt) with an AeroChamber Vent spacer (Trudell Medical International, Canada). Both VM and JN groups received 5000 mg of salbutamol respiratory solution (Farcolin, 5000 mg/mL; Pharco Pharmaceuticals, Egypt) with a dose volume of 2 mL. The metered dose inhaler with spacer (MDI-AV) group received 1600 mg (16 actuations at 100 mg per puff) of salbutamol. For each experiment the MDI was shaken well and primed with 2 actuation prior to use, with >30 s intervals between actuations. All devices were placed in the inspiratory limb of mechanical ventilation circuit (Int’air medical, Bresse, France) downstream from the humidifier (VH 2100 humidifier with humidifier chamber; Great Group Medical Co. (GGM), Changhua County, Taiwan). Subjects were randomized to receive aerosol during conventional mechanical ventilation with and without heated humidification at >24 h intervals with >12 h washout prior to each salbutamol dose. Salbutamol administration was withheld for at least 12 h prior dosing with salbutamol, with ipratropium bromide (Atrovent inhalation solution containing nominal dose of 25 mg mL1, Boehringer Ingelheim, Egypt) substituted during those periods. According to previous reports.21,24,26,29 using similar method, salbutamol was totally cleared from the urine after 24 h. Urine samples were collected 15 min before each study dose to establish baseline and again at 0.5 h (USAL0.5) after dose completion. Urine was then collected over the next 24 h (USAL24). All samples were measured and assayed for salbutamol using HPLC. Salbutamol was extracted from urine samples using solid phase extraction with Oasis MCX cartridge (Waters corporation, USA), with bambuterol hydrochloride added as an internal standard, and then injected into HPLC system.29 An ODS 5 mm, (4.6 250 mm, ZORBAX Eclipse) C-18 HPLC column with (4 mm 3 mm, Agilent, USA) C-18 (ODS) guard column was used. Mobile phase, acetonitrile: water containing 0.1% orthophosphoric acid (90:10, v/v), was pumped through columns at a flow of 1 mL min1 maintained at 25 C and photodiode array detection was set at 220 nm. Limit of detection and lower limit of quantification for salbutamol was 0.36 and 1.00 mg mL1, respectively. One way ANOVA with the application of the least significant difference (LSD) correction was used to determine differences between urinary salbutamol levels from the three inhalation methods with SPSS V17.0 (SPSS Inc., Chicago, USA). Independent T-test was used to determine difference between urinary salbutamol excretions at different humidity conditions (p < 0.05). Results 36 (18 females) consented subjects receiving mechanical ventilation were enrolled and randomly assigned to one of the three treatment groups. All subjects completed both study doses.
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There was no significant difference between the studied subjects in age, weight and height in the 3 groups. The percentage of nominal or emitted dose assayed from excreted urine at 0.5 h and over 24 h post aerosol dosing from the inhalation devices at different humidification condition are shown in Table 1. Data are shown as 6 groups (12 results in each) representing each aerosol generator and humidity condition. Data are also shown in Table 2 as 3 aerosol generators groups (24 results in each group), regardless of the humidity condition. Subject anthropomorphic characteristics are shown in Table 2. Table 3 compares the 2 humidity conditions (36 results in each group), regardless of the aerosol generators used. MDI-AV resulted in a higher URSAL0.5% compared to the JN and VM (p < 0.001 and p ¼ 0.041, respectively). The VM resulted in significantly higherURSAL0.5% compared to JN (p ¼ 0.001). The URSAL24% was greater with the VM than the JN and MDI-AV (p ¼ 0.002 and 0.048, respectively). For each aerosol delivery device, USAL0.5% and USAL24% were similar with both dry and humid conditions. Discussion Similar to prior reports, we found a difference in drug delivery efficiency between devices.5,26,29 However, no significant difference was found between the two conditions of humidification. Ari et al.3 demonstrated similar inhaled dose efficiency of approximately 17% of nominal and emitted dose with both VM and MDI-AV with lower dose efficiency using the JN (3.6%) under heated humidified conditions. In the same paper, Ari and colleagues reported a higher inhaled dose with VM (30.2%), JN (9.7%) and MDI-AV (27.8%) under nonheated humidified conditions representing increases over humidified conditions of 79%, 62% and 169%, respectively. This was similar to reports by Fink et al.30 of inhaled dose of 16% with MDI-AV during heated humidified gas increasing to 30% with non-heated dry gas delivered through the ventilator. Many authors have demonstrated greater inhaled dose of aerosol during mechanical ventilation with dry gas, compared the heated humidity up to 170%.1e3,7 In a sole report showing increased aerosol delivery with dry gas in-vivo, Miller et al. compared aerosol delivery via nebulizer during mechanical ventilation with non-humidified and humidified gas, reporting a 2e3 fold greater sputum level of amikacin with non-humidified conditions.31 Based on these studies, some authors have suggested that the humidifier should be turned off prior to aerosol administration to optimize aerosol delivery to the ventilated patient. In contrast, we found no difference in urine levels at 0.5 and 24 h post administration. This may be explained in part by variances inherent to aspiration of sputum specimens which provides less homogenous sampling than systemic measurements such as urine. Many variables differentiate in-vitro vs. in-vivo delivery. In-vitro models collect aerosol on an absolute filter, where lungs exhale a greater proportion of inhaled aerosol resulting in method bias with the in-vitro model overestimating dose inhaled during mechanical ventilation. Fink and colleagues compared in-vivo and in-vitro estimates of exhaled albuterol during aerosol administration with MDI-AV under heated humidified conditions, demonstrating 4.8% Table 1 Salbutamol urine levels, as percent [mean (SD)] of dose, achieved after aerosol administration by JN, VM and MDI-AV during mechanical ventilation with (Humidity) and without (Dry) heated humidification.
URSAL0.5% URSAL24%
JN humidity
JN dry
VM humidity
VM dry
MDI-AV humidity
MDI-AV dry
0.7 (0.5) 6.2 (3.3)
0.9 (0.6) 6.6 (4.1)
1.7 (0.8) 10.1 (6.9)
1.8 (1.1) 10.5 (4.0)
2.0 (1.1) 7.8 (2.5)
2.5 (1.3) 8.0 (3.4)
3
Table 2 Anthropomorphic characteristics of the patients and salbutamol urine levels, as percent [mean (SD)] of dose, achieved after aerosol administration by JN, VM and MDI-AV during mechanical ventilation. Aerosol generator results
JN
VM
MDI-AV
Age (years) Weight (kg) Height (cm) URSAL0.5% URSAL24%
62.4 (8.5) 77.6 (13.9) 172.5 (8.7) 0.8 (0.5) 6.4 (3.6)
61.7 (9.0) 74.6 (7.8) 170.4 (7.3) 1.7 (1.0) 10.3 (5.5)
61.8 (9.5) 78.2 (10.6) 169.8 (9.8) 2.3 (1.2) 7.8 (2.9)
more of the emitted drug exhaled in-vivo than in-vitro, suggesting a corrected inhaled dose of 11% in-vivo which was consistent with previous scintigraphy deposition under similar ventilator conditions.32 The calculated lung dose with MDI-AV is similar to the 10e10.5% total salbutamol recovered from urine post treatment under both humidified and dry conditions. A partial explanation may lie in the role of exhaled humidity on the delivery of aerosol through an artificial airway. Patients exhale gas that has been actively heated and humidified in the lungs, while the commonly described bench model does not. Ari et al. have described the effects of providing active heated humidity to exhaled gas in their lung model, resulting in lower inhaled aerosol doses during administration of aerosol with dry gases than with standard passive exhalation.7 Their findings suggest that at least a portion of the difference between inhaled dose with heated humidified and dry gas may be due of the particulars of the model used, and how well it simulates patient aerosol interface.7 Even without active exhaled humidity, Lin et al. showed that switching off the humidifier for up to 30 min prior to administration of an MDI-AV did not result in greater aerosol delivery compared to administration with humidity.6 Our findings support the notion that aerosol administration with heated humidified gas does not result in up to a 3 fold increase in lung delivery with dry gas during mechanical ventilation. There was no significant difference in USAL0.5% as an index of lung deposition and USAL24% as an index of systemic absorption when inhalation methods were used in humidified or dry condition. Consequently, our findings suggest that turning off the humidifier may not improve aerosol delivery efficiency. Another important factor that supports our recommendation for aerosol delivery to ventilated patient under humidified conditions is that previous recommendation for switching off the humidifier may contribute to problems associated with administration of dry cold gas to the lungs such as; lung irritation, bronchospasm, and desiccation of secretions.33 These risks are even greater should the clinician fail to turn on the humidifier upon conclusion of aerosol administration. Consequently, based on our finding we would recommend not interrupting humidity during aerosol administration, especially after Moustafa et al. found no significant effect on patients’ clinical status with changing humidity during aerosol delivery to ventilated patient.8 The choice of aerosol delivery method has a greater impact than the effect of humidity. As previously shown, the VM and MDI-AV were more efficient than the JN.7,24,26,34,35 The VM resulted in highest USAL24% (p < 0.05) suggesting highest systemic absorption Table 3 Salbutamol urine levels, as percent [mean (SD)] of dose, achieved after aerosol administration during mechanical ventilation with (Humidity) and without (Dry) heated humidification. Condition results
Dry delivery
Humid delivery
URSAL0.5% URSAL24%
1.5 (1.0) 8.0 (4.8)
1.7 (1.2) 8.4 (4.1)
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at all conditions. Also, MDI-AV resulted in higher USAL0.5% (p < 0.05) suggesting highest lung deposition efficiency. The higher USAL24% of VM as an index of systemic absorption was due to the very small residual volume of VM compared to JN.7,24,34,36e38 and the spacer’s effect of MDI-AV in which most of the large aerosolized particles rained out.25,35,39 The higher USAL0.5% of MDI-AV maybe due to the distance of the MDI actuation in the AV spacer which allowed the MDI propellants to evaporate more and result in smaller MMAD that increased lung deposition compared to JN and VM.35,39 Limitations While the size of each group may have hidden some of the statistical differences between conditions, our range of ventilator parameters were similar across all groups. Further studies with a wider variety of ventilator parameters and patient conditions with a larger sample size may be of value. Conclusions In all conditions studied, the JN had the lowest USAL0.5% and USAL24%. MDI-AV had the highest USAL0.5% and VM had the highest USAL24%. The effect of heat and humidity on aerosol delivery was less than previously reported by in-vitro models using passive, non-humidified exhalation. The in-vivo urinary method demonstrated similarity of delivered aerosol dose to the lung with heated humidity and dry conditions in mechanically ventilated patients. References 1. Lange CF, Finlay WH. Overcoming the adverse effect of humidity in aerosol delivery via pressurized metered-dose inhalers during mechanical ventilation. Am J Respir Crit Care Med. 2000;161:1614e1618. 2. Ari A, Areabi H, Fink J. Evaluation of aerosol generator devices at 3 locations in humidified and non-humidified circuits during adult mechanical ventilation. Respir Care. 2010;55:837e844. 3. Ari A, Atalay OT, Harwood R, et al. Influence of nebulizer type, position, and bias flow on aerosol drug delivery in simulated pediatric and adult lung models during mechanical ventilation. Respir Care. 2010;55:845e851. 4. Saeed H, Mohsen M, Fink JB, et al. Fill volume, humidification and heat effects on aerosol delivery and fugitive emissions during noninvasive ventilation. J Drug Deliv Sci Technol. 2017;39:372e378. 5. Mohsen M, Elberry AE, Salah Eldin A, Hussein RR, Abdelrahim EM. Effects of heat and humidification on aerosol delivery during auto-CPAP noninvasive ventilation. Arch Pulmonol Respir Care. 2017;3:11e15. 6. Lin H-L, Fink JB, Zhou Y, Cheng Y-S. Influence of moisture accumulation in inline spacer on delivery of aerosol using metered-dose inhaler during mechanical ventilation. Respir Care. 2009;54:1336e1341. 7. Ari A, Harwood R, Sheard M, et al. Quantifying aerosol delivery in simulated spontaneously breathing patients with tracheostomy using different humidification systems with or without exhaled humidity. Respir Care. 2016;61:600e606. 8. Moustafa IOF, ElHansy MHE, Al Hallag M, et al. Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients. Pulm Pharmacol Ther. 2017;45:40e46. 9. Hindle M, Chrystyn H. Determination of the relative bioavailability of salbutamol to the lung following inhalation. Br J Clin Pharmacol. 1992;34:311e315. 10. Tomlinson HS, Corlett SA, Chrystyn H. Dose-response relationship and reproducibility of urinary salbutamol excretion during the first 30 min after an inhalation. Br J Clin Pharmacol. 2003;56:225e227. 11. Aswania OA, Corlett SA, Chrystyn H. Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion. Br J Clin Pharmacol. 1999;47:613e618. 12. Nadarassan DK, Chrystyn H, Clark BJ, Assi KH. Validation of high-performance liquid chromatography assay for quantification of formoterol in urine samples after inhalation using UV detection technique. J Chromatogr B Biomed Sci Appl. 2007;850:31e37. 13. Abdelrahim ME, Assi KH, Chrystyn H. Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion. Br J Clin Pharmacol. 2011;71:608e610.
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