- Email: [email protected]
Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients
Accepted Manuscript Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients Islam O.F. Moustafa, Muhammad H.E. ElHansy, Moataz Al Hallag, James B. Fink, Patricia Dailey, Hoda Rabea, Mohamed E.A. Abdelrahim, Associate professor PII:
S1094-5539(17)30036-6
DOI:
10.1016/j.pupt.2017.04.007
Reference:
YPUPT 1616
To appear in:
Pulmonary Pharmacology & Therapeutics
Received Date: 25 January 2017 Revised Date:
27 March 2017
Accepted Date: 19 April 2017
Please cite this article as: Moustafa IOF, ElHansy MHE, Al Hallag M, Fink JB, Dailey P, Rabea H, Abdelrahim MEA, Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients, Pulmonary Pharmacology & Therapeutics (2017), doi: 10.1016/j.pupt.2017.04.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients
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Islam O.F.Moustafa, 3Muhammad H. E.ElHansy,4Moataz Al Hallag,5James B Fink, Patricia Dailey, 2Hoda Rabea,2,7Mohamed E.A.Abdelrahim 1 Clinical Pharmacist department, Saudi German Hospital SGH, Cairo, Egypt 2 Clinical Pharmacy Department, Faculty of Pharmacy, Beni-suef University, Benisuef, Egypt 3 Clinical Pharmacy Department, Teaching Hospital of Faculty of Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt 4 Critical care medicine, Critical Care, Faculty of medicine, Cairo University 5 Division of Respiratory Therapy, School of Health Professions, Georgia State University, Atlanta, Georgia, USA 6 Medical Affairs/Clinical, Medical Science Liaison, Aerogen, Ltd., Galway, Ireland 7 Clinical Pharmacy Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
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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)
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Short title: Inhalers and humidity in ventilated asthmatic Keywords: Vibrating mesh nebulisers; MDI; Spacer; Non-invasive ventilation; Urinary salbutamol; Humidification R&D Approval for patient study:Beni-suef Teaching Hospitals Research Ethics Committee approval number: FMBSU REC FWA#: FWA00015574
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Correspondence: Mohamed E. Abdelrahim Associate professor Department of Clinical Pharmacy Faculty of Pharmacy, University of Ahram Canadian Giza, Egypt Tel No. 00201118261953. Fax no: 0020822317953 Email: [email protected]
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ACCEPTED MANUSCRIPT Abstract Background Inhaled-medication delivered during mechanical-ventilation is affected by type of aerosol-generator and humidity-condition. Despite many in-vitro studies related to
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aerosol-delivery to mechanically-ventilated patients, little has been reported on clinical effects of these variables.
The aim of this study was to determine effect of humidification and type of aerosol-
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generator on clinical status of mechanically ventilated asthmatics. Method
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72 (36 females) asthmatic subjects receiving invasive mechanical ventilation were enrolled and assigned randomly to 6 treatment groups of 12 (6 females) subjects each received, as possible, all inhaled medication using their assigned aerosol generator and humidity condition during delivery. Aerosol-generators were placed immediately
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after humidifier within inspiratory limb of mechanical ventilation circuit. First group used vibrating-mesh-nebulizer (Aerogen Solo; VMN) with humidification; Second used VMN without humidification; Third used metered-dose-inhaler with
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AeroChamber Vent (MDI-AV) with humidification; Forth used MDI-AV without
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humidification; Fifth used Oxycare jet-nebulizer (JN) with humidification; Sixth used JN without humidification. Measured parameters included clinical-parameters reflected patient response (CP) and endpoint parameters e.g. length-of-stay in the intensive-care-unit (ICU-days) and mechanical-ventilation days (MV-days). Results There was no significant difference between studied subjects in the 6 groups in baseline of CP.
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ACCEPTED MANUSCRIPT VMN resulted in trend to shorter ICU-days (~1.42days) compared to MDI-AV (p=0.39) and relatively but not significantly shorter ICU-days (~0.75days) compared JN. Aerosol-delivery with or without humidification did not have any significant
at humid condition to decrease MV-days and ICU-days.
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effect on any of parameters studied with very light insignificant tendency of delivery
No significant effect was found of changing humidity during aerosol-delivery to ventilated-patient.
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Conclusions
VMN to deliver aerosol in ventilated patient resulted in trend to decreased ICU-days
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compared to JN and MDI-AV. Aerosol-delivery with or without humidification did not have any significant effect on any of parameters studied. However, we recommend increasing the number of patients studied to corroborate this finding. Introduction
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Researchers have focused in the last decades on optimizing medical aerosol delivery to ventilated patients. Many researchers studied the effect of type of aerosol generator used;[1-7] the position of the aerosol generator in the ventilator circuit;[4,
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8-10] ventilator parameter ;[4, 11, 12] the type of ventilator circuit; volume of
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nebulised medication; and the effect of humidity [4, 12, 13] among other factors. All have focused on the effect of those factors on total inhalable dose and possible lung deposition.
To date no study has reported benefit of different aerosol generator or humidification conditions during delivery on the clinical status of the ventilated patient reason why we increase the delivery of inhaled medication to such patients.
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ACCEPTED MANUSCRIPT The aim of the present study was to determine or help in determination of the effect of type of aerosol generator and humidity change during aerosol delivery on clinical outcomes and status of mechanically ventilated patients. Methods
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Patients
This study was conducted in accordance with amended Declaration of Helsinki. Local institutional review boards (IRB) and independent ethics committees
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approved protocol. Written informed consent was obtained from all patients. Patients
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with previous diagnosis of asthma that had been admitted to respiratory intensive care unit of Beni-suef University hospital with an acute exacerbation, receiving invasive ventilation were eligible for study. All patients were recruited using hospital approved delayed consent procedure.
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Patients were ineligible to be included in this study if they had taken part in research study during previous 6 months
Patient ventilation modes used with asthmatic patients studied
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The ventilation protocol for acute asthma exacerbations used in this study was the same protocol used by the hospital where the study took place. Upon admission to
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the intensive care unit (ICU) the exacerbated asthmatic patient was initially placed in the volume assist control (V/AC) mode with tidal volume (TV) = 500mL, respiratory rate=12 breaths.min-1, inspiratory flow rate = 60L.min-1, inspiratory: expiratory (I:E) ratio was 1:3. If the clinician observed that the patient could reliably trigger inspiration, V/AC was changed to pressure support ventilation (PSV) with a positive end-expiratory pressure (PEEP) = 5 cmH2O and the clinician checked the patient’s spontaneous tidal volumes. If the patients could not achieve a TV of 500 mL, then the clinician titrated the inspiratory pressure support to reach the targeted TV = 500 ml. 4
ACCEPTED MANUSCRIPT Mostly the inspiratory pressures in PSV were between15-20 cmH2O. We tried to minimize pressures to avoid pulmonary barotraumas unless the patient had higher ventilatory requirements. No documented incidence of barotrauma occurred in any of the subjects studied. The clinician weaned the patient by decreasing and eventually
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removing added inspiratory pressure on the ventilator to prepare for extubation and transfer from ICU to a normal ward, as tolerated. Some patients may have required
transition from the weaning mode (PSV) back to the support mode (V/AC) based on
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their clinical needs. Study design and procedures
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We compared clinical outcomes associated with the use of different aerosol generators with and without humidification. The study was a prospective randomized. 72 (36 females) asthmatic subjects receiving invasive mechanical ventilation using Bellavista 1000e ventilator (Imtmedical, Buchs, Switzerland) were enrolled per
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institutional review board (IRB), and randomly assigned to 6 treatment groups of 12 (6 females) subjects. Each subject received, as possible, all inhaled medication using
delivery.
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his or her randomly selected aerosol generator and humidity condition during aerosol
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As shown in Figure 1, all aerosol generators were placed after the humidification chamber (VH 2100 humidifier with humidifier chamber; Great Group Medical Co. (GGM), Changhua County, Taiwan) within the inspiratory limb of a 2 limb ventilator circuit (Int’air Medical, Bresse, France) consisted of a smooth 22mm internal diameter (ID) tubing of 160 cm length. A water trap was placed in the inspiratory limb; with no elbow connection placed between the circuit and the patient airway.
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ACCEPTED MANUSCRIPT A vibrating mesh nebulizer (Aerogen Solo; Aerogen Limited, Galway, Ireland); metered dose inhaler with spacer (AeroChamber Vent; Trudell Medical International, Canada); and an Oxycare jet nebulizer (Ceren Uretim A.S., Istanbol, Turkey) operated with air flow of 6 L/min where all placed in the inspiratory limb of
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the ventilator circuit proximal to the patient. All devices were operated with and without heated humidity.
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Clinical responses of patients based on different clinical parameters and response to different treatment groups were recorded daily. Measured parameters, that
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reflected patient response, were partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), Oxygen saturation % (O2 SAT%), pH, respiratory rate and heart rate. These parameters were measured every day from the initial ICU admit day to the last day in the ICU. Measured parameters that reflected endpoints were length
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of stay in the intensive care unit (ICU-days), mechanical ventilation days (MV-days) and mortality.
One-way ANOVA with the application of least significant difference (LSD)
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correction was used to determine any difference between the clinical parameters,
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reflecting patient response, results on the baseline and throughout the study period from the three aerosol generators at different humidity conditions. One-way ANOVA with the application of least significant difference (LSD) correction was also used to determine any difference between results of mortality, if present, ICU-days and MV-days from the three aerosol generators at different humidity conditions. Results
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ACCEPTED MANUSCRIPT 72 (36 females) ventilated patients were randomized into 6 treatment groups , mean (SD) age, weight and height are shown in Table 1, agreed to be included in the study using the delayed consent procedure and they all completed the study with no
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mortality. The subjects in the 6 groups were similar in the baseline of pO2, pCO2, O2
SAT%, pH, respiratory rate and heart rate as clinical parameters reflecting the severity of their disease. Medications used by patients in the 6 groups were comparable.
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Comparison of individual value of all the clinical parameters reflecting patient
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response (pO2, pCO2, O2 SAT%, pH, respiratory rate and heart rate) showed that they tend to approach a stable value relatively shortly after the study commenced. Neither device type nor humidification had significant impact on the profile of theses parameters.
Mean ICU days and days receiving mechanical ventilation (MV-days) are
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shown in Table 1 and Figures 2 and 3. Data are shown as 6 groups (12 results in each group). Each group had its own aerosol generator and humidity condition. Data are
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also shown as 3 aerosol generator groups (24 results in each group), regardless of the humidity condition. Data are also shown as 2 humidity conditions groups (36 results
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in each group), regardless of the aerosol generator used. The vibrating mesh nebulizer (VMN) Dry resulted in significantly shorter ICU-days compared to metered dose inhaler with spacer (MDI-AV) dry (p=0.034). VMN resulted in significantly shorter ICU-days compared to MDI-AV
(p=0.039) and relatively but not significantly shorter ICU-days compared to jet nebulizer (JN). MDI-AV showed the highest MV-days and ICU-days.
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ACCEPTED MANUSCRIPT Aerosol delivery with or without humidification did not have any significant effect on any of the parameters studied with trend to lower values associated with aerosol delivery with humid condition. Discussion
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Many previous in-vitro studies have reported great differences between
aerosol generators in mechanical ventilations.[2, 10, 14-17] Previous in-vitro data has also reported that more aerosols are delivered to the mechanically ventilated patient
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without humidification and due to this finding; many clinicians choose to turn off humidification during aerosol delivery.[4, 12, 13, 18, 19]
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No previous study had ever evaluated the effect of aerosol generator used or humidity condition setting on the clinical status of the ventilated patient and to our knowledge this is the first one.
In the study presented here there was no effect of humidification change in all
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the parameters studied. With 36 subjects in each arm, regardless of the aerosol generator used, the statistical analysis resulted in a very high p-value (0.642 and 0.754, respectively) for MV-days and ICU-days with a trend to decrease the MV-days
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and the ICU-days by delivering aerosol in humid condition, opposing the finding of
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the in-vitro studies that suggested better aerosol delivery by turning off the humidifier. [4, 12, 13, 18] The high p-values of comparison suggest the need of a very large sample size
to find significant effects of humidity change during aerosol delivery on the clinical status of the ventilated patients, that if actually present. In the dry arm of the study, with the insignificantly higher MV-days and ICU-days, humidifier was turned off during delivery and switched back on immediately after delivery., Some clinicians turn off humidifier during aerosol delivery and might forget
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ACCEPTED MANUSCRIPT to turn it back on. This would have a potentially detrimental effect on the lung and the patient.[20-25] In such a situation the increase in the MV-days and the ICU-days would be expected to be much more than our finding here. Some researchers have recommended delivering a somewhat higher dose to
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overcome the humidity effect on aerosol delivery.[26-29] Dhand and Guntur
recommended the use of a dry circuit for delivery of very expensive agents or agents for which lung deposition is critical e.g. antibiotics and prostaglandins.[30] Also,
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when a dry ventilation circuit is used, aerosol delivery should be finished within a
short period of time, less than 10 to 15 min, to minimize the effects of dry gas on the
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airway mucosa.[20-25, 30] Also, it was found that switching off the humidifier does not result in a decrease in the circuit humidity if less than 20 minutes due to the patient’s exhalation into the circuit and the evaporation of the condensate in the ventilation circuit.[31]
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Our results did not support these in-vitro data suggesting better aerosol delivery in a dry circuit. Also, there is no clinical evidence to support the need for increasing the dose or turning off the humidifier with the above mentioned
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medications, since, most of the dose delivered to the ventilated patient would be on
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the plateau of the effect of inhaled drug.[32, 33] Also, more recent in-vitro evidence using an adult model with simulated exhaled gas has shown that the humidity in the exhaled air decreased the total inhalable dose that could reach the tracheostomized patient in a dry circuit.[11] All these studies could discourage the clinical practice of aerosol delivery in dry circuit and encourage the use of aerosol generators with the humidifier on. In our study, the effect of the aerosol generator on patient‘s clinical status with the 24 patients in each arm; MV-days were not affected by the aerosol generator type,
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ACCEPTED MANUSCRIPT with a high p-value of comparison which is obvious from Figure 2b.However, the VMN showed a tendency toward decreased ICU-days by ~0.75 days as seen from Figure 3b. This VMN tendency was not found significance compared to JN (p=0.268) but with MDI-AV there was a significant decrease in the ICU-days by ~1.42 days
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(p=0.039) when using VMN. Also, significantly higher ICU-days were found from
MDI-AV dry than VMN dry (p=0.034). The higher ICU-days by MDI-AV might be due to the greater total amount of aerosol delivered by the VMN to the patients that
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resulted in a possible faster cure, since the optimum clinical efficiency, increased
FEV1, of inhaled therapy depends on the amount of drug reaching the lungs.[34-36]
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This possible rational is supported by the shorter ICU-days of the VMN compared the JN, even though the difference was not significant (p=0.268) since JN was proven to deliver much smaller total inhalable dose than the VMN.[2, 3, 10, 37]The difference in the ICU-days might also be due to the presence of propellants in the aerosol from
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the MDI-AV, which might cause bronchoconstriction to such a critically ill patient recruited in this study.[38-45]
This finding could discourage the use of MDI-AV in ventilation circuit, however, this
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lower effect of MDI with adaptors in mechanically ventilated patient was also found
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to be due to technical problems associated with health care providers delivery with dosing the MDI properly.[2] Inconsistency in the administration technique and MDI adaptor used may lead to marked differences in the aerosol delivered to lower respiratory tract.[46, 47] Thus, optimal aerosol delivery by MDI requires careful consideration of many factors that affect aerosol delivery to the lungs of mechanically ventilated patients. When used with optimal technique, MDIs and nebulizers were found to be equally effective in the management of mechanically ventilated patients with different obstructive lung disease. [48] For routine bronchodilator therapy, MDIs
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ACCEPTED MANUSCRIPT may be preferred because of their convenience, more consistent dosing, and, similar to VMN, potential reduced risk of bacterial contamination when compared to JN. [49, 50] In one survey of neonatal ICUs, MDI use was reported to have increased significantly over a period of approximately 20 years. [51] The majority of adult ICUs
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in the United States (U.S.) also prefer MDIs for routine bronchodilator therapy. [52, 53] However, in the U.S. MDIs are more expensive and place a cost burden on
hospitals and inpatient pharmacies. Loboerc et. al, used an automatic formulary
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substitution of ipratropium–albuterol nebulized solution with VMN for conversion
from MDI and projected an annualized savings of $257,936 in associated cost.[54] In
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addition, nebulizers continue to be employed for a proportion of bronchodilator treatments, and for delivery of antibiotics, surfactant, prostaglandins, and other formulations that are not available in MDIs. [29, 55] Conclusion
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No significant effect on patients’ clinical status was found in this study from changing humidity during aerosol delivery to ventilated patient. Hence we discourage the practice of turning off the humidifier during aerosol delivery, which might be
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forgotten in the off position.
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The use of VMN to deliver aerosol to ventilated patient resulted in a trend toward decreased ICU-days compared to JN and MDI-AV. We recommend increasing the number of patients studied to confirm and
possibly extend these findings.
Figure Legend Figure 1
Schematic design of the inhalation device positions within the invasive ventilator circuit.
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ACCEPTED MANUSCRIPT Figure 2
a. Mean (SD) MV-days after receiving inhaled medication by 3 different aerosol generators at 2 different humidity conditions b. Mean (SD) MV-days after receiving inhaled medication by 3 different
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aerosol generators regardless of the humidity conditions c. Mean (SD) MV-days after receiving inhaled medication at 2 different humidity conditions regardless of aerosol generators used
a. Mean (SD) ICU-days after receiving inhaled medication by 3 different
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Figure 3
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aerosol generators at 2 different humidity conditions
b. Mean (SD) ICU-days after receiving inhaled medication by 3 different aerosol generators regardless of the humidity conditions c. Mean (SD) ICU-days after receiving inhaled medication at 2 different
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humidity conditions regardless of aerosol generators used
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cepacia respiratory tract colonization and infection associated with nebulized albuterol therapy. Annals of internal medicine, 1995. 122(10): p. 762-766.
50.
Craven, D.E., et al., Contaminated medication nebulizers in mechanical ventilator circuits: source of bacterial aerosols. The American journal of medicine, 1984. 77(5): p. 834-838.
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Ballard, J., R.A. Lugo, and J.W. Salyer, A survey of albuterol administration practices in intubated patients in the neonatal intensive care unit. Respiratory Care, 2002. 47(1): p. 31-38.
52.
Ehrmann, S., et al., Aerosol therapy in intensive and intermediate care units:
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prospective observation of 2808 critically ill patients. Intensive care medicine, 2015: p. 1-10. 53.
Ehrmann, S., et al., Aerosol therapy during mechanical ventilation: an
54.
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international survey. Intensive care medicine, 2013. 39(6): p. 1048-1056.
Loborec, S.M., S.E. Johnson, and E.A. Keating, Financial effect of converting
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ipratropium-albuterol therapy from inhalers to nebulizer treatments at an academic health system. American journal of health-system pharmacy, 2016. 73(3). 55.
Dhand, R., Inhalation therapy in invasive and noninvasive mechanical
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ventilation. Current opinion in critical care, 2007. 13(1): p. 27-38.
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ACCEPTED MANUSCRIPT Table 1.Mean (SD) MV-days and ICU-days after receiving the inhaled medication by JN, VMN or MDI-AV during mechanical ventilation with (Humidity) or without (Dry) heated humidification JN JN VMN VMN MDI-AV MDIDry
Humidity
61.2
Age
63.6 (8.0) (7.7)
77.6
76.5 (11.7)
81.2 (8.6)
(9.0) 5.4
MV6.0 (1.5)
(1.0) 8.3
ICU8.7 (2.5)
(1.9)
ICU-
(8.1)
5.6
6.2 (1.1)
5.7 (1.4)
9.7 (2.8)
8.7 (2.3)
(1.0) 7.9
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(2.0)
JN
VMN
MDI-AV
5.71 (1.27)
5.67 (0.96)
5.92 (1.25)
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days
(9.3)
7.6 (2.5)
days
170.5
176.2 (8.6)
5.8 (1.0)
days
(10.2)
175.5 174.4 (11.8)
(cm)
79.1
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171.9 (7.8)
(5.6)
80.9 (12.8)
(9.3)
173.2
Height
60.9
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(10.7)
(kg)
AV Dry
61.7 (8.6)
(7.0)
82.2
Weight
Humidity
60.2
62.5 (9.6) (years)
MV-
Dry
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Humidity
7.75 (2.23)
9.17 (2.57)
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8.50 (2.17)
days
Dry delivery
Humid delivery
5.97 (1.18)
5.56 (1.11)
8.64 (2.68)
8.31 (2.03)
MVdays
ICUdays
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S1094-5539(17)30036-6
DOI:
10.1016/j.pupt.2017.04.007
Reference:
YPUPT 1616
To appear in:
Pulmonary Pharmacology & Therapeutics
Received Date: 25 January 2017 Revised Date:
27 March 2017
Accepted Date: 19 April 2017
Please cite this article as: Moustafa IOF, ElHansy MHE, Al Hallag M, Fink JB, Dailey P, Rabea H, Abdelrahim MEA, Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients, Pulmonary Pharmacology & Therapeutics (2017), doi: 10.1016/j.pupt.2017.04.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Clinical outcome associated with the use of different inhalation method with and without humidification in asthmatic mechanically ventilated patients
1,2
Islam O.F.Moustafa, 3Muhammad H. E.ElHansy,4Moataz Al Hallag,5James B Fink, Patricia Dailey, 2Hoda Rabea,2,7Mohamed E.A.Abdelrahim 1 Clinical Pharmacist department, Saudi German Hospital SGH, Cairo, Egypt 2 Clinical Pharmacy Department, Faculty of Pharmacy, Beni-suef University, Benisuef, Egypt 3 Clinical Pharmacy Department, Teaching Hospital of Faculty of Medicine, Faculty of Medicine, Fayoum University, Fayoum, Egypt 4 Critical care medicine, Critical Care, Faculty of medicine, Cairo University 5 Division of Respiratory Therapy, School of Health Professions, Georgia State University, Atlanta, Georgia, USA 6 Medical Affairs/Clinical, Medical Science Liaison, Aerogen, Ltd., Galway, Ireland 7 Clinical Pharmacy Department, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt
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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)
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Short title: Inhalers and humidity in ventilated asthmatic Keywords: Vibrating mesh nebulisers; MDI; Spacer; Non-invasive ventilation; Urinary salbutamol; Humidification R&D Approval for patient study:Beni-suef Teaching Hospitals Research Ethics Committee approval number: FMBSU REC FWA#: FWA00015574
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Correspondence: Mohamed E. Abdelrahim Associate professor Department of Clinical Pharmacy Faculty of Pharmacy, University of Ahram Canadian Giza, Egypt Tel No. 00201118261953. Fax no: 0020822317953 Email: [email protected]
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ACCEPTED MANUSCRIPT Abstract Background Inhaled-medication delivered during mechanical-ventilation is affected by type of aerosol-generator and humidity-condition. Despite many in-vitro studies related to
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aerosol-delivery to mechanically-ventilated patients, little has been reported on clinical effects of these variables.
The aim of this study was to determine effect of humidification and type of aerosol-
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generator on clinical status of mechanically ventilated asthmatics. Method
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72 (36 females) asthmatic subjects receiving invasive mechanical ventilation were enrolled and assigned randomly to 6 treatment groups of 12 (6 females) subjects each received, as possible, all inhaled medication using their assigned aerosol generator and humidity condition during delivery. Aerosol-generators were placed immediately
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after humidifier within inspiratory limb of mechanical ventilation circuit. First group used vibrating-mesh-nebulizer (Aerogen Solo; VMN) with humidification; Second used VMN without humidification; Third used metered-dose-inhaler with
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AeroChamber Vent (MDI-AV) with humidification; Forth used MDI-AV without
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humidification; Fifth used Oxycare jet-nebulizer (JN) with humidification; Sixth used JN without humidification. Measured parameters included clinical-parameters reflected patient response (CP) and endpoint parameters e.g. length-of-stay in the intensive-care-unit (ICU-days) and mechanical-ventilation days (MV-days). Results There was no significant difference between studied subjects in the 6 groups in baseline of CP.
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ACCEPTED MANUSCRIPT VMN resulted in trend to shorter ICU-days (~1.42days) compared to MDI-AV (p=0.39) and relatively but not significantly shorter ICU-days (~0.75days) compared JN. Aerosol-delivery with or without humidification did not have any significant
at humid condition to decrease MV-days and ICU-days.
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effect on any of parameters studied with very light insignificant tendency of delivery
No significant effect was found of changing humidity during aerosol-delivery to ventilated-patient.
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Conclusions
VMN to deliver aerosol in ventilated patient resulted in trend to decreased ICU-days
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compared to JN and MDI-AV. Aerosol-delivery with or without humidification did not have any significant effect on any of parameters studied. However, we recommend increasing the number of patients studied to corroborate this finding. Introduction
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Researchers have focused in the last decades on optimizing medical aerosol delivery to ventilated patients. Many researchers studied the effect of type of aerosol generator used;[1-7] the position of the aerosol generator in the ventilator circuit;[4,
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8-10] ventilator parameter ;[4, 11, 12] the type of ventilator circuit; volume of
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nebulised medication; and the effect of humidity [4, 12, 13] among other factors. All have focused on the effect of those factors on total inhalable dose and possible lung deposition.
To date no study has reported benefit of different aerosol generator or humidification conditions during delivery on the clinical status of the ventilated patient reason why we increase the delivery of inhaled medication to such patients.
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ACCEPTED MANUSCRIPT The aim of the present study was to determine or help in determination of the effect of type of aerosol generator and humidity change during aerosol delivery on clinical outcomes and status of mechanically ventilated patients. Methods
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Patients
This study was conducted in accordance with amended Declaration of Helsinki. Local institutional review boards (IRB) and independent ethics committees
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approved protocol. Written informed consent was obtained from all patients. Patients
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with previous diagnosis of asthma that had been admitted to respiratory intensive care unit of Beni-suef University hospital with an acute exacerbation, receiving invasive ventilation were eligible for study. All patients were recruited using hospital approved delayed consent procedure.
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Patients were ineligible to be included in this study if they had taken part in research study during previous 6 months
Patient ventilation modes used with asthmatic patients studied
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The ventilation protocol for acute asthma exacerbations used in this study was the same protocol used by the hospital where the study took place. Upon admission to
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the intensive care unit (ICU) the exacerbated asthmatic patient was initially placed in the volume assist control (V/AC) mode with tidal volume (TV) = 500mL, respiratory rate=12 breaths.min-1, inspiratory flow rate = 60L.min-1, inspiratory: expiratory (I:E) ratio was 1:3. If the clinician observed that the patient could reliably trigger inspiration, V/AC was changed to pressure support ventilation (PSV) with a positive end-expiratory pressure (PEEP) = 5 cmH2O and the clinician checked the patient’s spontaneous tidal volumes. If the patients could not achieve a TV of 500 mL, then the clinician titrated the inspiratory pressure support to reach the targeted TV = 500 ml. 4
ACCEPTED MANUSCRIPT Mostly the inspiratory pressures in PSV were between15-20 cmH2O. We tried to minimize pressures to avoid pulmonary barotraumas unless the patient had higher ventilatory requirements. No documented incidence of barotrauma occurred in any of the subjects studied. The clinician weaned the patient by decreasing and eventually
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removing added inspiratory pressure on the ventilator to prepare for extubation and transfer from ICU to a normal ward, as tolerated. Some patients may have required
transition from the weaning mode (PSV) back to the support mode (V/AC) based on
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their clinical needs. Study design and procedures
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We compared clinical outcomes associated with the use of different aerosol generators with and without humidification. The study was a prospective randomized. 72 (36 females) asthmatic subjects receiving invasive mechanical ventilation using Bellavista 1000e ventilator (Imtmedical, Buchs, Switzerland) were enrolled per
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institutional review board (IRB), and randomly assigned to 6 treatment groups of 12 (6 females) subjects. Each subject received, as possible, all inhaled medication using
delivery.
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his or her randomly selected aerosol generator and humidity condition during aerosol
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As shown in Figure 1, all aerosol generators were placed after the humidification chamber (VH 2100 humidifier with humidifier chamber; Great Group Medical Co. (GGM), Changhua County, Taiwan) within the inspiratory limb of a 2 limb ventilator circuit (Int’air Medical, Bresse, France) consisted of a smooth 22mm internal diameter (ID) tubing of 160 cm length. A water trap was placed in the inspiratory limb; with no elbow connection placed between the circuit and the patient airway.
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ACCEPTED MANUSCRIPT A vibrating mesh nebulizer (Aerogen Solo; Aerogen Limited, Galway, Ireland); metered dose inhaler with spacer (AeroChamber Vent; Trudell Medical International, Canada); and an Oxycare jet nebulizer (Ceren Uretim A.S., Istanbol, Turkey) operated with air flow of 6 L/min where all placed in the inspiratory limb of
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the ventilator circuit proximal to the patient. All devices were operated with and without heated humidity.
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Clinical responses of patients based on different clinical parameters and response to different treatment groups were recorded daily. Measured parameters, that
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reflected patient response, were partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), Oxygen saturation % (O2 SAT%), pH, respiratory rate and heart rate. These parameters were measured every day from the initial ICU admit day to the last day in the ICU. Measured parameters that reflected endpoints were length
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of stay in the intensive care unit (ICU-days), mechanical ventilation days (MV-days) and mortality.
One-way ANOVA with the application of least significant difference (LSD)
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correction was used to determine any difference between the clinical parameters,
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reflecting patient response, results on the baseline and throughout the study period from the three aerosol generators at different humidity conditions. One-way ANOVA with the application of least significant difference (LSD) correction was also used to determine any difference between results of mortality, if present, ICU-days and MV-days from the three aerosol generators at different humidity conditions. Results
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ACCEPTED MANUSCRIPT 72 (36 females) ventilated patients were randomized into 6 treatment groups , mean (SD) age, weight and height are shown in Table 1, agreed to be included in the study using the delayed consent procedure and they all completed the study with no
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mortality. The subjects in the 6 groups were similar in the baseline of pO2, pCO2, O2
SAT%, pH, respiratory rate and heart rate as clinical parameters reflecting the severity of their disease. Medications used by patients in the 6 groups were comparable.
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Comparison of individual value of all the clinical parameters reflecting patient
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response (pO2, pCO2, O2 SAT%, pH, respiratory rate and heart rate) showed that they tend to approach a stable value relatively shortly after the study commenced. Neither device type nor humidification had significant impact on the profile of theses parameters.
Mean ICU days and days receiving mechanical ventilation (MV-days) are
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shown in Table 1 and Figures 2 and 3. Data are shown as 6 groups (12 results in each group). Each group had its own aerosol generator and humidity condition. Data are
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also shown as 3 aerosol generator groups (24 results in each group), regardless of the humidity condition. Data are also shown as 2 humidity conditions groups (36 results
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in each group), regardless of the aerosol generator used. The vibrating mesh nebulizer (VMN) Dry resulted in significantly shorter ICU-days compared to metered dose inhaler with spacer (MDI-AV) dry (p=0.034). VMN resulted in significantly shorter ICU-days compared to MDI-AV
(p=0.039) and relatively but not significantly shorter ICU-days compared to jet nebulizer (JN). MDI-AV showed the highest MV-days and ICU-days.
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ACCEPTED MANUSCRIPT Aerosol delivery with or without humidification did not have any significant effect on any of the parameters studied with trend to lower values associated with aerosol delivery with humid condition. Discussion
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Many previous in-vitro studies have reported great differences between
aerosol generators in mechanical ventilations.[2, 10, 14-17] Previous in-vitro data has also reported that more aerosols are delivered to the mechanically ventilated patient
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without humidification and due to this finding; many clinicians choose to turn off humidification during aerosol delivery.[4, 12, 13, 18, 19]
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No previous study had ever evaluated the effect of aerosol generator used or humidity condition setting on the clinical status of the ventilated patient and to our knowledge this is the first one.
In the study presented here there was no effect of humidification change in all
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the parameters studied. With 36 subjects in each arm, regardless of the aerosol generator used, the statistical analysis resulted in a very high p-value (0.642 and 0.754, respectively) for MV-days and ICU-days with a trend to decrease the MV-days
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and the ICU-days by delivering aerosol in humid condition, opposing the finding of
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the in-vitro studies that suggested better aerosol delivery by turning off the humidifier. [4, 12, 13, 18] The high p-values of comparison suggest the need of a very large sample size
to find significant effects of humidity change during aerosol delivery on the clinical status of the ventilated patients, that if actually present. In the dry arm of the study, with the insignificantly higher MV-days and ICU-days, humidifier was turned off during delivery and switched back on immediately after delivery., Some clinicians turn off humidifier during aerosol delivery and might forget
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ACCEPTED MANUSCRIPT to turn it back on. This would have a potentially detrimental effect on the lung and the patient.[20-25] In such a situation the increase in the MV-days and the ICU-days would be expected to be much more than our finding here. Some researchers have recommended delivering a somewhat higher dose to
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overcome the humidity effect on aerosol delivery.[26-29] Dhand and Guntur
recommended the use of a dry circuit for delivery of very expensive agents or agents for which lung deposition is critical e.g. antibiotics and prostaglandins.[30] Also,
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when a dry ventilation circuit is used, aerosol delivery should be finished within a
short period of time, less than 10 to 15 min, to minimize the effects of dry gas on the
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airway mucosa.[20-25, 30] Also, it was found that switching off the humidifier does not result in a decrease in the circuit humidity if less than 20 minutes due to the patient’s exhalation into the circuit and the evaporation of the condensate in the ventilation circuit.[31]
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Our results did not support these in-vitro data suggesting better aerosol delivery in a dry circuit. Also, there is no clinical evidence to support the need for increasing the dose or turning off the humidifier with the above mentioned
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medications, since, most of the dose delivered to the ventilated patient would be on
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the plateau of the effect of inhaled drug.[32, 33] Also, more recent in-vitro evidence using an adult model with simulated exhaled gas has shown that the humidity in the exhaled air decreased the total inhalable dose that could reach the tracheostomized patient in a dry circuit.[11] All these studies could discourage the clinical practice of aerosol delivery in dry circuit and encourage the use of aerosol generators with the humidifier on. In our study, the effect of the aerosol generator on patient‘s clinical status with the 24 patients in each arm; MV-days were not affected by the aerosol generator type,
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ACCEPTED MANUSCRIPT with a high p-value of comparison which is obvious from Figure 2b.However, the VMN showed a tendency toward decreased ICU-days by ~0.75 days as seen from Figure 3b. This VMN tendency was not found significance compared to JN (p=0.268) but with MDI-AV there was a significant decrease in the ICU-days by ~1.42 days
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(p=0.039) when using VMN. Also, significantly higher ICU-days were found from
MDI-AV dry than VMN dry (p=0.034). The higher ICU-days by MDI-AV might be due to the greater total amount of aerosol delivered by the VMN to the patients that
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resulted in a possible faster cure, since the optimum clinical efficiency, increased
FEV1, of inhaled therapy depends on the amount of drug reaching the lungs.[34-36]
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This possible rational is supported by the shorter ICU-days of the VMN compared the JN, even though the difference was not significant (p=0.268) since JN was proven to deliver much smaller total inhalable dose than the VMN.[2, 3, 10, 37]The difference in the ICU-days might also be due to the presence of propellants in the aerosol from
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the MDI-AV, which might cause bronchoconstriction to such a critically ill patient recruited in this study.[38-45]
This finding could discourage the use of MDI-AV in ventilation circuit, however, this
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lower effect of MDI with adaptors in mechanically ventilated patient was also found
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to be due to technical problems associated with health care providers delivery with dosing the MDI properly.[2] Inconsistency in the administration technique and MDI adaptor used may lead to marked differences in the aerosol delivered to lower respiratory tract.[46, 47] Thus, optimal aerosol delivery by MDI requires careful consideration of many factors that affect aerosol delivery to the lungs of mechanically ventilated patients. When used with optimal technique, MDIs and nebulizers were found to be equally effective in the management of mechanically ventilated patients with different obstructive lung disease. [48] For routine bronchodilator therapy, MDIs
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ACCEPTED MANUSCRIPT may be preferred because of their convenience, more consistent dosing, and, similar to VMN, potential reduced risk of bacterial contamination when compared to JN. [49, 50] In one survey of neonatal ICUs, MDI use was reported to have increased significantly over a period of approximately 20 years. [51] The majority of adult ICUs
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in the United States (U.S.) also prefer MDIs for routine bronchodilator therapy. [52, 53] However, in the U.S. MDIs are more expensive and place a cost burden on
hospitals and inpatient pharmacies. Loboerc et. al, used an automatic formulary
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substitution of ipratropium–albuterol nebulized solution with VMN for conversion
from MDI and projected an annualized savings of $257,936 in associated cost.[54] In
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addition, nebulizers continue to be employed for a proportion of bronchodilator treatments, and for delivery of antibiotics, surfactant, prostaglandins, and other formulations that are not available in MDIs. [29, 55] Conclusion
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No significant effect on patients’ clinical status was found in this study from changing humidity during aerosol delivery to ventilated patient. Hence we discourage the practice of turning off the humidifier during aerosol delivery, which might be
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forgotten in the off position.
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The use of VMN to deliver aerosol to ventilated patient resulted in a trend toward decreased ICU-days compared to JN and MDI-AV. We recommend increasing the number of patients studied to confirm and
possibly extend these findings.
Figure Legend Figure 1
Schematic design of the inhalation device positions within the invasive ventilator circuit.
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ACCEPTED MANUSCRIPT Figure 2
a. Mean (SD) MV-days after receiving inhaled medication by 3 different aerosol generators at 2 different humidity conditions b. Mean (SD) MV-days after receiving inhaled medication by 3 different
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aerosol generators regardless of the humidity conditions c. Mean (SD) MV-days after receiving inhaled medication at 2 different humidity conditions regardless of aerosol generators used
a. Mean (SD) ICU-days after receiving inhaled medication by 3 different
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Figure 3
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aerosol generators at 2 different humidity conditions
b. Mean (SD) ICU-days after receiving inhaled medication by 3 different aerosol generators regardless of the humidity conditions c. Mean (SD) ICU-days after receiving inhaled medication at 2 different
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humidity conditions regardless of aerosol generators used
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ACCEPTED MANUSCRIPT Table 1.Mean (SD) MV-days and ICU-days after receiving the inhaled medication by JN, VMN or MDI-AV during mechanical ventilation with (Humidity) or without (Dry) heated humidification JN JN VMN VMN MDI-AV MDIDry
Humidity
61.2
Age
63.6 (8.0) (7.7)
77.6
76.5 (11.7)
81.2 (8.6)
(9.0) 5.4
MV6.0 (1.5)
(1.0) 8.3
ICU8.7 (2.5)
(1.9)
ICU-
(8.1)
5.6
6.2 (1.1)
5.7 (1.4)
9.7 (2.8)
8.7 (2.3)
(1.0) 7.9
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(2.0)
JN
VMN
MDI-AV
5.71 (1.27)
5.67 (0.96)
5.92 (1.25)
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days
(9.3)
7.6 (2.5)
days
170.5
176.2 (8.6)
5.8 (1.0)
days
(10.2)
175.5 174.4 (11.8)
(cm)
79.1
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171.9 (7.8)
(5.6)
80.9 (12.8)
(9.3)
173.2
Height
60.9
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(10.7)
(kg)
AV Dry
61.7 (8.6)
(7.0)
82.2
Weight
Humidity
60.2
62.5 (9.6) (years)
MV-
Dry
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Humidity
7.75 (2.23)
9.17 (2.57)
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8.50 (2.17)
days
Dry delivery
Humid delivery
5.97 (1.18)
5.56 (1.11)
8.64 (2.68)
8.31 (2.03)
MVdays
ICUdays
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