Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally Intubated COPD Patients

• Sponsor: Shin-hwar Wu (Other)
• Overall Status: Completed
• CT.gov ID: NCT01933984
• Collaborator: (none)
• Enrollment: 51
• Location: 1
• Arms: 2
• Duration (Months): 66
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This study evaluates whether individualized dosing schedule of inhaled bronchodilator is more effective than fixed dosing in reducing airway resistance of intubated COPD patients.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: Bronchodilators inhalation	N/A

Detailed Description

*Study Design

• This is an open-label, randomized controlled study comparing individualized versus fixed bronchodilator dosing schedule for patients with COPD with acute respiratory failure.

*Patients Enrollment

• We will collect 100 patients just admitted to the intensive care unit of Changhua Christian Hospital (Changhua, Taiwan) due to COPD with acute respiratory failure.All participants will be randomly assigned to either group according to a computer-generated allocation sequence in block size of 4 patients.

*Airway Resistance (Raw) Determination

• Enrolled patients will be ventilated by either AVEA (CareFusion, Yorba Linda, CA, USA),e500 (Newport Medical Instrument Inc. CA, USA) or Eivta 4 (Drager) ventilator. When evaluating Raw, the ventilator settings will be transiently switched to volume control mode with fixed tidal volume (500 ml) and constant flow (with a rate of 60 L/min). Plateau pressure is measured by manually controlled end-inspiratory pause12. Every effort will be exercised to avoid excessive airway secretion or patient agitation during measurement. Each measurement will be repeated three times with an interval of at lease 1 minute and calculate their average. Raw will be calculated by an equation of (peak inspiratory pressure - plateau pressure)/flow. After each measurement, the ventilator will soon be reverted to its usual settings. Raw will be routinely determined every 8 hours for 28 days if the ventilator is not discontinued.

*Technique of Metered Dose Inhaler (MDI) administration through endotracheal tube

• The technique basically follows the recommendation of Dhand and Guntur. Airway secretions should be sucked out before drug administration. Heat moisture exchanger, but not humidifier, is removed. After shaking and warming MDI to hand temperature, the canister is connected to an AeroChamber HC MV spacer (Trudell Medical International, London, Canada) placed in the inspiratory limb of ventilator circuit 15 cm away from the endotracheal tube. Actuation is synchronized with the initiation of inspiration. Each actuation is at least 15 second apart.

*Personal Target Raw Determination

• The target Raw of each patient should be determined within 72 hours after their admission to intensive care unit. After confirming no inhaled bronchodilator given in preceding 2 hours (for fenoterol) or 12 hours (for salmeterol/fluticasone), we will deliver 3 consecutive doses of 4 puffs, 8 puffs and 16 puffs of fenoterol MDI (100 mcg/puff, Berotec;Boehringer Ingelheim, Ingelheim, Germany) inhalation with each dose 15 minutes apart. The Raw measured 15 minutes later is assigned as this patient's personal target Raw.

*Bronchodilator Delivery Schedule

• Each patient will routinely receive 4 puffs of 25 mcg salmeterol /250 mcg fluticasone (Seretide Evohaler 250; GlaxoSmithKline Inc. Evreux, France) every 12 hours until the discontinuation of ventilator. Each patient will also routinely receive 1 vial of Combivent (ipatropium bromide 0.5 mg and salbutamol sulfate 2.5 mg) every 6 hours and be injected with intravenous methylprednisolone 40mg every 8 hours in the initial 3 days.The use of short acting bronchodilator in an as-needed basis is not restricted. According to the Raw data determined every 8 hours, individualized dosing group will receive an additional 4 puffs of 25 mcg salmeterol /250 mcg fluticasone plus 4 puffs of fenoterol if the value is higher than personal target Raw (Once it coincides with regular dosing period of salmeterol/fluticasone, only fenoterol will be added). No such extra dose will be given to fixed dosing (control) group regardless of Raw value.

*Statistical Analysis

• Student's t test will be used to compare ∆Raw of both groups. For the comparisons of other continuous variables without distribution normality, Wilcoxon rank sum test will be used. When comparing two categorical variables, Chi-square or Fisher's exact test will be used when appropriate. A P value of less than 0.05 is considered significant.

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally Intubated Chronic Obstructive Pulmonary Disease Patients
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Jan 31, 2019
• Actual Study Completion Date: Jan 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Individualized dosing Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days Additional broncho-dilators inhalation: Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met (until ventilator discontinuation or the 28th day if ventilator-dependent)	Drug: Bronchodilators inhalation; Salmeterol/fluticasone (Seretide Evohaler) 4 puffs plus fenoterol (Berotec)(0.1mg/puff) 4 puffs inhalation when target airway resistance, measured every 8 hours, not met; Other Names: Salmeterol/fluticasone (Seretide Evohaler) fenoterol (Berotec)(0.1mg/puff)
Active Comparator: Fixed dosing Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met	Drug: Bronchodilators inhalation; Salmeterol/fluticasone (Seretide Evohaler) 4 puffs plus fenoterol (Berotec)(0.1mg/puff) 4 puffs inhalation when target airway resistance, measured every 8 hours, not met; Other Names: Salmeterol/fluticasone (Seretide Evohaler) fenoterol (Berotec)(0.1mg/puff)

Outcome Measures

Primary Outcome Measures

1. ∆Raw (the Difference Between Measured and Target Airway Resistance) [Airway resistance will be recorded everyday. If a patient's ventilator was liberated less than 28 days, the day of liberation was the reported time frame. If the day of ventilator liberation was over 28 days, the 28th day was the reported time frame.]

   The value can be expressed as relative deviation from target =(measured Raw - target Raw)/target Raw X100

2. Rapidity of ∆Raw Change [Airway resistance will be recorded everyday. If a patient's ventilator was liberated less than 28 days, the day of liberation was the reported time frame. If the day of ventilator liberation was over 28 days, the 28th day was the reported time frame.]

   The deviation of ∆Raw from the personal target, which was calculated as (measured Raw-target Raw)/target Raw multiplied by 100.

Secondary Outcome Measures

1. Ventilator-free Days From Day 1 to 28 [From day 1 to day 28 after enrollment]

   Ventilator-free days from day 1 to 28 after enrollment

2. The Participants of Breathing Without Assistance by Day 28 [the 28th day after enrollment]

   The number of participants who breath without ventilator by day 28

3. Number of Episode of Nosocomial Pneumonia [the 28th day after enrollment]

   The number of episodes of nosocomial pneumonia happened by day 28. And nosocomial pneumonia is a lower respiratory infection that was not incubating at the time of hospital admission and that presents clinically 2 or more days after hospitalization.

4. Number of Total Puff of Rescue Short-acting Bronchodilator [the 28th day after enrollment]

   The number of total puff of rescue short-acting bronchodilator.

5. Numbers of Episode of Drug-related Adverse Effect [From day 1 to day 28 after enrollment]

   The numbers of episode of drug-related adverse effect. Naranjo score should be over 4 to be considered drug-related adverse effect. Naranjo score range form 0 to 9, and the higher scores means a higher relationship with drug-related adverse effect.

6. Mortality Rate [the 180th day after enrollment]

   The percentage of participants died at day 180.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• chronic obstructive pulmonary disease

• acute respiratory failure under ventilator support for less than 72 hours

• endotracheal tube inserted

Exclusion Criteria:

• confirmed asthma

• Acute Physiology and Chronic Health Evaluation II score over 35

• a co-morbidity of septic shock

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Changhua Christian Hospital	Changhua	Taiwan	China	50006

Sponsors and Collaborators

• Shin-hwar Wu

Investigators

• Principal Investigator: Shin-hwar Wu, Changhua Christian Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 24, 2013

More Information

Publications

• Aerosol consensus statement. Consensus Conference on Aerosol Delivery. Chest. 1991 Oct;100(4):1106-9. Review.
• Dhand R, Duarte AG, Jubran A, Jenne JW, Fink JB, Fahey PJ, Tobin MJ. Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients. Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 1):388-93.
• Fuller HD, Dolovich MB, Posmituck G, Pack WW, Newhouse MT. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Comparison of dose to the lungs. Am Rev Respir Dis. 1990 Feb;141(2):440-4.
• Malliotakis P, Linardakis M, Gavriilidis G, Georgopoulos D. Duration of salmeterol-induced bronchodilation in mechanically ventilated chronic obstructive pulmonary disease patients: a prospective clinical study. Crit Care. 2008;12(6):R140. doi: 10.1186/cc7117. Epub 2008 Nov 14.
• Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981 Aug;30(2):239-45.

• Responsible Party: Shin-hwar Wu, Attending physician, Changhua Christian Hospital
• ClinicalTrials.gov Identifier: NCT01933984
• Other Study ID Numbers: 102-CCH-IRP-017
• First Posted: Sep 4, 2013
• Last Update Posted: Jul 21, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Shin-hwar Wu, Attending physician, Changhua Christian Hospital: Bronchodilator agents,; chronic obstructive pulmonary disease,; endotracheal intubation,; mechanical ventilator
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Fluticasone; Fenoterol; Salmeterol Xinafoate; Bronchodilator Agents

Study Results

Participant Flow

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days Additional Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Period Title: Overall Study
STARTED	26	25
COMPLETED	26	25
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Individualized Dosing	Fixed Dosing	Total
Arm/Group Description	Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days Additional broncho-dilators inhalation: Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met (until ventilator discontinuation or the 28th day if ventilator-dependent)	Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met	Total of all reporting groups
Overall Participants	26	25	51
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.6 (13.3)	77.9 (8.7)	75.7 (11.3)
Sex: Female, Male (Count of Participants)
Female	5 19.2%	2 8%	7 13.7%
Male	21 80.8%	23 92%	44 86.3%
Race/Ethnicity, Customized (participants) [Number]
Asian	26 100%	25 100%	51 100%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.6 (11.6)	23.4 (4.9)	24.5 (8.9)

Outcome Measures

1. Primary Outcome

Title	∆Raw (the Difference Between Measured and Target Airway Resistance)
Description	The value can be expressed as relative deviation from target =(measured Raw - target Raw)/target Raw X100
Time Frame	Airway resistance will be recorded everyday. If a patient's ventilator was liberated less than 28 days, the day of liberation was the reported time frame. If the day of ventilator liberation was over 28 days, the 28th day was the reported time frame.

Outcome Measure Data

Analysis Population Description

The deviation of Raw from the personal target, which was calculated as (measured Raw-target Raw)/target Raw.

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days Additional broncho-dilators inhalation: Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met (until ventilator discontinuation or the 28th day if ventilator-dependent) salmeterol/fluticasone: Each puff contains 25 mcg salmeterol /250 mcg fluticasone ipatropium/salbutamol: Each vial contains ipatropium bromide 0.5 mg and salbutamol sulfate 2.5 mg Methylprednisolone Additional broncho-dilators inhalation: Salmeterol/fluticasone (Seretide Evohaler) 4 puffs plus fenoterol (Berotec)(0	Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met salmeterol/fluticasone: Each puff contains 25 mcg salmeterol /250 mcg fluticasone ipatropium/salbutamol: Each vial contains ipatropium bromide 0.5 mg and salbutamol sulfate 2.5 mg Methylprednisolone Determining personal target airway resistance: Three consecutive doses of 4, 8 and 16 puffs of fenoterol MDI (100 mcg/puff, Berotec;Boehringer Ingelheim, Ingelheim, Germany) inhalation with each dose 15 minutes apart. The airway resistance measured 15 minutes later is assigned as th
Measure Participants	26	25
Mean (Standard Deviation) [percentage of relative Raw deviation]	9 (10)	44 (11)

2. Primary Outcome

Title	Rapidity of ∆Raw Change
Description	The deviation of ∆Raw from the personal target, which was calculated as (measured Raw-target Raw)/target Raw multiplied by 100.
Time Frame	Airway resistance will be recorded everyday. If a patient's ventilator was liberated less than 28 days, the day of liberation was the reported time frame. If the day of ventilator liberation was over 28 days, the 28th day was the reported time frame.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days Additional broncho-dilators inhalation: Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met (until ventilator discontinuation or the 28th day if ventilator-dependent)	Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Measure Participants	26	25
Mean (Standard Deviation) [percentage of relative Raw deviation]	-3 (9.7)	0.4 (13.9)

3. Secondary Outcome

Title	Ventilator-free Days From Day 1 to 28
Description	Ventilator-free days from day 1 to 28 after enrollment
Time Frame	From day 1 to day 28 after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days Additional Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Measure Participants	26	25
Number [day]	19	22

4. Secondary Outcome

Title	The Participants of Breathing Without Assistance by Day 28
Description	The number of participants who breath without ventilator by day 28
Time Frame	the 28th day after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days Additional Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Measure Participants	26	25
Number [the number of participants]	19 73.1%	22 88%

5. Secondary Outcome

Title	Number of Episode of Nosocomial Pneumonia
Description	The number of episodes of nosocomial pneumonia happened by day 28. And nosocomial pneumonia is a lower respiratory infection that was not incubating at the time of hospital admission and that presents clinically 2 or more days after hospitalization.
Time Frame	the 28th day after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days Additional Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Measure Participants	26	25
Median (Standard Deviation) [episodes of nosocomial pneumonia]	0 (0)	0 (0)

6. Secondary Outcome

Title	Number of Total Puff of Rescue Short-acting Bronchodilator
Description	The number of total puff of rescue short-acting bronchodilator.
Time Frame	the 28th day after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days Additional Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Measure Participants	26	25
Number [puffs]	0	0

7. Secondary Outcome

Title	Numbers of Episode of Drug-related Adverse Effect
Description	The numbers of episode of drug-related adverse effect. Naranjo score should be over 4 to be considered drug-related adverse effect. Naranjo score range form 0 to 9, and the higher scores means a higher relationship with drug-related adverse effect.
Time Frame	From day 1 to day 28 after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days Additional Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Measure Participants	26	25
Median (Standard Deviation) [episodes]	0 (0)	0 (0)

8. Secondary Outcome

Title	Mortality Rate
Description	The percentage of participants died at day 180.
Time Frame	the 180th day after enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Individualized Dosing	Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days Additional Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met	Ventilator support Determining personal target airway resistance Salmeterol/fluticasone 4 puffs inhalation q12h until ventilator discontinuation or the 28th day if ventilator-dependent Ipatropium/salbutamol 1 vial inhalation q6h for the first 3 days Methylprednisolone 40 mg intravenous injection q8h for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met
Measure Participants	26	25
Number [percentage of participants]	35 134.6%	40 160%

Adverse Events

Time Frame	From day 1 to day 28
Adverse Event Reporting Description	The definition of adverse event and/or serious adverse event, used to collect adverse event information, are same with the clinicaltrials.gov definitions. However, only events with Naranjo score over 4 were be considered as drug-related. No treatment-related adverse events could be found in this study. So, no additional information could be offered.
Arm/Group Title	Individualized Dosing		Fixed Dosing
Arm/Group Description	Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days Additional broncho-dilators inhalation: Salmeterol/fluticasone (Seretide) 4 puffs plus fenoterol (Berotec) 4 puffs inhalation if personal target airway resistance (measured every 8 hours) not met (until ventilator discontinuation or the 28th day if ventilator-dependent) salmeterol/fluticasone: Each puff contains 25 mcg salmeterol /250 mcg fluticasone ipatropium/salbutamol: Each vial contains ipatropium bromide 0.5 mg and salbutamol sulfate 2.5 mg Methylprednisolone Additional broncho-dilators inhalation: Salmeterol/fluticasone (Seretide Evohaler) 4 puffs plus fenoterol (Berotec)(0		Ventilator support Determining personal target airway resistance Bronchodilator:Salmeterol/fluticasone 4 puffs inhalation every 12 hours until ventilator discontinuation or the 28th day if ventilator-dependent Bronchodilator:Ipatropium/salbutamol 1 vial inhalation every 6 hours for the first 3 days Steroid:Methylprednisolone 40 mg intravenous injection every 8 hours for the first 3 days No additional bronchodilator given if personal target airway resistance (measured every 8 hours) not met salmeterol/fluticasone: Each puff contains 25 mcg salmeterol /250 mcg fluticasone ipatropium/salbutamol: Each vial contains ipatropium bromide 0.5 mg and salbutamol sulfate 2.5 mg Methylprednisolone Determining personal target airway resistance: Three consecutive doses of 4, 8 and 16 puffs of fenoterol MDI (100 mcg/puff, Berotec;Boehringer Ingelheim, Ingelheim, Germany) inhalation with each dose 15 minutes apart. The airway resistance measured 15 minutes later is assigned as th
All Cause Mortality
	Individualized Dosing		Fixed Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)		10/25 (40%)
Serious Adverse Events
	Individualized Dosing		Fixed Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Individualized Dosing		Fixed Dosing
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/25 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.