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This study evaluates whether individualized dosing schedule of inhaled bronchodilator is more effective than fixed dosing in reducing airway resistance of intubated COPD patients.
*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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Individualized dosing | Experimental |
|
|
| Fixed dosing | Active Comparator |
|
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bronchodilators inhalation | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| ∆Raw (the Difference Between Measured and Target Airway Resistance) | The value can be expressed as relative deviation from target =(measured Raw - target Raw)/target Raw X100 | 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. |
| Rapidity of ∆Raw Change | The deviation of ∆Raw from the personal target, which was calculated as (measured Raw-target Raw)/target Raw multiplied by 100. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Ventilator-free Days From Day 1 to 28 | Ventilator-free days from day 1 to 28 after enrollment | From day 1 to day 28 after enrollment |
| The Participants of Breathing Without Assistance by Day 28 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Shin-hwar Wu | Changhua Christian Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Changhua Christian Hospital | Changhua | Taiwan | 50006 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 2154154 | Background | 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. doi: 10.1164/ajrccm/141.2.440. | |
| 1914568 | Background | Aerosol consensus statement. Consensus Conference on Aerosol Delivery. Chest. 1991 Oct;100(4):1106-9. No abstract available. |
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We have no plan to share IPD.
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| ID | Title | Description |
|---|---|---|
| FG000 | Individualized Dosing |
|
| FG001 | Fixed Dosing | Ventilator support
|
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Individualized Dosing |
|
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | ∆Raw (the Difference Between Measured and Target Airway Resistance) | The value can be expressed as relative deviation from target =(measured Raw - target Raw)/target Raw X100 | The deviation of Raw from the personal target, which was calculated as (measured Raw-target Raw)/target Raw. | Posted | Mean | Standard Deviation | percentage of relative Raw deviation | 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. |
|
From day 1 to day 28
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Individualized Dosing |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Shin-Hwar Wu | Division of Critical Care Medicine, Department of Medicine, Changhua Christian Hospital | 886-4-7238595 | 3971 | 126366@cch.org.tw |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 24, 2013 | Feb 6, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| ID | Term |
|---|---|
| D000068299 | Salmeterol Xinafoate |
| D000068298 | Fluticasone |
| D005280 | Fenoterol |
| ID | Term |
|---|---|
| D000420 | Albuterol |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 |
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|
The number of participants who breath without ventilator by day 28
| the 28th day after enrollment |
| Number of Episode of Nosocomial Pneumonia | 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. | the 28th day after enrollment |
| Number of Total Puff of Rescue Short-acting Bronchodilator | The number of total puff of rescue short-acting bronchodilator. | the 28th day after enrollment |
| Numbers of Episode of Drug-related Adverse Effect | 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. | From day 1 to day 28 after enrollment |
| Mortality Rate | The percentage of participants died at day 180. | the 180th day after enrollment |
| 8756811 | Background | 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. doi: 10.1164/ajrccm.154.2.8756811. |
| 7249508 | Background | 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. doi: 10.1038/clpt.1981.154. No abstract available. |
| 19014570 | Background | 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. |
| 29474893 | Derived | Wu SH, Shyu LJ, Li CH, Yu CH, Chen HC, Kor CT, Wang CH, Lin KH. Better airway resistance reduction profile in intubated COPD patients by personalized bronchodilator dosing: A pilot randomized control trial. Pulm Pharmacol Ther. 2018 Apr;49:134-139. doi: 10.1016/j.pupt.2018.02.004. Epub 2018 Feb 21. |
| BG001 | Fixed Dosing |
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| OG001 | Fixed Dosing |
|
|
|
| Primary | Rapidity of ∆Raw Change | The deviation of ∆Raw from the personal target, which was calculated as (measured Raw-target Raw)/target Raw multiplied by 100. | Posted | Mean | Standard Deviation | percentage of relative Raw deviation | 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. |
|
|
|
| Secondary | Ventilator-free Days From Day 1 to 28 | Ventilator-free days from day 1 to 28 after enrollment | Posted | Number | day | From day 1 to day 28 after enrollment |
|
|
|
| Secondary | The Participants of Breathing Without Assistance by Day 28 | The number of participants who breath without ventilator by day 28 | Posted | Number | the number of participants | the 28th day after enrollment |
|
|
|
| Secondary | Number of Episode of Nosocomial Pneumonia | 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. | Posted | Median | Standard Deviation | episodes of nosocomial pneumonia | the 28th day after enrollment |
|
|
|
| Secondary | Number of Total Puff of Rescue Short-acting Bronchodilator | The number of total puff of rescue short-acting bronchodilator. | Posted | Number | puffs | the 28th day after enrollment |
|
|
|
| Secondary | Numbers of Episode of Drug-related Adverse Effect | 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. | Posted | Median | Standard Deviation | episodes | From day 1 to day 28 after enrollment |
|
|
|
| Secondary | Mortality Rate | The percentage of participants died at day 180. | Posted | Number | percentage of participants | the 180th day after enrollment |
|
|
|
| 9 |
| 26 |
| 0 |
| 26 |
| 0 |
| 26 |
| EG001 | Fixed Dosing |
| 10 | 25 | 0 | 25 | 0 | 25 |
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| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Organic Chemicals |
| D000588 | Amines |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
| D000730 | Androstadienes |
| D000736 | Androstenes |
| D000731 | Androstanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D009921 | Metaproterenol |
| D002395 | Catecholamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |