Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally Intubated COPD Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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*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.

Official Title
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Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally Intubated Chronic Obstructive Pulmonary Disease Patients

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Bronchodilators inhalation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individualized dosing<br>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<br>* 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<br>* Other names: fenoterol (Berotec)(0.1mg/puff);|
| Active Comparator: Fixed dosing<br>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<br>* 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<br>* Other names: fenoterol (Berotec)(0.1mg/puff);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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. | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bronchodilator agents,, chronic obstructive pulmonary disease,, endotracheal intubation,, mechanical ventilator