Clinical trial NCT01933984: Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally Intubated COPD Patients
Official title: Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally Intubated Chronic Obstructive Pulmonary Disease Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: Bronchodilator agents,
chronic obstructive pulmonary disease,
endotracheal intubation,
mechanical ventilator
Lead sponsor: Changhua Christian Hospital
Sponsor class: OTHER
First posted: 2013-09-04
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: ∆Raw (the Difference Between Measured and Target Airway Resistance)
timeFrame: 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: Rapidity of ∆Raw Change
timeFrame: 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 outcomes:
measure: Ventilator-free Days From Day 1 to 28
timeFrame: From day 1 to day 28 after enrollment
measure: The Participants of Breathing Without Assistance by Day 28
timeFrame: the 28th day after enrollment
measure: Number of Episode of Nosocomial Pneumonia
timeFrame: the 28th day after enrollment
measure: Number of Total Puff of Rescue Short-acting Bronchodilator
timeFrame: the 28th day after enrollment
measure: Numbers of Episode of Drug-related Adverse Effect
timeFrame: From day 1 to day 28 after enrollment
measure: Mortality Rate
timeFrame: the 180th day after enrollment
Other outcomes:
Locations:
city: Changhua
country: China
facility: Changhua Christian Hospital
state: Taiwan
Study officials:
affiliation: Changhua Christian Hospital
name: Shin-hwar Wu
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Aerosol consensus statement. Consensus Conference on Aerosol Delivery. Chest. 1991 Oct;100(4):1106-9. No abstract available.
citation: 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.
citation: 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.
citation: 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.
citation: 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.