Clinical trial NCT01933984
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: Bronchodilator agents, chronic obstructive pulmonary disease, endotracheal intubation, mechanical ventilator
Sponsor: Shin-hwar Wu
Start date: 2013-08-01; Completion date: 2019-01-31
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: * 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) arm 2: * 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
Interventions: intervention 1: Bronchodilators inhalation
Intervention descriptions: intervention 1: 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

Protocol documents:
Prot_SAP_000.pdf: 
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Study:  
Individualized Dosing Schedule of Inhaled Bronchodilator 
for Endotracheally Intubated COPD Patients: A Randomized 
Control Trial 
 
NCT01933984 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
              
 
 


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1. Methods 
1.1. 
Study design 
This was an open-label, randomized controlled study comparing a personalized versus fixed MDI 
dosing schedule for intubated COPD patients with acute respiratory failure. 
1.2. 
Patient enrollment 
We enrolled intubated COPD patients who were newly admitted to the intensive care unit of 
Changhua Christian Hospital (Changhua, Taiwan). A diagnosis of COPD was defined as audible 
expiratory wheezing or rhonchus or obstructive ventilatory impairment when assessed by 
spirometry, in addition to a history of smoking or exposure to other forms of toxic stimuli. All of the 
enrolled patients were endotracheally intubated and had been mechanically ventilated for less than 
72 h. The exclusion criteria were: (1) age less than 18 years, (2) confirmed history of asthma, (3) an 
Acute Physiology and Chronic Health Evaluation II score of more than 35, and (4) comorbid septic 
shock. The study was approved by the Institutional Review Board of Changhua Christian Hospital 
(approval No. 120703). Informed consent was obtained from the surrogates of all participants. All 
of the participants were randomly assigned to the personalized-dosing or fixed-dosing group 
according to a computer-generated allocation sequence in a block size of four patients. 
1.3. 
Raw determination 
The enrolled patients were ventilated with either an AVEA® (CareFusion, Yorba Linda, CA, USA), 
e500 (Newport Medical Instrument Inc. CA, USA), or Evita® 4 (Drager, Lubeck, Germany) 
ventilator. When evaluating Raw, the ventilator settings were transiently switched to volume control 


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mode with a fixed tidal volume (500 ml) and constant flow (with a rate of 60 L/min). Plateau 
pressure was measured using a manually controlled end-inspiratory pause lasting for 0.5–1.0 s by 
qualified respiratory therapists [11]. Consistent with several previous clinical studies [12, 13], our 
patients were not routinely sedated before Raw measurements. We made every effort to ensure that 
the patients were calm during the measurements, including additional sedation if necessary. Each 
measurement was repeated three times with an interval of at least 1 min, and the average value was 
calculated. Raw was calculated using the equation (peak inspiratory pressure − plateau 
pressure)/flow [14]. After each measurement, the ventilator was set to its usual settings. Thereafter, 
Raw was routinely determined every 8 h until the discontinuation of ventilation or the 28th day of the 
study. 
1.4. 
Technique of MDI administration through the ventilator circuit 
The technique of MDI administration was based on that reported by Dhand and Guntur [15]. 
Airway secretions were sucked out before drug administration. The heat moisture exchanger was 
removed, but the humidifier was not. After shaking and warming the MDI to hand temperature, the 
canister was connected to an AeroChamber® HC MV spacer (Trudell Medical International, 
London, Canada) and placed in the inspiratory limb of the ventilator circuit 15 cm away from the 
endotracheal tube. Actuation was synchronized with the initiation of inspiration. Each actuation was 
performed with an interval of at least 15 s. 
1.5. 
Personal target Raw determination 


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The target Raw of each patient was determined within 72 h after their admission to the intensive care 
unit. After confirming that no inhaled bronchodilator has been administered in the preceding 2 h 
(for fenoterol) or 12 h (for salmeterol/fluticasone), four puffs of fenoterol MDI (100 μg/puff, 
Berotec®; Boehringer Ingelheim, Ingelheim, Germany) were administered, followed by 8 puffs 
after 15 minutes, and then 16 puffs after another 15-minute interval. These intensive doses were 
intended to produce near maximum bronchodilation. Fifteen minutes after these 28 puffs of 
bronchodilators, we measured Raw. This Raw value was possibly the lowest achievable, and was 
assigned as the patient’s personal target Raw [16]. This personal target Raw served as the standard (or 
baseline) to judge responsiveness to subsequent bronchodilator doses. 
1.6. 
Bronchodilator delivery schedule 
All patients in both the personalized-dosing and fixed-dosing groups routinely received four puffs 
of 25 μg salmeterol/250 μg fluticasone (Seretide® Evohaler® 250; GlaxoSmithKline Inc. Evreux, 
France) every 12 h until the discontinuation of ventilation. Each patient also routinely received one 
vial of ipratropium bromide 0.5 mg and salbutamol sulfate 2.5 mg (Combivent®; Boehringer 
Ingelheim, Ingelheim, Germany) every 6 h, and an injection of  intravenous methylprednisolone 
40 mg every 8 h for the first 3 days. The use of short-acting bronchodilators on an as-needed basis 
was not restricted. Based on the Raw data determined every 8 h, the personalized-dosing group 
received an additional four puffs of 25 μg salmeterol/250 μg fluticasone plus four puffs of fenoterol 
(0.1 mg/puff) if the Raw value was higher than the personal target Raw (once it coincided with the 
regular dosing period of salmeterol/fluticasone, only fenoterol was added). No extra doses were 


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given to the fixed-dosing (control) group of patients regardless of their Raw value. The 
bronchodilator delivery schedules are summarized in Fig. 1. 
1.7. 
Outcome measurements 
The primary outcome was the deviation of Raw from the personal target, which was calculated as 
(measured Raw − target Raw)/target Raw. The evolution of this deviation over the treatment course 
was also calculated. The secondary outcomes included the number of ventilator-free days from day 
1 to day 28, the percentage of breathing without assistance by day 28, the number of episodes of 
nosocomial pneumonia, the total number of puffs of rescue short-acting bronchodilators, the 
number of drug-related adverse effects (arrhythmia or hypokalemia with a Naranjo score [17] of 
more than 4), and the mortality rate at day 180. 
1.8. 
Statistical analysis 
Data were expressed as number (percentage), mean ± standard deviation or median, inter-quartile 
range (IQR). Each variable was tested for normal distribution using the Kolmogorov-Smirnov test. 
To compare two continuous variables, we used the Student’s t-test or the Wilcoxon rank sum test 
depending on their distribution. For categorical variables, we used the chi-square test or Fisher’s 
exact test as appropriate. A general linear mixed regression model was used to analyze the relative 
deviation of Raw over time. This model included fixed effects for the personalized-dosing group, 
time, and an interaction term of group-by-time, as well as a random intercept and slope. Different 
durations of stay were considered as the random slope. A P value <0.05 was considered to be 
statistically significant. All statistical analyses were performed using SPSS software (IBM SPSS 


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Statistics, version 20, IBM Corporation, Chicago, IL, USA). The power of calculating the difference 
in mean Raw deviation was 100% with a sample size of 51 and an alpha value of 0.05.