Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally 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.

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