Individualized Dosing Schedule of Inhaled Bronchodilator for Endotracheally Intubated COPD Patients

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

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 Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Bronchodilators inhalation

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.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Taiwan
    • Changhua, Taiwan, China, 50006
      • Changhua Christian Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Individualized dosing; 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; 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; Other Names: Salmeterol/fluticasone (Seretide Evohaler); fenoterol (Berotec)(0.1mg/puff)
ACTIVE_COMPARATOR: Fixed dosing; 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; 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; Other Names: Salmeterol/fluticasone (Seretide Evohaler); fenoterol (Berotec)(0.1mg/puff)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Shin-hwar Wu
• Investigators: Principal Investigator: Shin-hwar Wu, Changhua Christian Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• Aerosol consensus statement. Consensus Conference on Aerosol Delivery. Chest. 1991 Oct;100(4):1106-9. No abstract available.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (ACTUAL): January 31, 2019
• Study Completion (ACTUAL): January 31, 2019

Study Registration Dates

• First Submitted: August 29, 2013
• First Submitted That Met QC Criteria: August 29, 2013
• First Posted (ESTIMATE): September 4, 2013

Study Record Updates

• Last Update Posted (ACTUAL): July 21, 2020
• Last Update Submitted That Met QC Criteria: July 8, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: mechanical ventilator; chronic obstructive pulmonary disease,; Bronchodilator agents,; endotracheal intubation,
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Adrenergic Agonists; Dermatologic Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Anti-Allergic Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Sympathomimetics; Fluticasone; Salmeterol Xinafoate; Bronchodilator Agents; Fenoterol
• Other Study ID Numbers: 102-CCH-IRP-017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We have no plan to share IPD.