## Protocol Section
### Identification Module
**NCT ID:** NCT01151579

**Brief Title:** Effect of Nebulized Bronchodilators on Heart Rate

**Official Title:** Prospective Trial of Effect of Nebulized Bronchodilators on Heart Rate and Arrhythmias in Critically Ill Adult Patients

#### Organization Study ID Info
**ID:** ME 07-0011
#### Organization
**Class:** INDUSTRY
**Full Name:** Ascension Health
### Status Module
#### Completion Date
**Date:** 2009-11

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2015-10-23

**Type:** ESTIMATED

**Last Update Submit Date:** 2015-09-23

**Overall Status:** COMPLETED

#### Primary Completion Date
**Date:** 2009-11

**Type:** ACTUAL

#### Results First Post Date
**Date:** 2015-10-23

**Type:** ESTIMATED

**Results First Submit Date:** 2015-03-12

**Results First Submit QC Date:** 2015-09-23

#### Start Date
**Date:** 2008-12

**Status Verified Date:** 2015-09

#### Study First Post Date
**Date:** 2010-06-28
**Type:** ESTIMATED
**Study First Submit Date:** 2010-06-24
**Study First Submit QC Date:** 2010-06-25
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Ascension Health

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** Fahim Khorfan, MD

#### Responsible Party

**Investigator Affiliation:** Ascension Health

**Investigator Full Name:** Fahim Khorfan, MD

**Investigator Title:** ICU Pulmonologist

**Type:** SPONSOR_INVESTIGATOR

### Oversight Module

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** The purpose of the study is to determine adverse events rates of nebulized albuterol versus levalbuterol among adult critically ill patients and determine if a differential exists in adverse events between the two drugs.

**Detailed Description:** A randomized, single-blind, cross-over, prospective study was conducted in seventy critically ill adult patients with acute air flow obstruction. Patients were randomized to nebulized albuterol alternating with levalbuterol every 4 to 6 hours. Group A received albuterol 2.5 mg alternating with levalbuterol 0.63 mg. Group B received albuterol 2.5 mg alternating with levalbuterol 1.25 mg. All patients received nebulized ipratropium bromide 500 micrograms with each treatment. Heart rate and cardiac rhythm were continuously recorded before and 15 minutes after finishing each treatment. Any new rhythm abnormalities between treatments were also recorded.

### Conditions Module

**Conditions:**

- COPD

- Sepsis

- Shock

**Keywords:**

- Tachycardia

- tachyarrhythmias

- bronchodilator therapy

- Critically ill patients

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

##### Masking Info

**Masking:** SINGLE

**Who Masked:**

- PARTICIPANT

**Primary Purpose:** SUPPORTIVE_CARE

#### Enrollment Info

**Count:** 89

**Type:** ACTUAL

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients received an initial dose of levalbuterol 0.63 mg alternating with albuterol 2.5 mg.

**Intervention Names:**

- Drug: Levalbuterol

- Drug: Albuterol

**Label:** Levalbuterol 0.63

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** Patients received an initial dose of levalbuterol 1.25 mg alternating with albuterol 2.5 mg.

**Intervention Names:**

- Drug: Levalbuterol

- Drug: Albuterol

**Label:** Levalbuterol 1.25

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Levalbuterol 0.63

- Levalbuterol 1.25

**Description:** inhaled Levalbuterol 0.625 mg inhaled Levalbuterol 2.5 mg

**Name:** Levalbuterol

**Other Names:**

- Xopenex

- ipratropium

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Levalbuterol 0.63

- Levalbuterol 1.25

**Description:** Nebulized albuterol 2.5mg

**Name:** Albuterol

**Other Names:**

- Salbutamol

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Average difference in Heart rate between pre and post breathing treatments

**Measure:** Heart Rate in Beats Per Minute

**Time Frame:** Five days

#### Secondary Outcomes

**Description:** Any new arrhythmia documented in the medical record that occurred between breathing treatments.

**Measure:** Arrhythmias

**Time Frame:** 15 minutes after each treatment for average of 3 to 5 days

**Description:** Documented new arrhythmia occurring during study.

**Measure:** Total Number of Participants With Arrhythmias

**Time Frame:** Five days

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Adults who required inhaled bronchodilator therapy in the form of short acting beta adrenergic receptor agonist and short acting anti-cholinergic treatment every 4-6 hours for respiratory functions

Exclusion Criteria:

* Known allergy or sensitivity to study medications
* Baseline heart rate was greater than 110 beats per minute

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Grand Blanc

**Country:** United States

**Facility:** Genesys Regional Medical Center

**State:** Michigan

**Zip:** 48439

#### Overall Officials

**Official 1:**

**Affiliation:** Ascension Health

**Name:** Fahim Khorfan, MD

**Role:** PRINCIPAL_INVESTIGATOR

**Official 2:**

**Affiliation:** Ascension Health

**Name:** Kimberly R Barber, PhD

**Role:** STUDY_DIRECTOR

### References Module

#### References

**Citation:** Khorfan FM, Smith P, Watt S, Barber KR. Effects of nebulized bronchodilator therapy on heart rate and arrhythmias in critically ill adult patients. Chest. 2011 Dec;140(6):1466-1472. doi: 10.1378/chest.11-0525. Epub 2011 Sep 29.

**PMID:** 21960699

## Derived Section

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: BC01

- Name: Infections

### Condition Browse Module - Browse Leaves

- ID: M15577

- Name: Shock

- Relevance: LOW

- As Found: Unknown

- ID: M4453

- Name: Arrhythmias, Cardiac

- Relevance: LOW

- As Found: Unknown

- ID: M19010

- Name: Critical Illness

- Relevance: LOW

- As Found: Unknown

- ID: M20864

- Name: Sepsis

- Relevance: LOW

- As Found: Unknown

- ID: M16869

- Name: Toxemia

- Relevance: LOW

- As Found: Unknown

- ID: M16384

- Name: Tachycardia

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Ancestors

- ID: D000001993

- Term: Bronchodilator Agents

- ID: D000001337

- Term: Autonomic Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000018927

- Term: Anti-Asthmatic Agents

- ID: D000019141

- Term: Respiratory System Agents

- ID: D000015149

- Term: Tocolytic Agents

- ID: D000012102

- Term: Reproductive Control Agents

- ID: D000058666

- Term: Adrenergic beta-2 Receptor Agonists

- ID: D000000318

- Term: Adrenergic beta-Agonists

- ID: D000000322

- Term: Adrenergic Agonists

- ID: D000018663

- Term: Adrenergic Agents

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000018680

- Term: Cholinergic Antagonists

- ID: D000018678

- Term: Cholinergic Agents

### Intervention Browse Module - Browse Branches

- Abbrev: Repr

- Name: Reproductive Control Agents

- Abbrev: Resp

- Name: Respiratory System Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M3767

- Name: Albuterol

- Relevance: HIGH

- As Found: Diameter

- ID: M12193

- Name: Ipratropium

- Relevance: HIGH

- As Found: Both eyes

- ID: M5269

- Name: Bronchodilator Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20963

- Name: Anti-Asthmatic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M21137

- Name: Respiratory System Agents

- Relevance: LOW

- As Found: Unknown

- ID: M17869

- Name: Tocolytic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20746

- Name: Adrenergic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M3670

- Name: Adrenergic beta-Agonists

- Relevance: LOW

- As Found: Unknown

- ID: M3673

- Name: Adrenergic Agonists

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

- ID: M20760

- Name: Cholinergic Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M20758

- Name: Cholinergic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000000420

- Term: Albuterol

- ID: D000009241

- Term: Ipratropium

### Misc Info Module

- Version Holder: 2024-05-24

## Results Section

### Adverse Events Module

**Description:** Cardiac arrhythmia

#### Event Groups

**Group ID:** EG000

**Title:** Nebulized Albuterol 2.5mg

**Description:** Patients were randomized to receive an initial dose of albuterol 2.5 mg alternating with levalbuterol 0.63 mg.

**ID:** EG000

**Other Num at Risk:** 58

**Serious Number Affected:** 2

**Serious Number At Risk:** 58

**Title:** Nebulized Albuterol 2.5mg

**Group ID:** EG001

**Title:** Levalbuterol 1.25

**Description:** Patients received an initial dose of levalbuterol 1.25 mg alternating with albuterol 2.5 mg.

**ID:** EG001

**Other Num at Risk:** 31

**Serious Number Affected:** 3

**Serious Number At Risk:** 31

**Title:** Levalbuterol 1.25

**Frequency Threshold:** 0

#### Serious Events

**Term:** Ventricular tachycardia

**Assessment Type:** SYSTEMATIC_ASSESSMENT

**Notes:** Cardiac arrhythmia as documented by healthcare provider.

**Organ System:** Cardiac disorders

##### Stats

**Group ID:** EG000

**Num Affected:** 2

**Num At Risk:** 58

**Num Events:** 2

**Group ID:** EG001

**Num Affected:** 3

**Num At Risk:** 31

**Num Events:** 3

**Time Frame:** Within 5 days of treatment initiation and within 15 minutes of each individual treatment.

## Results Section - Baseline Characteristics Module

### Denomination Counts

**Group ID:** BG000

**Value:** 58

**Group ID:** BG001

**Value:** 31

**Group ID:** BG002

**Value:** 89

**Units:** Participants

### Group

**ID:** BG000

**Title:** Nebulized Albuterol 2.5mg

**Description:** Patients were randomized to receive an initial dose of albuterol 2.5 mg alternating with levalbuterol 0.63 mg.

### Group

**ID:** BG001

**Title:** Levalbuterol 1.25

**Description:** Patients received an initial dose of levalbuterol 1.25 mg alternating with albuterol 2.5 mg.

### Group

**ID:** BG002

**Title:** Total

**Description:** Total of all reporting groups

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 0

#### Measurement

**Group ID:** BG001

**Value:** 0

#### Measurement

**Group ID:** BG002

**Value:** 0

**Category Title:** <=18 years

#### Measurement

**Group ID:** BG000

**Value:** 18

#### Measurement

**Group ID:** BG001

**Value:** 9

#### Measurement

**Group ID:** BG002

**Value:** 27

**Category Title:** Between 18 and 65 years

#### Measurement

**Group ID:** BG000

**Value:** 40

#### Measurement

**Group ID:** BG001

**Value:** 22

#### Measurement

**Group ID:** BG002

**Value:** 62

**Category Title:** >=65 years

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Spread:** 13.1

**Value:** 67.3

#### Measurement

**Group ID:** BG001

**Spread:** 13.7

**Value:** 67.5

#### Measurement

**Group ID:** BG002

**Spread:** 13.4

**Value:** 67.3

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 31

#### Measurement

**Group ID:** BG001

**Value:** 12

#### Measurement

**Group ID:** BG002

**Value:** 43

**Category Title:** Female

#### Measurement

**Group ID:** BG000

**Value:** 27

#### Measurement

**Group ID:** BG001

**Value:** 19

#### Measurement

**Group ID:** BG002

**Value:** 46

**Category Title:** Male

**Class Title:** 

### Measure

#### Measurement

**Group ID:** BG000

**Value:** 58

#### Measurement

**Group ID:** BG001

**Value:** 31

#### Measurement

**Group ID:** BG002

**Value:** 89

**Class Title:** United States

**Denomination Units Selected:** 

## Results Section - Baseline Characteristics Module

### Measure 1
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Age, Categorical
**Unit of Measure:** Participants
### Measure 2
**Dispersion Type:** STANDARD_DEVIATION
**Parameter Type:** MEAN
**Title:** Age, Continuous
**Unit of Measure:** years
### Measure 3
**Parameter Type:** COUNT_OF_PARTICIPANTS
**Title:** Sex: Female, Male
**Unit of Measure:** Participants
### Measure 4
**Parameter Type:** NUMBER
**Title:** Region of Enrollment
**Unit of Measure:** participants
**Population Description:** The number analyzed was determined by the power calculation and based on the number of participants randomized to treatment.
## Results Section - More Information Module
### Certain Agreement
**PI Sponsor Employee:** True
### Limitations and Caveats
**Description:** Potential limitations are its single-center site and that the design may not have adequately eliminated all carryover effects from the levalbuterol. However, the number of side effects without carryover would be even lower than we observed.
### Point of Contact
**Email:** kbarber@genesys.org
**Organization:** Genesys Regional Medical Center
**Phone:** 810-606-7722
**Title:** Dr. Fahim Khorfan
## Results Section - Outcome Measures Module
### Outcome Measure 1
#### Analysis
**CI Lower Limit:** 
**CI Number of Sides:** TWO_SIDED
**CI Percentage Value:** 95
**CI Upper Limit:** 
**CI Upper Limit Comment:** 
**Dispersion Type:** STANDARD_ERROR_OF_MEAN
**Dispersion Value:** 0.5
**Estimate Comment:** 
**Group Description:** Null Hypothesis: No difference between groups in heart rate changes from baseline following treatment. Sample size calculation determined a need for at least 400 breathing treatments among 65 patients.
**Non-Inferiority Comment:** A total of at least 400 treatemnts or 65 patients was required to achieve 94% power to determine a 1% change by treatment or a 5% change between groups to be significant at p-value of 0.01 and o.05, respectively.
**Non-Inferiority Type:** NON_INFERIORITY_OR_EQUIVALENCE
**Other Analysis Description:** 
**P-Value:** 0.01
**P-Value Comment:** 
**Parameter Type:** Mean Difference (Final Values)
**Parameter Value:** 1
**Statistical Comment:** 
**Statistical Method:** Mixed Models Analysis
**Tested Non-Inferiority:** True
### Outcome Measure 2
#### Analysis
**CI Lower Limit:** 
**CI Number of Sides:** TWO_SIDED
**CI Percentage Value:** 95
**CI Upper Limit:** 
**CI Upper Limit Comment:** 
**Dispersion Type:** 
**Dispersion Value:** 
**Estimate Comment:** 
**Group Description:** Null hypothesis: no difference in incidence of arrhythmias between groups within the total number of breathing treatments.
**Non-Inferiority Comment:** 
**Non-Inferiority Type:** SUPERIORITY_OR_OTHER
**Other Analysis Description:** 
**P-Value:** 0.05
**P-Value Comment:** Analysis adjusted with Fischer exact chi-square for rare occurrences.
**Parameter Type:** Risk Ratio (RR)
**Parameter Value:** 1
**Statistical Comment:** 
**Statistical Method:** Chi-squared
**Tested Non-Inferiority:** False
### Outcome Measure 3
#### Analysis
**CI Lower Limit:** 
**CI Number of Sides:** TWO_SIDED
**CI Percentage Value:** 
**CI Upper Limit:** 
**CI Upper Limit Comment:** 
**Dispersion Type:** 
**Dispersion Value:** 
**Estimate Comment:** 
**Group Description:** To report on the number of events.
**Non-Inferiority Comment:** 
**Non-Inferiority Type:** SUPERIORITY_OR_OTHER
**Other Analysis Description:** 
**P-Value:** 0
**P-Value Comment:** 
**Parameter Type:** 
**Parameter Value:** 
**Statistical Comment:** Descriptive statistics (frequency) used to report the number of participants experiencing an event.
**Statistical Method:** descriptive
**Tested Non-Inferiority:** False
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 5.1
- **Upper Limit:** 
- **Value:** -0.16
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 
- **Spread:** 5.4
- **Upper Limit:** 
- **Value:** 1.40
**Title:** 
#### Outcome Measure 2
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 0.33
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 1.3
**Title:** 
#### Outcome Measure 3
**Class:**
##### Category
**Measurements:**
- **Comment:** 
- **Group ID:** OG000
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 2
- **Comment:** 
- **Group ID:** OG001
- **Lower Limit:** 
- **Spread:** 
- **Upper Limit:** 
- **Value:** 3
**Title:** 
## Results Section
### Outcome Measures Module
#### Outcome Measure 1
**Description:** Average difference in Heart rate between pre and post breathing treatments
**Dispersion Type:** Standard Deviation
**Parameter Type:** MEAN
**Population Description:** Average change in heart rate from baseline to final breathing treatment.
**Reporting Status:** POSTED
**Time Frame:** Five days
**Title:** Heart Rate in Beats Per Minute
**Type:** PRIMARY
**Type Units Analyzed:** Breathing treatment episodes
**Unit of Measure:** bpm
##### Group
**Description:** Patients were randomized to receive an initial dose of albuterol 2.5 mg alternating with levalbuterol 0.63 mg.
**ID:** OG000
**Title:** Nebulized Albuterol 2.5mg
##### Group
**Description:** Patients received an initial dose of levalbuterol 1.25 mg alternating with albuterol 2.5 mg.
**ID:** OG001
**Title:** Levalbuterol 1.25
#### Outcome Measure 2
**Description:** Any new arrhythmia documented in the medical record that occurred between breathing treatments.
**Parameter Type:** NUMBER
**Population Description:** The percentage of arrhythmias among the number of breathing treatments.
**Reporting Status:** POSTED
**Time Frame:** 15 minutes after each treatment for average of 3 to 5 days
**Title:** Arrhythmias
**Type:** SECONDARY
**Unit of Measure:** percent
##### Group
**Description:** Patients were randomized to receive an initial dose of albuterol 2.5 mg alternating with levalbuterol 0.63 mg.
**ID:** OG000
**Title:** Nebulized Albuterol 2.5mg
##### Group
**Description:** Patients received an initial dose of levalbuterol 1.25 mg alternating with albuterol 2.5 mg.
**ID:** OG001
**Title:** Levalbuterol 1.25
#### Outcome Measure 3
**Description:** Documented new arrhythmia occurring during study.
**Parameter Type:** NUMBER
**Population Description:** Number of patients for whom arrhythmias occurred within 5 days after treatment initiation.
**Reporting Status:** POSTED
**Time Frame:** Five days
**Title:** Total Number of Participants With Arrhythmias
**Type:** SECONDARY
**Unit of Measure:** participants
##### Group
**Description:** Patients were randomized to receive an initial dose of albuterol 2.5 mg alternating with levalbuterol 0.63 mg.
**ID:** OG000
**Title:** Nebulized Albuterol 2.5mg
##### Group
**Description:** Patients received an initial dose of levalbuterol 1.25 mg alternating with albuterol 2.5 mg.
**ID:** OG001
**Title:** Levalbuterol 1.25
### Participant Flow Module
#### Group
**Description:** Patients were randomized to receive an initial dose of albuterol 2.5 mg alternating with levalbuterol 0.63 mg.
**ID:** FG000
**Title:** Nebulized Albuterol 2.5mg
#### Group
**Description:** Patients received an initial dose of levalbuterol 1.25 mg alternating with albuterol 2.5 mg.
**ID:** FG001
**Title:** Levalbuterol 1.25
#### Period
**Title:** Overall Study
##### Withdraw
**Type:** Physician Decision
###### Reason
**Group ID:** FG000
**Number of Subjects:** 3
###### Reason
**Group ID:** FG001
**Number of Subjects:** 1
##### Withdraw
**Type:** Withdrawal by Subject
###### Reason
**Group ID:** FG000
**Number of Subjects:** 3
###### Reason
**Group ID:** FG001
**Number of Subjects:** 2
##### Withdraw
**Type:** Not meet inclusion criteria
###### Reason
**Group ID:** FG000
**Number of Subjects:** 6
###### Reason
**Group ID:** FG001
**Number of Subjects:** 4
##### Milestone
**Type:** STARTED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 58
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 31
##### Milestone
**Type:** COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 46
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 24
##### Milestone
**Type:** NOT COMPLETED
###### Achievement
**Group ID:** FG000
**Number of Subjects:** 12
###### Achievement
**Group ID:** FG001
**Number of Subjects:** 7
**Pre-Assignment Details:** Patients were excluded if they had a known allergy or sensitivity to study medications or if baseline heart rate was greater than 110 bpm. Treating physicians detremined the need for and frequency of treatment with bronchodilator therapy. All other medications were allowed.
**Recruitment Details:** Recruitment began initially August 21, 2007 at the medical center ICU.
**Has Results:** True