Measurement of Bispectral Index and Awareness in Patients Undergoing Electrophysiology Studies With Isoproterenol

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01377636
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Duration (Months): 26
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

Isoproterenol is used as a cardiac stimulant in electrophysiology studies (EP). Preliminary data suggests that administration of isoproterenol increases the Bispectral index (BIS). BIS is used to monitor neuronal signals under anesthesia. The BIS level is suggested to correspond to the level of consciousness. We hypothesize that isoproterenol increases BIS values because it increases the patient's level of consciousness through its central nervous system (CNS) stimulatory effects. In this study, we will administer increasing doses of isoproterenol to EPS patients. We will measure the BIS levels continuously before and after isoproterenol administration. In addition, we will test the level of awareness of patients by their response to a modified isolated forearm technique.

Condition or Disease	Intervention/Treatment	Phase
Intraoperative Awareness	Drug: Isoproterenol	N/A

Detailed Description

Isoproterenol is a direct acting Beta-1 and Beta-2 agonist useful for its effects on bronchodilation and myocardial contractility. Its CNS side effects include nervousness, headache, dizziness, restlessness, insomnia, anxiety, tension, blurring of vision, fear, and excitement. In addition to our preliminary data, two case reports show an increase in BIS with administration of isoproterenol. Our hypothesis is that administration of isoproterenol will increase the level of consciousness of the patient as reflected in the BIS reading.

The BIS Vista Monitor is a non-invasive device that measures the electrical activity of the brain. It computes a number between 0 and 100 which corresponds to a level of consciousness which is known as the Bispectral (BIS) value. Using the BIS value to guide administration of anesthetic medication, clinicians can make informed decisions for optimal anesthesia. This technology has the potential to prevent over sedation, but is currently not a standard monitoring device.

Another approach to evaluating the level of consciousness of anesthetized patients is to assess their ability to form memories or recall events which occurred while under anesthesia. Conscious recall is the first to disappear with decreasing levels of consciousness. A BIS of 60 or less has been shown in various studies to be sufficient to prevent conscious recall in the vast majority of patients. We propose to use a modified isolated forearm technique test in which the patient is asked to squeeze an observer's hand during anesthesia to ascertain if awareness can occur without recall at a BIS of 60 to 70. (6) Implicit memory in which there is no conscious recall or evaluation of awareness can be assessed by word stem completion tests and has been shown to occur with a BIS as low as 40 - 60 although these results are not consistent across all studies. (7)

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study to Measure BIS and Awareness in Patients Receiving Isoproterenol During Catheter Ablation for Atrial Fibrillation
• Study Start Date: Aug 1, 2009
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Isoproterenol, BIS, forearm test 30 consecutive patients scheduled for EP studies under general anesthesia will participate in the study. Patients with neuromuscular disease precluding the use of succinylcholine will be excluded. The only other exclusions will be patient or cardiologist refusal. No attempts will be made to alter concurrent patient medication.	Drug: Isoproterenol; patients will receive isoproterenol, have a BIS monitoring device and a modified isolated forearm test (no neuromuscular blockade).; Other Names: isoprenaline

Outcome Measures

Primary Outcome Measures

1. Number of Participants With an Increase in BIS Readings During Steady State [During time of Electrophysiology (EP) studies.]

   Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. BIS levels were measured continuously before and after isoproterenol administration. Number of participants with increase in BIS reading during anesthetic steady state are reported below. The BIS scale ranges from 0 to 100. The individual's baseline BIS was measured continuously and was maintained in an anesthetic steady state with minimum variance prior to isoproterenol. A deviation from the mean in excess of 3 points (2 STD) was defined categorically as a positive response and was counted dichotomously.

2. BIS Change [Within 20 minutes of starting isoproterenol infusion]

   The BIS scale ranges from 0 to 100. The individual's baseline BIS was measured continuously and was maintained in an anesthetic steady state with minimum variance prior to isoproterenol. A deviation from the mean in excess of 3 points (2 STD) was defined categorically as a positive response and was counted dichotomously.The difference between Pre-BIS and Post-BIS was calculated.

Secondary Outcome Measures

1. Number of Participants With Spontaneous Musculoskeletal Movement [Within 20 minutes of starting isoproterenol infusion]

   Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. Patients under steady state total venous anesthesia (TIVA) with propofol and remifentanil infusions with BIS around 50 normally do not move even in the absence of neuromuscular blockade. Spontaneous movement appearing like restlessness during sleep is unusual. Several patients under anesthesia after isoproterenol appear to wake up and move spontaneously.

2. Number of Participants Who Follow Verbal Command to Squeeze Hands [Within 20 minutes of starting isoproterenol infusion]

   Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. Ability to follow verbal commands before and after isoproterenol infusion was assessed by asking subjects to "squeeze my hands".

Other Outcome Measures

1. Number of Participants With Significant Change in Heart Rate [Within 20 minutes of starting isoproterenol infusion]

   Heart rate measured by standard EKG monitor during anesthesia. Pre- and Post Heart rates where noted. An increase of 8 percent or more was defined as a significant change in heart rate.

2. Number of Participants With Change in Blood Pressure [Within 20 minutes of starting isoproterenol infusion]

   Non-Invasive Blood Pressure (NIBP) is measured routinely as part of an anesthetic. Pre- and Post Blood Pressures where noted. An increase or decrease of 10 percent or more was defined as a significant change in systolic blood pressure.

3. Number of Participants With Amnesia or No Recall During Steady State [Within one hour of completing anesthesia]

   Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. Specific pre-determined test words were spoken to the subject during administration of isoproterenol. After anesthesia, patients were tested for possible recall of those specific words. If no words were recalled, the result was categorically defined as amnesia.

4. Number of Participants With New Arrhythmia During Steady State. [Within 20 minutes of start of isoproterenol]

   Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation after return to sinus rhythm. If a non-sinus arrhythmia resulted from the infusion, the arrhythmia was defined categorically as a positive response and was counted dichotomously.

5. Number of Participants Who Developed Ischemia or ST Segment Changes [Within 20 minutes of starting isoproterenol infusion]

   The (ST) segment on the EKG was monitored for changes suggestive of demand ischemia. An observable EKG change compared to baseline was defined categorically as a positive response and was counted dichotomously.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients scheduled for EP studies for catheter ablation of atrial fibrillation under general anesthesia will participate in the study

Exclusion Criteria:

• Patients with neuromuscular disease precluding the use of succinylcholine will be excluded.

• Patient or cardiologist refusal

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYU Langone Medical Center, Department of Anesthesiology	New York City	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health

Investigators

• Principal Investigator: Patrick Linton, MD, NYU School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• O'Neill DK, Aizer A, Linton P, Bloom M, Rose E, Chinitz L. Isoproterenol infusion increases level of consciousness during catheter ablation of atrial fibrillation. J Interv Card Electrophysiol. 2012 Aug;34(2):137-42. doi: 10.1007/s10840-011-9652-3. Epub 2012 Feb 25.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT01377636
• Other Study ID Numbers: H#: 09-0440
• First Posted: Jun 21, 2011
• Last Update Posted: Feb 23, 2015
• Last Verified: Feb 1, 2015

• Keywords provided by NYU Langone Health: Isoproterenol; Bispectral index (BIS); electrophysiology studies (EPS)
• Additional relevant MeSH terms: Intraoperative Awareness; Isoproterenol

Study Results

Participant Flow

Recruitment Details	During the preoperative evaluation for anesthesia, the patients scheduled for catheter ablation for atrial fibrillation were approached by the research associate for informed consent and enrollment into the study. The research consent was separate from the clinical anesthesia and procedural consents.

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	Bispectral EEG (BIS) monitoring and neurological examinations were repeated throughout an isoproterenol infusion protocol (20 minutes maximum) to measure the changes in arousal and ability to follow commands under anesthesia
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	Subjects undergoing catheter ablation for atrial fibrillation had measurements pre and post isoproterenol infusion
Overall Participants	20
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 55%
>=65 years	9 45%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62 (8.2)
Sex: Female, Male (Count of Participants)
Female	5 25%
Male	15 75%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With an Increase in BIS Readings During Steady State
Description	Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. BIS levels were measured continuously before and after isoproterenol administration. Number of participants with increase in BIS reading during anesthetic steady state are reported below. The BIS scale ranges from 0 to 100. The individual's baseline BIS was measured continuously and was maintained in an anesthetic steady state with minimum variance prior to isoproterenol. A deviation from the mean in excess of 3 points (2 STD) was defined categorically as a positive response and was counted dichotomously.
Time Frame	During time of Electrophysiology (EP) studies.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	BIS monitoring and neurological examinations were repeated throughout an isoproterenol infusion protocol (20 minutes maximum) to measure the changes in arousal and ability to follow commands under anesthesia
Measure Participants	20
Number [participants]	19 95%

2. Secondary Outcome

Title	Number of Participants With Spontaneous Musculoskeletal Movement
Description	Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. Patients under steady state total venous anesthesia (TIVA) with propofol and remifentanil infusions with BIS around 50 normally do not move even in the absence of neuromuscular blockade. Spontaneous movement appearing like restlessness during sleep is unusual. Several patients under anesthesia after isoproterenol appear to wake up and move spontaneously.
Time Frame	Within 20 minutes of starting isoproterenol infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isoproterenol, BIS, Forearm Test
Arm/Group Description	30 consecutive patients scheduled for EP studies under general anesthesia will participate in the study. Patients with neuromuscular disease precluding the use of succinylcholine will be excluded. The only other exclusions will be patient or cardiologist refusal. No attempts will be made to alter concurrent patient medication. Isoproterenol: patients will receive isoproterenol, have a BIS monitoring device and a modified isolated forearm test (no neuromuscular blockade).
Measure Participants	20
Number [participants]	12 60%

3. Secondary Outcome

Title	Number of Participants Who Follow Verbal Command to Squeeze Hands
Description	Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. Ability to follow verbal commands before and after isoproterenol infusion was assessed by asking subjects to "squeeze my hands".
Time Frame	Within 20 minutes of starting isoproterenol infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isoproterenol, BIS, Forearm Test
Arm/Group Description	30 consecutive patients scheduled for EP studies under general anesthesia will participate in the study. Patients with neuromuscular disease precluding the use of succinylcholine will be excluded. The only other exclusions will be patient or cardiologist refusal. No attempts will be made to alter concurrent patient medication. Isoproterenol: patients will receive isoproterenol, have a BIS monitoring device and a modified isolated forearm test (no neuromuscular blockade).
Measure Participants	20
Number [participants]	10 50%

4. Other Pre-specified Outcome

Title	Number of Participants With Significant Change in Heart Rate
Description	Heart rate measured by standard EKG monitor during anesthesia. Pre- and Post Heart rates where noted. An increase of 8 percent or more was defined as a significant change in heart rate.
Time Frame	Within 20 minutes of starting isoproterenol infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	Subjects undergoing catheter ablation for atrial fibrillation had measurements pre and post isoproterenol infusion
Measure Participants	20
Number [participants]	18 90%

5. Other Pre-specified Outcome

Title	Number of Participants With Change in Blood Pressure
Description	Non-Invasive Blood Pressure (NIBP) is measured routinely as part of an anesthetic. Pre- and Post Blood Pressures where noted. An increase or decrease of 10 percent or more was defined as a significant change in systolic blood pressure.
Time Frame	Within 20 minutes of starting isoproterenol infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	Subjects undergoing catheter ablation for atrial fibrillation had measurements pre and post isoproterenol infusion
Measure Participants	20
Number [participants]	13 65%

6. Other Pre-specified Outcome

Title	Number of Participants With Amnesia or No Recall During Steady State
Description	Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation. Specific pre-determined test words were spoken to the subject during administration of isoproterenol. After anesthesia, patients were tested for possible recall of those specific words. If no words were recalled, the result was categorically defined as amnesia.
Time Frame	Within one hour of completing anesthesia

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Isoproterenol, BIS, Forearm Test
Arm/Group Description	30 consecutive patients scheduled for EP studies under general anesthesia will participate in the study. Patients with neuromuscular disease precluding the use of succinylcholine will be excluded. The only other exclusions will be patient or cardiologist refusal. No attempts will be made to alter concurrent patient medication. Isoproterenol: patients will receive isoproterenol, have a BIS monitoring device and a modified isolated forearm test (no neuromuscular blockade).
Measure Participants	20
Number [participants]	20 100%

7. Other Pre-specified Outcome

Title	Number of Participants With New Arrhythmia During Steady State.
Description	Increasing doses of isoproterenol (5,10,15,20 mcg/minute) were administered to patients undergoing catheter ablation for atrial fibrillation after return to sinus rhythm. If a non-sinus arrhythmia resulted from the infusion, the arrhythmia was defined categorically as a positive response and was counted dichotomously.
Time Frame	Within 20 minutes of start of isoproterenol

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	Subjects undergoing catheter ablation for atrial fibrillation had measurements pre and post isoproterenol infusion
Measure Participants	20
Number [participants]	4 20%

8. Other Pre-specified Outcome

Title	Number of Participants Who Developed Ischemia or ST Segment Changes
Description	The (ST) segment on the EKG was monitored for changes suggestive of demand ischemia. An observable EKG change compared to baseline was defined categorically as a positive response and was counted dichotomously.
Time Frame	Within 20 minutes of starting isoproterenol infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	Subjects undergoing catheter ablation for atrial fibrillation had measurements pre and post isoproterenol infusion
Measure Participants	20
Number [participants]	2 10%

9. Primary Outcome

Title	BIS Change
Description	The BIS scale ranges from 0 to 100. The individual's baseline BIS was measured continuously and was maintained in an anesthetic steady state with minimum variance prior to isoproterenol. A deviation from the mean in excess of 3 points (2 STD) was defined categorically as a positive response and was counted dichotomously.The difference between Pre-BIS and Post-BIS was calculated.
Time Frame	Within 20 minutes of starting isoproterenol infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	Subjects undergoing catheter ablation for atrial fibrillation had measurements pre and post isoproterenol infusion
Measure Participants	20
Mean (95% Confidence Interval) [units on a scale]	24.6

Adverse Events

Time Frame	24 hours
Arm/Group Title	Pre and Post Isoproterenol Infusion
Arm/Group Description	In this study, serious adverse events were considered clinically significant adverse events. The well known isoproterenol effects on heart rate, rhythm, ST segments, and blood pressure were noted.
All Cause Mortality
	Pre and Post Isoproterenol Infusion
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Pre and Post Isoproterenol Infusion
	Affected / at Risk (%)	# Events
Total	0/20 (0%)
Cardiac disorders
Death	0/20 (0%)	0
Cardiac arrest	0/20 (0%)	0
Nervous system disorders
Stroke	0/20 (0%)	0
Seizure	0/20 (0%)	0
Other (Not Including Serious) Adverse Events
	Pre and Post Isoproterenol Infusion
	Affected / at Risk (%)	# Events
Total	19/20 (95%)
Blood and lymphatic system disorders
Bleeding	0/20 (0%)	0
Cardiac disorders
Tachycardia	19/20 (95%)	19
Atrial Fibrillation/Junctional Rhythm	4/20 (20%)	4
ST Changes (transient)	2/20 (10%)	2
Hypotension	6/20 (30%)	6
Hypertension	6/20 (30%)	6
Bradycardia	0/20 (0%)	0
Ventricular arrhythmia	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/20 (0%)	0
Pneumonia	0/20 (0%)	0
Pulmonary embolism	0/20 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.