- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03446599
Hemodynamic Effects of Methylene Blue vs Hydroxocobalamin in Patients at Risk of Vasoplegia During Cardiac Surgery
February 27, 2020 updated by: Ying H. Low, Dartmouth-Hitchcock Medical Center
A Randomized, Placebo-controlled Single-center Pilot Study of the Hemodynamic Effects of Methylene Blue vs Hydroxocobalamin in Patients at Risk of Vasoplegia Undergoing Cardiac Surgery With Cardiopulmonary Bypass
This is a pilot study to determine the hemodynamic effects when hydroxocobalamin vs methylene blue is administered during cardiopulmonary bypass in patients at risk of vasoplegia by measuring mean arterial pressure (MAP), systemic vascular resistance (SVR) and vasopressor requirement.
Study Overview
Status
Withdrawn
Intervention / Treatment
Detailed Description
Type of study: Randomized, placebo-controlled single-center pilot study Expected duration of subject participation: from the start of cardiac surgical procedure to 24 hours after separation from CPB.
Summary description of sequence and duration of all trial periods:
- Recruitment and Enrollment: Patients undergoing CABG and/or valve surgery will be approached by their anesthesia provider regarding their interest in participating in this study. Those who express interest will be screened for inclusion and exclusion criteria the morning or day before scheduled surgery. Informed consent will be obtained from participants by study personnel.
- Preoperative data will be obtained from the electronic medical record and verified with the patient: sex, age, height/weight/BSA, type of surgery, preoperative use of ACEi, beta-blocker, calcium-channel blocker, amiodarone, LVEF), and mean arterial pressure (MAP).
- Intraoperative events, Operative and Medication Data: All participants will undergo routine induction of anesthesia. Anesthesia will be induced and maintained with midazolam, fentanyl, propofol, and isoflurane. The patient will undergo routine monitoring for all cardiac surgical patients at DHMC, which includes: arterial line mean arterial pressure (MAP, mmHg), central venous pressure (CVP, mmHg), cardiac output (CO, liters.min-1) by pulmonary artery catheter (PAC) thermodilution, serum pH, pCO2 and lactate by blood gas sampling during the pre-CPB period, during CPB and after separation from CPB, and transesophageal echocardiography (TEE). Vasopressor will be initiated and titrated to maintain MAP>60mmHg in the pre- and post-CPB period, MAP>50mmHg while on CPB, and vasopressor doses will be recorded on the anesthesia record by the providing team. After the induction of cardiopulmonary bypass, all patients will undergo non-pulsatile hypothermic (32-34 degrees celsius) CPB with a membrane oxygenator and an arterial line filter. The pump will be primed with crystalloid and serial hematocrit levels will be maintained at > 18%. Perfusion will be maintained at pump flow rates of 2-2.5L.min1.m2 throughout CPB to maintain mean arterial pressures 50-80mmg. Arterial blood gases will be measured every 20-30minutes to maintain arterial carbon dioxide partial pressures of 35-40mmHg, unadjusted for temperature (alpha-stat) and oxygen partial pressures of 150-250mmHg. An automated anesthesia record keeping system (e-DH, EPIC®™) records intraoperative hemodynamics at one-minute intervals and stores them into a networked drive. Total CPB time and cross-clamp time and intraoperative medications will also be recorded into e-DH.
- On the initiation of CPB, participants will be randomized to: Group 1 - Hydroxocobalamin (n=20), Group 2 - Methylene blue (n=20) or Group 3 - Placebo (n=20)
- 15 minutes after the initiation of CPB, the study drug will be administered intravenously through the central venous line by the anesthesia providers.
- The study endpoints will be recorded from the anesthesia record above: MAP, CVP, CO, serum pH, pCO2 and lactate, vasopressor requirements, LVEF by TEE and end-tidal isoflurane dose at the following time points: 30 minutes after the induction of anesthesia (A), 15 minutes after the initiation of CPB just before the administration of study drug (pre-drug; time B), 30- and 60- minutes after the administration of study drug (post drug, times C and D), and 15-30 and 60-90 minutes after separation from CPB (post CPB, times E and F).
- From the above measurements, calculated endpoints are derived: cardiac index calculated by CI=CO/body surface area (BSA), and systemic vascular resistance (SVR in dynes.s.cm-5) = (MAP-CVP)/CO x 800, and SVR index (SVRI) = (MAP-CVP)/CI x 800.
- Follow-up will be carried out 24 hours after separation from CPB. Most patients are extubated in the intensive care unit at this time. The following data will be recorded: whether the patient has been extubated, vasopressor requirement, MAP and SVR, and adverse events at 24 hours.
Study Type
Interventional
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
New Hampshire
-
Lebanon, New Hampshire, United States, 03756
- Dartmouth-Hitchcock
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
16 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- 60 patients > 18 years of age
- undergoing coronary artery bypass grafting (CABG) and/or valve surgery on cardiopulmonary bypass (CPB)
who have 2 or more preoperative risk factors for vasoplegia1-6:
- angiotensin-converting enzyme (ACE)-inhibitor, beta-blocker or amiodarone use within 24 hours of surgery
- anticipated CPB duration greater than 120minutes (combined CABG and valve procedure, >3 planned grafts, > 2 valve surgery)
- baseline left ventricular ejection fraction (LVEF) of less than 40%.
Exclusion Criteria:
- Emergency surgery
- Severe renal insufficiency (preoperative Cr > 1.8)
- Severe hepatic disease (preoperative diagnosis of liver cirrhosis, or recent elevated liver function tests)
- Pregnancy or women of childbearing potential
- Known hypersensitivity to hydroxocobalamin or cyanocobalamin
- Known hypersensitivity to methylene blue
- Other known contraindications to methylene blue use: glucose-6-phosphate dehydrogenase (G6PD) deficiency, or ongoing selective serotonin reuptake inhibitor (SSRI), selective norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA) or monoamine inhibitor (MAOi) use.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Hydroxocobalamin
Participants in this arm will receive one intravenous 5-gram dose of hydroxocobalamin reconstituted in 200ml of normal saline over 10-15minutes at the time of initiation of cardiopulmonary bypass.
|
One intravenous dose of 5mg hydroxocobalamin, which is the current FDA-approved adult dose for carbon monoxide poisoning, reconstituted in 200ml normal saline will be administered over 10-15minutes at the time of initiation of cardiopulmonary bypass.
|
Experimental: Methyelene blue
Participants in this arm will receive one intravenous 2mg/kg dose of methylene blue diluted in 200ml of normal saline over 10-15minutes at the time of initiation of cardiopulmonary bypass.
|
One intravenous dose of methylene blue 2mg/kg, which has been the accepted dose for vasoplegia, diluted in 200ml normal saline will be administered over 10-15minutes at the time of initiation of cardiopulmonary bypass.
|
Placebo Comparator: Normal saline
Participants in this arm will receive an intravenous administration of 200ml normal saline over 10-15minutes at the time of initiation of cardiopulmonary bypass.
|
200ml normal saline will be administered intravenously over 10-15minutes at the time of initiation of cardiopulmonary bypass.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
ΔMAP (baseline to 30 min after CPB separation) in OH-CO and placebo groups.
Time Frame: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
Our primary outcome measure is the change in MAP between one of the treatment (hydroxocobalamin) and placebo groups measured at 30 minutes post-CPB
|
From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
ΔMAP (baseline to 30 min after CPB separation) in OH-CO and MB groups.
Time Frame: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
Our first secondary outcome measure is the change in MAP between the two treatment groups measured at 30 minutes post-CPB
|
From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
ΔMAP between baseline and all time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation) between all 3 groups.
Time Frame: From baseline to all measured time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation).
|
Our next secondary outcome measure is the change in MAP between all 3 groups at all measured time points.
|
From baseline to all measured time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation).
|
ΔSVR (baseline to 30 min after CPB separation) in OH-CO and placebo groups.
Time Frame: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
Change in SVR between one of the treatment (hydroxocobalamin) and placebo groups measured at 30 minutes post-CPB
|
From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
ΔSVR (baseline to 30 min after CPB separation) in OH-CO and MB groups.
Time Frame: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
Change in SVR between the two treatment groups measured at 30 minutes post-CPB
|
From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)
|
ΔSVR between baseline and all time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation) between all 3 groups.
Time Frame: From baseline to all measured time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation).
|
Change in SVR between all 3 groups at all measured time points.
|
From baseline to all measured time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation).
|
Differences in phenylephrine requirements during CPB between all 3 groups during CPB
Time Frame: At 30 and 60 minutes after initiation of CPB
|
Phenylephrine dose in mcg/kg/min will be recorded from electronic medical record
|
At 30 and 60 minutes after initiation of CPB
|
Differences in Norepinephrine requirements during CPB between all 3 groups during and after CPB
Time Frame: At 30 and 60 minutes after initiation of CPB, and 30 and 60 minutes after separation from CPB
|
Norepinephrine dose in mcg/kg/min will be recorded from electronic medical record
|
At 30 and 60 minutes after initiation of CPB, and 30 and 60 minutes after separation from CPB
|
Differences in Vasopressin requirements during CPB between all 3 groups during and after CPB
Time Frame: At 30 and 60 minutes after initiation of CPB, and 30 and 60 minutes after separation from CPB
|
Vasopressin dose in units/min will be recorded from electronic medical record
|
At 30 and 60 minutes after initiation of CPB, and 30 and 60 minutes after separation from CPB
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Anticipated)
November 1, 2019
Primary Completion (Anticipated)
May 1, 2020
Study Completion (Anticipated)
June 30, 2020
Study Registration Dates
First Submitted
February 20, 2018
First Submitted That Met QC Criteria
February 20, 2018
First Posted (Actual)
February 27, 2018
Study Record Updates
Last Update Posted (Actual)
March 2, 2020
Last Update Submitted That Met QC Criteria
February 27, 2020
Last Verified
February 1, 2020
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Myocardial Ischemia
- Heart Diseases
- Cardiovascular Diseases
- Vascular Diseases
- Arteriosclerosis
- Arterial Occlusive Diseases
- Postoperative Complications
- Coronary Disease
- Coronary Artery Disease
- Hypotension
- Heart Valve Diseases
- Vasoplegia
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Micronutrients
- Vitamins
- Vitamin B Complex
- Hematinics
- Vitamin B 12
- Hydroxocobalamin
- Methylene Blue
Other Study ID Numbers
- D17173
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
No
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
product manufactured in and exported from the U.S.
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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