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VasoplegiaPhase 2NCT03446599

Hemodynamic Effects of Methylene Blue vs Hydroxocobalamin in Patients at Risk of Vasoplegia During Cardiac Surgery

A Phase 2 study testing Hydroxocobalamin, Methylene Blue and Normal saline in people with Vasoplegia and Hypotension, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Vasoplegia, Hypotension, Coronary Artery Disease
What is being tested?
Hydroxocobalamin, Methylene Blue and Normal saline
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
0 participants
Where
1 siteUnited States
Study dates
Nov 2019to 30 Jun 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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%.

Who cannot join

  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Dartmouth-Hitchcock

    Lebanon, New Hampshire, 03756

Other trials in United States

About this study

Official title: 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.

Read the 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:

  1. 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.
  2. 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).
  3. 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.
  4. 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)
  5. 15 minutes after the initiation of CPB, the study drug will be administered intravenously through the central venous line by the anesthesia providers.
  6. 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).
  7. 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.
  8. 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.
Being tested
Hydroxocobalamin, Methylene Blue, Normal saline
Keywords
cardiac surgery, vasoplegia, cardiopulmonary bypass
Medical subject headings
Vasoplegia, Hypotension, Coronary Artery Disease, Heart Valve Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • HydroxocobalaminDrug

    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.

  • Methylene BlueDrug

    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.

  • Normal salineDrug

    200ml normal saline will be administered intravenously over 10-15minutes at the time of initiation of cardiopulmonary bypass.

Study groups in NCT03446599
Study groupRoleWhat they receive
HydroxocobalaminExperimentalParticipants 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.
Receives: Drug: Hydroxocobalamin
Methyelene blueExperimentalParticipants 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.
Receives: Drug: Methylene Blue
Normal salinePlacebo comparatorParticipants in this arm will receive an intravenous administration of 200ml normal saline over 10-15minutes at the time of initiation of cardiopulmonary bypass.
Receives: Drug: Normal saline

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. ΔMAP (baseline to 30 min after CPB separation) in OH-CO and placebo groups.

    Our primary outcome measure is the change in MAP between one of the treatment (hydroxocobalamin) and placebo groups measured at 30 minutes post-CPB

    Measured: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)

Secondary outcomes (8)
  1. ΔMAP (baseline to 30 min after CPB separation) in OH-CO and MB groups.

    Our first secondary outcome measure is the change in MAP between the two treatment groups measured at 30 minutes post-CPB

    Measured: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)

  2. 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.

    Our next secondary outcome measure is the change in MAP between all 3 groups at all measured time points.

    Measured: From baseline to all measured time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation).

  3. ΔSVR (baseline to 30 min after CPB separation) in OH-CO and placebo groups.

    Change in SVR between one of the treatment (hydroxocobalamin) and placebo groups measured at 30 minutes post-CPB

    Measured: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)

  4. ΔSVR (baseline to 30 min after CPB separation) in OH-CO and MB groups.

    Change in SVR between the two treatment groups measured at 30 minutes post-CPB

    Measured: From baseline to 30 minutes after successful separation from cardiopulmonary bypass (CPB)

  5. 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.

    Change in SVR between all 3 groups at all measured time points.

    Measured: From baseline to all measured time points (30 and 60 minutes after CPB initiation, and 30 and 60 minutes after CPB separation).

  6. Differences in phenylephrine requirements during CPB between all 3 groups during CPB

    Phenylephrine dose in mcg/kg/min will be recorded from electronic medical record

    Measured: At 30 and 60 minutes after initiation of CPB

  7. Differences in Norepinephrine requirements during CPB between all 3 groups during and after CPB

    Norepinephrine dose in mcg/kg/min will be recorded from electronic medical record

    Measured: At 30 and 60 minutes after initiation of CPB, and 30 and 60 minutes after separation from CPB

  8. Differences in Vasopressin requirements during CPB between all 3 groups during and after CPB

    Vasopressin dose in units/min will be recorded from electronic medical record

    Measured: At 30 and 60 minutes after initiation of CPB, and 30 and 60 minutes after separation from CPB

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Feb 2018
  2. Study startNov 2019 (estimated)
  3. Primary completionMay 2020 (estimated)
  4. Study completion30 Jun 2020 (estimated)

Why it stopped: Lack of funding

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03446599
Sponsor's protocol ID
D17173
Status last verified
Feb 2020
First submitted
20 Feb 2018
Last updated
2 Mar 2020
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Hydroxocobalamin, Methylene Blue and Normal saline in people with Vasoplegia and Hypotension, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 2 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Mar 2020.

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