WithdrawnNCT03446599Updated Mar 2, 2020

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

A Phase 2 interventional study of Hydroxocobalamin and Methylene Blue in Vasoplegia, Hypotension and Coronary Artery Disease, sponsored by Dartmouth-Hitchcock Medical Center. Withdrawn at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-03-02.

Sponsored by Dartmouth-Hitchcock Medical Center · Phase 2, Interventional, and Treatment

Why this study was withdrawn

Lack of funding

Phase: Phase 2
Study type: Interventional
Enrollment: 0
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study 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 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:

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.

Conditions studied

Vasoplegia
Hypotension
Coronary Artery Disease
Cardiac Valve Disease

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Keywords

cardiac surgery
vasoplegia
cardiopulmonary bypass

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

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:
1. angiotensin-converting enzyme (ACE)-inhibitor, beta-blocker or amiodarone use within 24 hours of surgery
2. anticipated CPB duration greater than 120minutes (combined CABG and valve procedure, >3 planned grafts, > 2 valve surgery)
3. baseline left ventricular ejection fraction (LVEF) of less than 40%.

Exclusion criteria

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 design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 0 participants (actual)

Study arms

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.
Drug: Hydroxocobalamin
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.
Drug: Methylene Blue
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.
Drug: Normal saline

Interventions

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

What researchers measure

Primary outcomes

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

Secondary outcomes

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
Time frame: 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.
Our next secondary outcome measure is the change in MAP between all 3 groups at all measured time points.
Time frame: 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.
Change in SVR between one of the treatment (hydroxocobalamin) and placebo groups measured at 30 minutes post-CPB
Time frame: 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.
Change in SVR between the two treatment groups measured at 30 minutes post-CPB
Time frame: 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.
Change in SVR between all 3 groups at all measured time points.
Time frame: 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
Phenylephrine dose in mcg/kg/min will be recorded from electronic medical record
Time frame: At 30 and 60 minutes after initiation of CPB
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
Time frame: 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
Vasopressin dose in units/min will be recorded from electronic medical record
Time frame: At 30 and 60 minutes after initiation of CPB, and 30 and 60 minutes after separation from CPB

Study locations

1 site

Dartmouth-Hitchcock
Lebanon, New Hampshire 03756, United States

References and documents

Individual participant data

Plan to share: No

No publications or documents are linked to this record.

Registry details

Key details

Study ID: NCT03446599
Lead sponsor: Dartmouth-Hitchcock Medical Center
Responsible party: Ying H. Low (Staff Physician, Dartmouth-Hitchcock Medical Center) — Principal investigator
First posted: Feb 27, 2018
Start date: Nov 2019 (estimated)
Primary completion: May 2020 (estimated)
Completion: Jun 30, 2020 (estimated)
Last update: Mar 2, 2020

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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