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

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.

Inclusion Criteria:

1. 60 patients > 18 years of age

2. undergoing coronary artery bypass grafting (CABG) and/or valve surgery on
cardiopulmonary bypass (CPB)

3. 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:

1. Emergency surgery

2. Severe renal insufficiency (preoperative Cr > 1.8)

3. Severe hepatic disease (preoperative diagnosis of liver cirrhosis, or recent elevated
liver function tests)

4. Pregnancy or women of childbearing potential

5. Known hypersensitivity to hydroxocobalamin or cyanocobalamin

6. Known hypersensitivity to methylene blue

7. 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.