Prophylactic Use of Hydroxycobolamin in the Prevention of Vasoplegic Syndrome in Adult Patients Undergoing Cardiopulmonary Bypass
Condition: Vasoplegic Syndrome
MeSH terms: Vasoplegia; Syndrome
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Several studies have described the use of alternative drugs as methylene blue (MB) (3) other
      than the standard limited options of the use of vasopressors and systemic corticosteroids (4)
      especially in the face of increasing incidence of vasoplegic syndrome. Hydroxycobolamin (HCO)
      has been used for treating cyanide poisoning for more than 40 years. Persistant and
      significant hypertension occurred as a result of the ability of (HCO) to bind nitric oxide
      (NO) to form nitrocobalamin.

      In this prospective randomized controlled trial, we hypothesized that the prophylactic use of
      HCO in high risk patients after CPB may decrease the incidence of vasoplegia.
    

Detailed description: 
      Patients and methods

      This randomized placebo-controlled single -center study will be conducted in Ain Shams
      University Hospital from May 2019 till October 2022. Patients undergoing Cardiopulmonary
      bypass grafting (CABG) and/or valve surgery will be approached by their anesthesia providers.
      Those who will be accepted to participate in the study were screened for inclusion and
      exclusion criteria on the day of the surgery or one day before. Informed consent will be
      taken from all participants by anesthesia providers. The duration of the study will be from
      the start of cardiac surgical procedure till after separation from CPB by 60 minutes.

      Patients will be included in the study are aged from18- 60 yrs old undergoing CABG and/or
      valve surgery on CPB and have 2 or more preoperative risk factors for Vasoplegia including

        -  Using preoperative beta blocker (BB) or Angiotensin converting enzyme inhibitor (ACEI).

        -  preoperative EF < 35%

        -  History of thyroid disease

        -  Preoperative diuretics

      Exclusion criteria are:

        1. Emergency surgery

        2. Severe renal Insufficiency (preoperative Cr > 1.8 mg / dL)

        3. Severe hepatic disease (preoperative diagnosis of liver cirrhosis or recent elevated
           liver function tests

        4. Pregnant or woman of child bearing potential

        5. Know hypersensitivity to hydroxycobolamin

      Preoperative data will be obtained from the medical records and verified with the patients;
      sex, age, Body surface index (BSI) , height and weight, type of surgery , preoperative use of
      ;ACEI- BB- calcium channel blocker (CCB) - amiodarone, mean arterial blood pressure (MAP),
      preoperative Ejection fraction (EF). Anesthesia will be induced in all patients and
      maintained by using midazolam, fentanyl, propofol, sevoflurane, pancurium.

        -  All patients were monitored with the routine monitoring of all cardiac patients which
           included: MAP in mmHg, oxygen saturation (SaO2), central venous pressure (CVP) in cmH2o,
           electrocardiography (ECG), Cardiac output (CO) L/min, arterial blood gases (ABG)
           measuring; PH, PaCo2, HCO3, lactate during the pre- during- post CPB, trans-esophageal
           echocardiography (TEE) measuring CO, CI, LVEF, SVR ( dyne.s/cm5)=MAP-CVP/CO✖ 800, SVRI=
           MAP-CVP/ CI ✖ 800.

      Vasopressors in the form of norepinephrine will be started and titrated to maintain MAP >60
      mmHg in the pre- during - post CPB period.

      The total doses of norepinephrine and epinephrine (if needed) in (µg/kg/min) will be recorded
      on the anesthesia record by anesthesia providers. After induction of CPB all patients undergo
      non pulsatile hypothermia (32-34 0C) CPB with a membrane oxygenator and the arterial line
      filter. Priming of CPB will be done by crystalloids and serial HCT level were at >18%. The
      flow rate on CPB was 2- 2.5L/ min/ m2 to maintain the MAP 50-80 mmHg. Blood gases samples
      will be measured every 30 min to maintain arterial CO2 of 35-40 mmHg uncorrected for
      temperature (alpha stat) and the partial pressure of O2 (150-250 mmHg). Hemodynamics will be
      recorded every 30 min intervals and stored into the anesthesia record. The time of CPB and
      cross clamping time will be recorded.

      At the end of CPB, the patients will be assigned randomly into 2 groups by using computer
      generated random numbers sequences and sealed envelopes.

      Group (OH CO): 30 patients will receive hydroxycobolamin (Cyanokit) 5 gm intravenously(iv)
      through the central venous catheter as bolus over 15 min reconstituted in 200 ml of NS.

      Group (C) control: 30 patients will receive 200ml of NS over 15 min iv.

      Primary outcome will be change in MAP between baseline and all time points (30 & 60 min after
      CPB initiation) and (30 & 60 min after CPB separation) between the two groups and within the
      same group.

      Secondary outcomes were:

        1. Change in SVR between baseline and all time points (30 & 60 min after CPB initiation)
           and (30 & 60 min after CPB separation) between the 2 groups and within the same group.

        2. Number of patients who needed norepinephrine ≥ 0.5µg/kg/min ± epinephrine as inotropic
           support during weaning from CPB.

        3. Incidence of vasoplegic syndrome occurrence which is defined as occurrence of one or
           more of these parameters: systemic vascular resistance of ≤ 800 dyne/ s/ cm, an MAP of ≤
           60 to 65 mm Hg, a cardiac index of ≥ 2.5 to 3 L/ min/ m2, a requirement for at least one
           or more high-dose of vasopressors (ie, norepinephrine >0.05 μg / kg/ min).

        4. Number of patients who developed norepinephrine refractory vasoplegia ( needed
           epinephrine as another inotropic support)

        5. Number of patients developed multiorgan failure in ICU

        6. Mortality rate.
    

Intervention name(s): Hydroxycobalamin
Intervention type(s): Drug
Intervention description(s): prophylactic to prevent vasoplegia in high risk patients undergoing CABG or valvular surgeries
Intervention MeSH terms: Hydroxocobalamin; Vitamin B 12
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: At the end of CPB, the patients will be assigned randomly into 2 groups by using computer generated random numbers sequences and sealed envelopes.
Group (OH CO): 30 patients will receive hydroxycobolamin (Cyanokit) 5 gm intravenously(iv) through the central venous catheter as bolus over 15 min reconstituted in 200 ml of NS.
Group (C) control: 30 patients will receive 200ml of NS over 15 min iv.
Primary outcome will be change in MAP between baseline and all time points (30 & 60 min after CPB initiation) and (30 & 60 min after CPB separation) between the two groups and within the same group.
Secondary outcomes were:
Masking: None (Open Label)
Primary purpose: Prevention