Prophylactic Use of Hydroxycobolamin in the Prevention of Vasoplegic Syndrome in Adult Patients Undergoing Cardiopulmonary Bypass

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.

Study Overview

• Status: Completed
• Conditions: Vasoplegic Syndrome
• Intervention / Treatment: Drug: Hydroxycobalamin

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • AinShams university hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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,
• Using preoperative beta blocker (BB) or Angiotensin converting enzyme inhibitor (ACEI).
• preoperative EF < 35%
• History of thyroid disease
• Preoperative diuretics

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group (OH CO); 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.	Drug: Hydroxycobalamin; prophylactic to prevent vasoplegia in high risk patients undergoing CABG or valvular surgeries
Placebo Comparator: Group (C) control; Group (C) control: 30 patients will receive 200ml of NS over 15 min iv.	Drug: Hydroxycobalamin; prophylactic to prevent vasoplegia in high risk patients undergoing CABG or valvular surgeries

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in systemic vascular resistance	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.	within 30 and 60 minutes

Collaborators and Investigators

• Sponsor: Ain Shams University

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2019
• Primary Completion (Actual): November 20, 2023
• Study Completion (Actual): November 27, 2023

Study Registration Dates

• First Submitted: November 29, 2023
• First Submitted That Met QC Criteria: November 29, 2023
• First Posted (Estimated): December 7, 2023

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Disease; Syndrome; Vasoplegia; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Hematinics; Vitamin B 12; Hydroxocobalamin
• Other Study ID Numbers: FMASU R46/2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No