Optimization of Prime Fluid Strategy to Preserve Microcirculatory Perfusion During Cardiac Surgery With Cardiopulmonary Bypass, Part I (PRIME part I)

Optimization of Prime Fluid Strategy to Preserve Microcirculatory Perfusion During Cardiac Surgery With Cardiopulmonary Bypass

Acute microcirculatory perfusion disturbances is common in critical illness and associated with higher morbidity and mortality. Recent findings by the investigators' group showed that microcirculatory perfusion is disturbed during cardiac surgery with cardiopulmonary bypass (CPB) and remain disturbed up to 72 (seventy two) hours after surgery. A cardiopulmonary bypass is a machine which takes over heart and lung function, during the procedure. The disturbed microcirculation is associated with organ dysfunction induced by cardiac surgery using CPB, which is frequently seen (up to 42%, forty two percent) and results in a six-fold increase in mortality rate. The underlying cause of disturbed microcirculation is a higher endothelial permeability and vascular leakage and are a consequence of systemic inflammation, hemodilution (dilution of blood), hypothermia and hemolysis (breakdown of red blood cells). To gain the knowledge regarding disturbed microcirculation the investigators previously showed that hemodilution attributes to this disturbed perfusion. Hemodilution lowers colloid oncotic pressure (COP). Also, COP is affected by free hemoglobin, which increases with hemolysis and attributes to a disturbed microcirculation following CPB. This is interesting, as to the best of our knowledge, the effect of minimizing hemodilution and hemolysis during cardiac surgery on the microcirculatory perfusion has never been investigated, but could be the key factor in reducing organ dysfunction.

Study Overview

• Status: Recruiting
• Conditions: Hemolysis; Endothelial Dysfunction; Fluid Overload
• Intervention / Treatment: Combination product: A: gelofusine + ringers; Combination product: B: albumine + ringers; Combination product: C: ringers + retrograde autologous priming

Detailed Description

In this project the investigators focus on reducing microcirculatory perfusion disturbances by exploring therapeutic approaches with different prime fluid strategies, by acting on COP (part I) and free hemoglobin scavenging with human albumin (part II).

In part I, patients undergoing elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass will be randomized in three groups receiving different prime fluid strategies. The study endpoint is the reduction in functional capillary density during the perioperative period. Sublingual microcirculatory measurements and blood sampling will take place after induction of anesthesia, during and after surgery to determine microcirculatory perfusion and parameters for hemodilution, hemolysis, COP, markers for endothelial damage and glycocalyx shedding. Measurements start on the day of surgery and end one day after surgery.

In part II, participants will be randomized in two groups receiving the first dose directly after aortic cross clamping and blood cardioplegia administration, and the second dose after the third blood cardioplegia administration (± 30 min after the first dose).The most optimal prime fluid in order to preserve microcirculatory perfusion from study one, will be used as prime fluid in the second study. Microcirculatory perfusion parameters will be measured at time points comparable with study one. Blood samples are taken to determine markers for hemodilution, hemolysis, COP and endothelial damage and glycocalyx shedding. For part II see trial registration: PRIME, part II.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: A.M. Beukers, MD; Phone Number: 020-4444444; Email: a.beukers@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1105AZ
      • Recruiting
      • Amsterdam UMC, AMC location
      • Contact: A.M. Beukers, MD; Phone Number: 020-4444444; Email: a.beukers@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult subjects
• Informed consent
• Elective coronary artery bypass surgery with cardiopulmonary bypass

Exclusion Criteria:

• Emergency operations
• Re-operation
• Elective thoracic aortic surgery
• Elective valve surgery
• Combined procedure CABG and valve surgery
• Known allergy for human albumin or gelofusine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A: gelofusine + ringers; Prime fluid strategy containing gelofusine and ringers	Combination product: A: gelofusine + ringers; 750 milliliter (mL) modified fluid gelatin (Braun Melsungen, Germany), 650 mL Ringer's solution (Baxter, Utrecht, Netherlands) and 100 mL mannitol (15%, Baxter, Utrecht, Netherlands)
Active Comparator: B: albumin + ringers; Prime fluid strategy containing albumin and ringers	Combination product: B: albumine + ringers; 200 mL human albumin (20%, Sanquin, Amsterdam, Netherlands), 1200 mL Ringer's solution (Baxter, Utrecht, Netherlands) and 100 mL mannitol (15%, Baxter, Utrecht, Netherlands)
Active Comparator: C: ringers + retrograde autologous priming; Prime fluid strategy containing ringers combined with retrograde autologous priming	Combination product: C: ringers + retrograde autologous priming; 1400 mL Ringer's solution (Baxter, Utrecht, Netherlands) and 100 mL mannitol (15%, Baxter, Utrecht, Netherlands) with retrograde autologous priming. Retrograde autologous priming (RAP) is applied using clinical parameters such as Central Venous Pressure, Mean Arterial Pressure (MAP), and intra cardiac filling pressure based on Trans Esophageal Echo as guidance to the amount of fluid displaced. RAP is applied to a maximum volume of 475 mL provided that systolic blood pressure will remain >90 millimeter of mercury (mmHg). Phenylephrine can be administered up to 200 mcg to keep the system hemodynamics stable during RAP. In case of a body surface area <1.7m2, a maximum volume of 375 mL is desired. Once the desired amount of prime is displaced, the transfusion bag is clamped and CPB is started. If additional fluids are needed during CPB to maintain optimal perfusion, the displaced prime is used prior to the vasoplegia protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T1: within 5-10 minutes after induction of anesthesia
Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T2 within 5-10 minutes after aortic cross clamping
Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T3 within 5-10 minutes after weaning from cardiopulmonary bypass
Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T4 within 15-30 min after arrival on the intensive care unit
Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T5 twenty four (24) hours after arrival on the intensive care unit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Colloid oncotic pressure (COP, mmHg)	colloid oncotic pressure in plasma	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
albumin (g L-¹)	concentration of albumin in plasma	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
hemolysis index (H-index)	the grade of hemolysis in plasma	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
haptoglobin (g L-¹)	concentration of haptoglobin in plasma	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
NO consumption (μmol L-¹)	consumption of nitric oxide in plasma	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
syndecan-1 (ng/ml)	Concentration of syndecan-1 in plasma	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
heparan sulphate (ng/ml)	concentration of heparan sulphate in plasma	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
hemoglobin (Hb, mmol L-¹)	concentration of hemoglobin in serum	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
hematocrit (Ht, L L-¹)	hematocrit in serum	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Total vessel density (TVD, mm mm-²)	density of capillaries reflecting the functional state of the microcirculatory diffusion capacity	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Proportion of perfused vessels (PPV, %)	reflecting the aspect of heterogeneity of microcirculatory perfusion	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Heterogeneity index	reflecting the aspect of heterogeneity of microcirculatory perfusion	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
perioperative use of packed red blood cells (PRBCs, mL)	amount of packed red blood cells	Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative
fluid balance (mL)	fluid balance	Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative
fluid requirements (mL)	Amount of fluids required	Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age	Age in years	Preoperative
Gender	Gender (male/female)	Preoperative
Smoking	Medical history of smoking (yes/no)	Preoperative
Diabetes on medication	Medical history of diabetes on medication (yes/no)	Preoperative
Comorbidities	Other comorbidities in medical history (yes/no)	Preoperative
Oxygen saturation (Sat, %)	Oxygen saturation in %	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Urine production (ml)	Urine production	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Blood pressure (mmHg)	Blood pressure (mmHg)	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Phenylephrine	Phenylephrine (mcg)	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Vasopressin (IU/min)	Vasopressin (IU/min)	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Lactate (mmol/L)	Serum lactate	T1, 5-10 min after induction of anesthesia; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Creatinin levels (umol/L)	serum creatinin level	T1, 5-10 min after induction of anesthesia; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Duration of mechanical ventilation (hours)	Duration of mechanical ventilation (hours)	Postoperative until 30 days postoperative
ICU stay (hours)	ICU stay (hours)	Postoperative until 30 days postoperative
Hospital stay (days)	Days until hospital discharge (days)	Postoperative until 30 days postoperative
Respiratory failure	Respiratory failure (yes/no)	Postoperative until 30 days postoperative
non-preexisting atrial fibrillation	non-preexisting atrial fibrillation (yes/no)	Postoperative until 30 days postoperative
re-do surgery	re-do surgery (yes/no)	Postoperative until 30 days postoperative
Extra corporeal membrane oxygenation (ECMO)	Extra corporeal membrane oxygenation (yes/no)	Postoperative until 30 days postoperative
Body Surface Area (BSA)	BSA in m2	Preoperative
EuroSCORE II	The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II predicts risk of in-hospital mortality after cardiac surgery.	Preoperative
CPB time (min)	Cardiopulmonary bypass time in minutes	intraoperative
Aortic cross clamping time (AoX time, min)	Aortic cross clamping time in minutes	intraoperative
heparin (IU)	Dosing of heparin in international units	intraoperative
protamin (mg)	dosing of protamin	intraoperative
Activated Clotting Time (ACT, min)	ACT in minutes	intraoperative
Temperature (celsius)	Temperature in celsius	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Noradrenaline infusion	Noradrenaline infusion (mcg/kg/min)	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Methylene Blue (mg)	Methylene blue (mg)	T1, 5-10 min after induction of anesthesia; T2, 5-10 min after aortic cross clamping; T3, 5-10 min after weaning from cardiopulmonary bypass; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
estimated glomerular filtration rate (eGFR, ml/min/1,73 m2)	estimated glomerular filtration rate	T1, 5-10 min after induction of anesthesia; T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit.
Blood product use	Blood product use (ml)	Intraoperative and up to 24 hours postoperative
Blood loss (ml)	Blood loss	T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit
Acute Kidney injury (AKI)	Acute kidney injury (yes/no)	Postoperative until 30 days postoperative
Pneumonia	Pneumonia (yes/no)	Postoperative until 30 days postoperative
Mortality	In-hospital mortality (yes/no)	Postoperative until 30 days postoperative

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Investigators: Principal Investigator: A.B.A. Vonk, MD, PhD, Cardiothoracic surgeon

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2023
• Primary Completion (Estimated): August 15, 2024
• Study Completion (Estimated): January 15, 2025

Study Registration Dates

• First Submitted: November 9, 2022
• First Submitted That Met QC Criteria: December 9, 2022
• First Posted (Actual): December 12, 2022

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Cardiopulmonary bypass; Microcirculation; Hemolysis; Colloid oncotic pressure; Hemodilution
• Additional Relevant MeSH Terms: Pathologic Processes; Hemolysis; Plasma Substitutes; Blood Substitutes; Polygeline
• Other Study ID Numbers: NL82500.029.22, part I

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Upon request
• IPD Sharing Time Frame: Upon request
• IPD Sharing Supporting Information Type: SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No