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NCT Number: NCT05647057

CPB Prime Fluid Strategies to Preserve Mcirocirculatory Perfusion

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.

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Key information

Conditions

Endothelial Dysfunction Edema Fluid Overload Hemolysis Pathologic Processes Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Amsterdam UMC, AMC location

Amsterdam, North Holland, 1105AZ, Netherlands

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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
  • The use of crystalloid cardioplegia
  • Combined procedure CABG and valve surgery
  • Known allergy for human albumin or gelofusine

Treatment and study plan

A: gelofusine + ringers

Combination Product

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)

B: albumine + ringers

Combination Product

200 mL human albumin (20%, Sanquin, Amsterdam, Netherlands), 1200 mL Ringer's solution (Baxter, Utrecht, Netherlands) and 100 mL mannitol (15%, Baxter, Utrecht, Netherlands)

C: ringers + retrograde autologous priming

Combination Product

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.

Primary outcomes

  1. Perfused vessel density (PVD, mm mm-²)

    Time frame: T1: within 5-10 minutes after induction of anesthesia

    reflecting microcirculatory diffusion capacity

  2. Perfused vessel density (PVD, mm mm-²)

    Time frame: T2 within 5-10 minutes after aortic cross clamping

    reflecting microcirculatory diffusion capacity

  3. Perfused vessel density (PVD, mm mm-²)

    Time frame: T3 within 5-10 minutes after weaning from cardiopulmonary bypass

    reflecting microcirculatory diffusion capacity

  4. Perfused vessel density (PVD, mm mm-²)

    Time frame: T4 within 15-30 min after arrival on the intensive care unit

    reflecting microcirculatory diffusion capacity

  5. Perfused vessel density (PVD, mm mm-²)

    Time frame: T5 twenty four (24) hours after arrival on the intensive care unit

    reflecting microcirculatory diffusion capacity

Secondary outcomes

  1. Colloid oncotic pressure (COP, mmHg)

    Time frame: 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.

    colloid oncotic pressure in plasma

  2. albumin (g L-¹)

    Time frame: 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.

    concentration of albumin in plasma

  3. hemolysis index (H-index)

    Time frame: 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.

    the grade of hemolysis in plasma

  4. haptoglobin (g L-¹)

    Time frame: 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.

    concentration of haptoglobin in plasma

  5. syndecan-1 (ng/ml)

    Time frame: T1, 5-10 min after induction of anesthesia; 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.

    Concentration of syndecan-1 in plasma

  6. heparan sulphate (ng/ml)

    Time frame: T1, 5-10 min after induction of anesthesia; 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.

    concentration of heparan sulphate in plasma

  7. hemoglobin (Hb, mmol L-¹)

    Time frame: 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.

    concentration of hemoglobin in serum

  8. hematocrit (Ht, L L-¹)

    Time frame: 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 in serum

  9. perioperative use of packed red blood cells (PRBCs, mL)

    Time frame: Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative

    amount of packed red blood cells

  10. fluid balance (mL)

    Time frame: Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative

    fluid balance

  11. fluid requirements (mL)

    Time frame: Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative

    Amount of fluids required

  12. Total vessel density (TVD, mm mm-²)

    Time frame: 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.

    density of capillaries reflecting the functional state of the microcirculatory diffusion capacity

  13. Proportion of perfused vessels (PPV, %)

    Time frame: 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.

    reflecting the aspect of heterogeneity of microcirculatory perfusion

  14. Heterogeneity index

    Time frame: 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.

    reflecting the aspect of heterogeneity of microcirculatory perfusion

  15. Thrombomodulin (ng mL-¹)

    Time frame: T1, 5-10 min after induction of anesthesia; 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.

    Thrombomodulin concentration in plasma

  16. Angiopoietin-2 (ng mL-¹)

    Time frame: T1, 5-10 min after induction of anesthesia; 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.

    Angiopoietin-2 concentration in plasma

  17. Interleukin-6 (ng mL-¹)

    Time frame: T1, 5-10 min after induction of anesthesia; 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.

    Interleukin-6 concentration in plasma

  18. Tumor necrosis factor (TNF-alpha, ng mL-¹)

    Time frame: T1, 5-10 min after induction of anesthesia; 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.

    TNF-alpha concentration in plasma

  19. Neutrophil gelatinase associated lipocalin (NGAL, ng mL-¹)

    Time frame: T1, 5-10 min after induction of anesthesia; 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.

    NGAL concentration in plasma

  20. Magnesium (mmol L-¹)

    Time frame: 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.

    Magnesium concentration in plasma

  21. Phosphate (mmol L-¹)

    Time frame: 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.

    Phosphate concentration in plasma

  22. Oxygen delivery (mL min-¹)

    Time frame: During cardiopulmonary bypass

    Oxygen delivery

  23. Microvascular Flow Index

    Time frame: 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.

    Microvascular Flow Index, semi-quantitative assessment of the average red blood cell velocity per quadrant

  24. De Backer-score

    Time frame: 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.

    De Backer-score, proxy of total vessel density

Other outcomes

  1. Age

    Time frame: Preoperative

    Age in years

  2. Gender

    Time frame: Preoperative

    Gender (male/female)

  3. Body Surface Area (BSA)

    Time frame: Preoperative

    BSA in m2

  4. Smoking

    Time frame: Preoperative

    Medical history of smoking (yes/no)

  5. Diabetes on medication

    Time frame: Preoperative

    Medical history of diabetes on medication (yes/no)

  6. Comorbidities

    Time frame: Preoperative

    Other comorbidities in medical history (yes/no)

  7. EuroSCORE II

    Time frame: Preoperative

    The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II predicts risk of in-hospital mortality after cardiac surgery.

  8. CPB time (min)

    Time frame: intraoperative

    Cardiopulmonary bypass time in minutes

  9. Aortic cross clamping time (AoX time, min)

    Time frame: intraoperative

    Aortic cross clamping time in minutes

  10. heparin (IU)

    Time frame: intraoperative

    Dosing of heparin in international units

  11. protamin (mg)

    Time frame: intraoperative

    dosing of protamin

  12. Activated Clotting Time (ACT, min)

    Time frame: intraoperative

    ACT in minutes

  13. Temperature (celsius)

    Time frame: 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.

    Temperature in celsius

  14. Oxygen saturation (Sat, %)

    Time frame: 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.

    Oxygen saturation in %

  15. Urine production (ml)

    Time frame: 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

  16. Blood pressure (mmHg)

    Time frame: 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)

  17. Noradrenaline infusion

    Time frame: 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 (mcg/kg/min)

  18. Phenylephrine

    Time frame: 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 (mcg)

  19. Vasopressin (IU/min)

    Time frame: 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)

  20. Methylene Blue (mg)

    Time frame: 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)

  21. Lactate (mmol/L)

    Time frame: 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.

    Serum lactate

  22. Creatinin levels (umol/L)

    Time frame: 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.

    serum creatinin level

  23. estimated glomerular filtration rate (eGFR, ml/min/1,73 m2)

    Time frame: 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.

    estimated glomerular filtration rate

  24. Blood product use

    Time frame: Intraoperative and up to 24 hours postoperative

    Blood product use (ml)

  25. Blood loss (ml)

    Time frame: T4, 15-30 min after arrival on the intensive care unit; T5, 24 hours after arrival on the intensive care unit

    Blood loss

  26. Duration of mechanical ventilation (hours)

    Time frame: Postoperative until 30 days postoperative

    Duration of mechanical ventilation (hours)

  27. ICU stay (hours)

    Time frame: Postoperative until 30 days postoperative

    ICU stay (hours)

  28. Hospital stay (days)

    Time frame: Postoperative until 30 days postoperative

    Days until hospital discharge (days)

  29. Acute Kidney injury (AKI)

    Time frame: Postoperative until 30 days postoperative

    Acute kidney injury (yes/no)

  30. Respiratory failure

    Time frame: Postoperative until 30 days postoperative

    Respiratory failure (yes/no)

  31. Pneumonia

    Time frame: Postoperative until 30 days postoperative

    Pneumonia (yes/no)

  32. non-preexisting atrial fibrillation

    Time frame: Postoperative until 30 days postoperative

    non-preexisting atrial fibrillation (yes/no)

  33. re-do surgery

    Time frame: Postoperative until 30 days postoperative

    re-do surgery (yes/no)

  34. Extra corporeal membrane oxygenation (ECMO)

    Time frame: Postoperative until 30 days postoperative

    Extra corporeal membrane oxygenation (yes/no)

  35. Mortality

    Time frame: Postoperative until 30 days postoperative

    In-hospital mortality (yes/no)

  36. Sodium (mmol/L)

    Time frame: 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.

    Serum sodium

  37. Potassium (mmol/L)

    Time frame: 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.

    Serum potassium

  38. Calcium (mmol/L)

    Time frame: 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.

    Serum calcium

  39. Chloride (mmol/L)

    Time frame: 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.

    Serum chloride

  40. Bicarbonate (mmol/L)

    Time frame: 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.

    Serum bicarbonate

  41. CO2 (kPa)

    Time frame: 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.

    Carbon dioxide pressure in plasma

  42. O2 (kPa)

    Time frame: 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.

    Oxygen pressure in plasma

  43. pH

    Time frame: 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.

    Measurement of hydrogen ions in plasma

Sponsors and collaborators

Lead sponsor

Amsterdam UMC, location VUmc

Other

Registry information

Official study title

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

Acronym: PRIME

Important dates

Study start
2023
Primary completion
2024
Study completion
2024
First posted
Dec 12, 2022
Registry last updated
Mar 27, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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