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

• Sponsor: Amsterdam UMC, location VUmc (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05647057
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 3
• Anticipated Duration (Months): 24
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Endothelial Dysfunction; Hemolysis; Fluid Overload	Combination Product: A: gelofusine + ringers; Combination Product: B: albumine + ringers; Combination Product: C: ringers + retrograde autologous priming	N/A

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 Design

• Study Type: Interventional
• Anticipated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: In two consecutive randomized controlled trials, the investigators study the effect of prime fluid strategies on perfused vessel density (part I) and the effect of additional albumin during cardiopulmonary bypass compared with ringers on perfused vessel density (part II). In this study part (I), the effect of prime fluid strategies on perfused vessel density.In two consecutive randomized controlled trials, the investigators study the effect of prime fluid strategies on perfused vessel density (part I) and the effect of additional albumin during cardiopulmonary bypass compared with ringers on perfused vessel density (part II). In this study part (I), the effect of prime fluid strategies on perfused vessel density.
• Masking: Double (Participant, Investigator)
• Masking Description: Single blind, masked to observer
• Primary Purpose: Treatment
• Official Title: Optimization of Prime Fluid Strategy to Preserve Microcirculatory Perfusion During Cardiac Surgery With Cardiopulmonary Bypass
• Anticipated Study Start Date: Jan 15, 2023
• Anticipated Primary Completion Date: Jul 15, 2024
• Anticipated Study Completion Date: Jan 15, 2025

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Perfused vessel density (PVD, mm mm-²) [T1: within 5-10 minutes after induction of anesthesia]

   reflecting microcirculatory diffusion capacity

2. Perfused vessel density (PVD, mm mm-²) [T2 within 5-10 minutes after aortic cross clamping]

   reflecting microcirculatory diffusion capacity

3. Perfused vessel density (PVD, mm mm-²) [T3 within 5-10 minutes after weaning from cardiopulmonary bypass]

   reflecting microcirculatory diffusion capacity

4. Perfused vessel density (PVD, mm mm-²) [T4 within 15-30 min after arrival on the intensive care unit]

   reflecting microcirculatory diffusion capacity

5. Perfused vessel density (PVD, mm mm-²) [T5 twenty four (24) hours after arrival on the intensive care unit]

   reflecting microcirculatory diffusion capacity

Secondary Outcome Measures

1. Colloid oncotic pressure (COP, 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.]

   colloid oncotic pressure in plasma

2. albumin (g L-¹) [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) [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) [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. NO consumption (μmol L-¹) [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.]

   consumption of nitric oxide in plasma

6. syndecan-1 (ng/ml) [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 syndecan-1 in plasma

7. heparan sulphate (ng/ml) [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 heparan sulphate in plasma

8. hemoglobin (Hb, mmol L-¹) [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

9. hematocrit (Ht, L L-¹) [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

10. perioperative use of packed red blood cells (PRBCs, mL) [Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative]

    amount of packed red blood cells

11. fluid balance (mL) [Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative]

    fluid balance

12. fluid requirements (mL) [Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative]

    Amount of fluids required

13. Total vessel density (TVD, mm mm-²) [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

14. Proportion of perfused vessels (PPV, %) [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. Heterogeneity index [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

Other Outcome Measures

1. Age [Preoperative]

   Age in years

2. Gender [Preoperative]

   Gender (male/female)

3. Body Surface Area (BSA) [Preoperative]

   BSA in m2

4. Smoking [Preoperative]

   Medical history of smoking (yes/no)

5. Diabetes on medication [Preoperative]

   Medical history of diabetes on medication (yes/no)

6. Comorbidities [Preoperative]

   Other comorbidities in medical history (yes/no)

7. EuroSCORE II [Preoperative]

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

8. CPB time (min) [intraoperative]

   Cardiopulmonary bypass time in minutes

9. Aortic cross clamping time (AoX time, min) [intraoperative]

   Aortic cross clamping time in minutes

10. heparin (IU) [intraoperative]

    Dosing of heparin in international units

11. protamin (mg) [intraoperative]

    dosing of protamin

12. Activated Clotting Time (ACT, min) [intraoperative]

    ACT in minutes

13. Temperature (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.]

    Temperature in celsius

14. Oxygen saturation (Sat, %) [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) [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) [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 [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 [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) [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) [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) [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) [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) [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 [Intraoperative and up to 24 hours postoperative]

    Blood product use (ml)

25. Blood loss (ml) [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) [Postoperative until 30 days postoperative]

    Duration of mechanical ventilation (hours)

27. ICU stay (hours) [Postoperative until 30 days postoperative]

    ICU stay (hours)

28. Hospital stay (days) [Postoperative until 30 days postoperative]

    Days until hospital discharge (days)

29. Acute Kidney injury (AKI) [Postoperative until 30 days postoperative]

    Acute kidney injury (yes/no)

30. Respiratory failure [Postoperative until 30 days postoperative]

    Respiratory failure (yes/no)

31. Pneumonia [Postoperative until 30 days postoperative]

    Pneumonia (yes/no)

32. non-preexisting atrial fibrillation [Postoperative until 30 days postoperative]

    non-preexisting atrial fibrillation (yes/no)

33. re-do surgery [Postoperative until 30 days postoperative]

    re-do surgery (yes/no)

34. Extra corporeal membrane oxygenation (ECMO) [Postoperative until 30 days postoperative]

    Extra corporeal membrane oxygenation (yes/no)

35. Mortality [Postoperative until 30 days postoperative]

    In-hospital mortality (yes/no)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Amsterdam UMC, AMC location	Amsterdam	Noord Holland	Netherlands	1105AZ

Sponsors and Collaborators

• Amsterdam UMC, location VUmc

Investigators

• Principal Investigator: A.B.A. Vonk, MD, PhD, Cardiothoracic surgeon

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alexander B.A. Vonk, Cardiothoracic surgeon, Principle Investigator, doctor., Amsterdam UMC, location VUmc
• ClinicalTrials.gov Identifier: NCT05647057
• Other Study ID Numbers: NL82500.029.22, part I
• First Posted: Dec 12, 2022
• Last Update Posted: Dec 12, 2022
• Last Verified: Dec 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Alexander B.A. Vonk, Cardiothoracic surgeon, Principle Investigator, doctor., Amsterdam UMC, location VUmc: Microcirculation; Cardiopulmonary bypass; Colloid oncotic pressure; Hemodilution; Hemolysis
• Additional relevant MeSH terms: Hemolysis; Polygeline

Study Results

No Results Posted as of Dec 12, 2022