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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Endothelial Dysfunction, Hemolysis, Fluid Overload

Intervention / Treatment
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* Combination Product: A: gelofusine + ringers
* Combination Product: B: albumine + ringers
* Combination Product: C: ringers + retrograde autologous priming


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A: gelofusine + ringers<br>Prime fluid strategy containing gelofusine and ringers | Combination Product: A: gelofusine + ringers<br>* 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)<br>|
| Active Comparator: B: albumin + ringers<br>Prime fluid strategy containing albumin and ringers | Combination Product: B: albumine + ringers<br>* 200 mL human albumin (20%, Sanquin, Amsterdam, Netherlands), 1200 mL Ringer's solution (Baxter, Utrecht, Netherlands) and 100 mL mannitol (15%, Baxter, Utrecht, Netherlands)<br>|
| Active Comparator: C: ringers + retrograde autologous priming<br>Prime fluid strategy containing ringers combined with retrograde autologous priming | Combination Product: C: ringers + retrograde autologous priming<br>* 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.<br>|

What is the study measuring?
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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. | 
| 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 | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microcirculation, Cardiopulmonary bypass, Colloid oncotic pressure, Hemodilution, Hemolysis