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

Endothelial Dysfunction Clinical Trial

— PRIME part I  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05647057
• Other study ID #: NL82500.029.22, part I
• Status: Recruiting
• Phase: N/A
• Start date: June 15, 2023
• Est. completion date: August 31, 2024

Study information

• Verified date: June 2024
• Source: Amsterdam UMC, location VUmc
• Contact: A.M. Beukers, MD
• Phone: 020-4444444
• Email: a.beukers[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: August 31, 2024
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Endothelial Dysfunction
• Fluid Overload
• Hemolysis

Intervention

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)
• 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)
• 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.

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC, AMC location	Amsterdam	Noord Holland

Sponsors (1)

Lead Sponsor	Collaborator
Amsterdam UMC, location VUmc

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Age	Age in years	Preoperative
Other	Gender	Gender (male/female)	Preoperative
Other	Body Surface Area (BSA)	BSA in m2	Preoperative
Other	Smoking	Medical history of smoking (yes/no)	Preoperative
Other	Diabetes on medication	Medical history of diabetes on medication (yes/no)	Preoperative
Other	Comorbidities	Other comorbidities in medical history (yes/no)	Preoperative
Other	EuroSCORE II	The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II predicts risk of in-hospital mortality after cardiac surgery.	Preoperative
Other	CPB time (min)	Cardiopulmonary bypass time in minutes	intraoperative
Other	Aortic cross clamping time (AoX time, min)	Aortic cross clamping time in minutes	intraoperative
Other	heparin (IU)	Dosing of heparin in international units	intraoperative
Other	protamin (mg)	dosing of protamin	intraoperative
Other	Activated Clotting Time (ACT, min)	ACT in minutes	intraoperative
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	Blood product use	Blood product use (ml)	Intraoperative and up to 24 hours postoperative
Other	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
Other	Duration of mechanical ventilation (hours)	Duration of mechanical ventilation (hours)	Postoperative until 30 days postoperative
Other	ICU stay (hours)	ICU stay (hours)	Postoperative until 30 days postoperative
Other	Hospital stay (days)	Days until hospital discharge (days)	Postoperative until 30 days postoperative
Other	Acute Kidney injury (AKI)	Acute kidney injury (yes/no)	Postoperative until 30 days postoperative
Other	Respiratory failure	Respiratory failure (yes/no)	Postoperative until 30 days postoperative
Other	Pneumonia	Pneumonia (yes/no)	Postoperative until 30 days postoperative
Other	non-preexisting atrial fibrillation	non-preexisting atrial fibrillation (yes/no)	Postoperative until 30 days postoperative
Other	re-do surgery	re-do surgery (yes/no)	Postoperative until 30 days postoperative
Other	Extra corporeal membrane oxygenation (ECMO)	Extra corporeal membrane oxygenation (yes/no)	Postoperative until 30 days postoperative
Other	Mortality	In-hospital mortality (yes/no)	Postoperative until 30 days postoperative
Primary	Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T1: within 5-10 minutes after induction of anesthesia
Primary	Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T2 within 5-10 minutes after aortic cross clamping
Primary	Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T3 within 5-10 minutes after weaning from cardiopulmonary bypass
Primary	Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T4 within 15-30 min after arrival on the intensive care unit
Primary	Perfused vessel density (PVD, mm mm-²)	reflecting microcirculatory diffusion capacity	T5 twenty four (24) hours after arrival on the intensive care unit
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	syndecan-1 (ng/ml)	Concentration of syndecan-1 in plasma	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.
Secondary	heparan sulphate (ng/ml)	concentration of heparan sulphate in plasma	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	fluid balance (mL)	fluid balance	Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative
Secondary	fluid requirements (mL)	Amount of fluids required	Intraoperative during cardiac surgery, postoperative period up to 24 hours postoperative
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Thrombomodulin (ng mL-¹)	Thrombomodulin concentration in plasma	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.
Secondary	Angiopoetin-2 (ng mL-¹)	Angiopoetin-2 concentration in plasma	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.
Secondary	Interleukin-6 (ng mL-¹)	Interleukin-6 concentration in plasma	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.
Secondary	Tumor necrosis factor (TNF-alpha, ng mL-¹)	TNF-alpha concentration in plasma	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.
Secondary	Neutrophil gelatinase associated lipocalin (NGAL, ng mL-¹)	NGAL concentration in plasma	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.
Secondary	Magnesium (mmol L-¹)	Magnesium concentration 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.
Secondary	Phosphate (mmol L-¹)	Phosphate concentration 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.
Secondary	Oxygen delivery (mL min-¹)	Oxygen delivery	During cardiopulmonary bypass
Secondary	Microvascular Flow Index	Microvascular Flow Index, semi-quantitative assessment of the average red blood cell velocity per quadrant	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.
Secondary	De Backer-score	De Backer-score, proxy of total vessel density	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.