Methylene Blue-Enhanced Ultrafiltration Improves Outcomes After Cardiopulmonary Bypass

NCT07212842 | Completed Phase 2

• 1 other identifier: 2.462.520
• Study Type: interventional
• Target: 124
• Locations: 1 country
• Sites: 1

Brief Summary

Introduction: Fluid overload and systemic inflammation are major contributors to postoperative complications in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Objective: To evaluate the effects of blood washing with methylene blue during zero-balance ultrafiltration (ZBUF) on fluid overload and systemic inflammatory response. Methodology: Fluid status was assessed using the InBody S10 precision bioimpedance device, measuring extracellular water (ECW), total body water (TBW), intracellular water (ICW), and the ECW/TBW ratio. Pulmonary congestion and intravascular volume were evaluated separately using a Philips Lumify S4-1 transducer with a Samsung tablet. Pulmonary congestion was confirmed by the presence of B-lines on lung ultrasound. Intravascular volume was assessed via the inferior vena cava (IVC) distensibility index (DI) during mechanical ventilation and collapsibility index (CI) during spontaneous breathing. Inflammatory cytokine levels were measured using a Luminex xMAP-based multiplex immunoassay.

Conditions

Cardiopulmonary Bypass Surgery; Aortic Valve Surgery; Mitral Valve Surgery; Myocardial Revascularization Surgery With Extracorporeal Circulation

Keywords

Cardiac surgery; water overload; pulmonary congestion; intravascular volemia; cardiopulmonary bypass; zero-balance ultrafiltration; methylene blue

Outcome Measures

Primary Outcomes (3)

• Systemic Inflammation

  To assess systemic inflammation, blood samples were collected via central venous access through the internal jugular vein at five time points: before surgery, during surgery, 10 minutes after cannulation, 10 minutes after blood lavage with methylene blue and ultrafiltration, and 4 hours after ICU admission. Samples were drawn into EDTA-containing syringes (50 mM, pH 8.0) at one-tenth of the total blood volume. Plasma was separated by centrifugation at 1,700 × g for 10 minutes at 4 °C, transferred to new tubes avoiding the buffy coat, and centrifuged again at 11,000 × g for 2 minutes at 4 °C. Plasma was aliquoted and stored at -80 °C. Cytokine concentrations were quantified using a Luminex xMAP multiplex immunoassay (8-27-plex) in triplicate, enabling simultaneous measurement of up to seven cytokines, chemokines, and interleukins from 50 μL plasma.

  Three years

• Water overload

  Fluid balance was meticulously monitored, including fluids removed by conventional ultrafiltration, surgical suction, sponges, and urine output. Discrepancies between infused and removed volumes were corrected using zero-balance ultrafiltration (ZBUF), removing excess fluid or compensating deficits to match preoperative volemic status. For example, if 100 mL more than planned had been removed, only 900 mL were withdrawn. Body fluid composition was assessed with the InBody S10 bioimpedance device. Extracellular water (ECW) was measured at 5 kHz, total body water (TBW) at 250 kHz, and intracellular water (ICW) calculated as TBW-ECW. The ECW/TBW ratio served as the primary parameter to monitor fluid status and detect overload.

  Three years

• Intravascular volume assessment using IVC indices

  Intravascular volume will be evaluated by analyzing mechanical and hemodynamic changes in the inferior vena cava (IVC) using subcostal ultrasound images. The collapsibility index (CI = (IVCmax - IVCmin)/IVCmax) will be used during spontaneous breathing, and the distensibility index (DI = (IVCmax - IVCmin)/IVCmin) during mechanical ventilation. Time Frame: Preoperatively, immediately postoperatively, and 24 hours after surgery. Unit of Measure: Percentage (%).

  Three years

Secondary Outcomes (1)

• Length of stay in the intensive care unit (ICU)

  Three years

Study Arms (3)

Conventional ultrafiltration

ACTIVE COMPARATOR

Conventional ultrafiltration (G-CUF) patients in this group underwent conventional ultrafiltration widely used in cardiac surgery with extracorporeal circulation.

Drug: Methylene Blue; Procedure: Conventional ultrafiltration; Procedure: Zero-balance ultrafiltration

Blood washing with physiological solution combined with zero-balance ultrafiltration

PLACEBO COMPARATOR

Blood washing with physiological solution combined with zero-balanced ultrafiltration (G-ZBUF) patients in this group underwent zero-balanced ultrafiltration, and for this purpose, the simulation was performed with physiological solution.

Drug: Methylene Blue; Procedure: Conventional ultrafiltration; Procedure: Zero-balance ultrafiltration

Methylene blue wash combined with zero-balanced ultrafiltration

EXPERIMENTAL

Methylene blue lavage combined with zero-balance ultrafiltration (MB+G-ZBUF). Patients assigned to this group underwent zero-balance ultrafiltration with concomitant blood lavage using methylene blue at a low dose of 1 mg/kg of body weight. Methylene blue was diluted in 1000 mL of 0.9% saline. An equivalent volume of fluid was simultaneously removed by zero-balance ultrafiltration, ensuring a balanced fluid state throughout the 20-minute procedure. For this purpose, a dedicated circuit was developed to allow simultaneous blood lavage and ultrafiltration. Blood was withdrawn through a dedicated port integrated into the SORIN oxygenator and directed by a centrifugal pump to a small reservoir containing the methylene blue solution. From this reservoir, the blood passed through a hemoconcentrator for filtration before being returned to the central reservoir of the cardiopulmonary bypass (CPB) circuit.

Drug: Methylene Blue; Procedure: Conventional ultrafiltration; Procedure: Zero-balance ultrafiltration

Interventions

Methylene Blue DRUG

This protocol was designed to perform intraoperative blood lavage with methylene blue at the end of surgery, with a duration of 20 minutes. A low dose of 1 mg/kg of body weight was administered. The objective was not to elicit hemodynamic effects, which require higher doses, but rather to exploit the anti-inflammatory and antioxidant properties of methylene blue. Methylene blue was diluted in 1000 mL of 0.9% saline. An equivalent volume of fluid was removed simultaneously by zero-balance ultrafiltration, maintaining a fluid-equilibrium state throughout the 20-minute procedure. For this purpose, a dedicated circuit was developed to enable concurrent blood lavage and ultrafiltration. Blood was withdrawn through a dedicated port integrated into the SORIN oxygenator and directed by a centrifugal pump to a small reservoir containing the methylene blue solution. From this reservoir, the blood passed through a hemoc

Also known as: zero-balance ultrafiltration

Blood washing with physiological solution combined with zero-balance ultrafiltration; Conventional ultrafiltration; Methylene blue wash combined with zero-balanced ultrafiltration

Conventional ultrafiltration PROCEDURE

Conventional ultrafiltration (CUF). CUF during cardiopulmonary bypass (CPB) is performed to remove excess fluid and solutes from the patient's blood during cardiac surgery, thereby limiting fluid accumulation and attenuating pro-inflammatory effects. This technique increases hematocrit, improves cardiopulmonary function, and reduces the need for blood transfusions. Unlike modified ultrafiltration (MUF), which is performed after weaning from CPB, CUF is carried out simultaneously with CPB while the heart-lung machine remains in operation.

Blood washing with physiological solution combined with zero-balance ultrafiltration; Conventional ultrafiltration; Methylene blue wash combined with zero-balanced ultrafiltration

Zero-balance ultrafiltration PROCEDURE

Zero-balance ultrafiltration (Z-BUF). Z-BUF is performed during cardiopulmonary bypass (CPB) to maintain fluid equilibrium by removing plasma water and solutes while simultaneously infusing an equal volume of replacement fluid, thereby achieving a net zero fluid balance. This technique has been shown to decrease urine output, reduce tissue edema and the inflammatory response, improve arterial oxygenation (PaO₂), and lower the need for postoperative blood transfusions.

Blood washing with physiological solution combined with zero-balance ultrafiltration; Conventional ultrafiltration; Methylene blue wash combined with zero-balanced ultrafiltration

Eligibility Criteria

• Age: 20 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Clinical diagnosis of cardiac disease requiring surgery with cardiopulmonary bypass (CPB)
• Age ≥ 18 years
• Ability to provide informed consent

You may not qualify if:

• Chronic renal failure
• Recent cardiac catheterization within the past month
• Planned cardiac surgeries with an estimated CPB time of less than 60 minutes
• Aortic surgery
• Significantly impaired hepatic function

Sponsors & Collaborators

• University of Sao Paulo: lead

Study Sites (1)

University of São Paulo Medical School in Ribeirão Preto

Ribeirão Preto, São Paulo, 14049-900, Brazil

Location

MeSH Terms

Interventions

Methylene Blue

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: The objective of this study was to evaluate the effects of methylene blue blood lavage during zero-balance ultrafiltration (ZBUF) on fluid overload and the systemic inflammatory response. Patients were randomly assigned to one of three groups: conventional ultrafiltration (G-CUF; n = 43), saline blood lavage combined with ZBUF (G-ZBUF; n = 39), and methylene blue lavage combined with ZBUF (MB+G-ZBUF; n = 42). Fluid status was assessed using the InBody S10 precision bioimpedance device, which measured extracellular water (ECW), total body water (TBW), intracellular water (ICW), and the ECW/TBW ratio. Pulmonary congestion and intravascular volume were assessed separately with a Philips Lumify S4-1 transducer connected to a Samsung tablet. Pulmonary congestion was defined by the presence of B-lines on lung ultrasound. Intravascular volume was assessed using the inferior vena cava (IVC) distensibility index (DI) during mechanical ventilation and the collapsibility index (CI) during spontan

Study Record Dates

• First Submitted: September 23, 2025
• First Posted: October 8, 2025
• Study Start: April 12, 2021
• Primary Completion: August 25, 2023
• Study Completion: March 16, 2024
• Last Updated: October 8, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)