Optimization of prime fluid strategy to preserve microcirculatory perfusion during cardiac surgery with cardiopulmonary bypass

Acute microcirculatory perfusion disturbances is common in critical illness and
associated with increased morbidity and mortality. Recent findings by our group
showed that microcirculatory perfusion is disturbed during cardiac surgery with
cardiopulmonary bypass (CPB) and remain disturbed up to 72 hours after surgery.
This disturbed microcirculation is associated with organ dysfunction induced by
cardiac surgery using CPB, which is frequently seen (up to 42%) and results in
a 6-fold increase in mortality rate. The underlying cause of disturbed
microcirculation is an increase of endothelial permeability and vascular
leakage and are a consequence of systemic inflammation, hemodilution,
hypothermia and hemolysis. To increase the knowledge regarding disturbed
microcirculation we 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.

Non-substantial amendment (Oct 18, 2023)
Metabolic acid-base derangement is a known complication of cardiac surgery with
cardiopulmonary bypass. Previous investigations have assessed the effects of
different priming crystalloids on post-surgery metabolic acid-base status.
Crystalloid priming fluid unequivocally cause a dilution of plasma albumin and
a corresponding hyperchloraemic acidosis. This is problematic as it may lead to
persistent acid-base abnormalities, especially in the context of renal
(microcirculatory) dysfunction. The effects of priming strategies with colloids
on post-surgical acid-base status and resolution has not been assessed. In this
study, these effects may be readily and adequately characterized using
Stewart*s physicochemical analysis method on previously collected plasma
electrolytes.

Amendment (Feb 26, 2024)
1. Randomisation of trial subjects into 3 groups (groups A/B/C) will be
conducted via Castor in a 1:1:1 ratio with block sizes of 3/6/9. Due to
exclusion of patients prior to the surgery date, but after inclusion and
randomisation, a skewed distribution has occurred in the groups. The reason
patients were excluded in this manner is that the surgery date was rescheduled
or patients opted for a different procedure (e.g., PCI instead of CABG). The
cause of the skewed distribution among the groups is that Castor does not
account for exclusions, despite participants being indicated as excluded in
Castor. Therefore, we will continue to include participants until the sample
size per arm reaches 10 participants.
2A. Addition of oxygen delivery as a secondary endpoint. Recent literature
indicates that low oxygen delivery during cardiopulmonary bypass is associated
with the development of acute kidney injury postoperatively. However, there is
no literature comparing the level of oxygen supply, measured in oxygen
delivery, between patients undergoing cardiopulmonary bypass with different
priming fluids. Oxygen delivery, calculated through previously determined blood
gas analysis and the flow rate during bypass, will be determined during CPB.
The results are exploratory, considering the power analysis was conducted on
the primary endpoint.
2B. Adding biomarkers (endothelial, inflammation, and renal function). It has
been shown in the literature that the destruction of the glycocalyx, an
important component of the microvasculature, is less when albumin is used as a
fluid (Cardiovasc Res 2010;87:300-310, Transplantation 2009;87:956-965, J Extra
Corpor Technol 2017; 49:174-171). Additional biomarkers are being measured to
assess the potential effect of the priming fluid on endothelial, inflammation,
and renal function through biomarkers.

Non-substantial amendment (24-07-24)
Adding secondary endpoints related to acid-base status before, during, and
after CPB when using three different colloid priming strategies: A. The
infusion of crystalloids, priming fluids, and cardioplegia during
cardiothoracic procedures can lead to acid-base disturbances. Colloids,
particularly albumin, serve as a buffer function in plasma. However, there is
no literature describing the effects of various colloid priming fluids on the
occurrence and course of acid-base disturbances. The existence or induction of
acid-base disturbances may also be an independent risk factor for the
development and maintenance of microcirculatory abnormalities, due to changes
in electrical and osmotic transmembrane gradients (such as the Gibbs-Donnan
equilibrium). Calculating acid-base endpoints only requires determining sodium,
potassium, magnesium, calcium, albumin, bicarbonate, chloride, lactate, and
phosphate at predefined measurement points. Additionally, markers of renal
damage, such as creatinine, will be included in the statistical model, as they
may interact with the occurrence of acid-base disturbances. Multivariate
testing will also assess whether the degree of acid-base disturbances is
independently associated with microcirculatory abnormalities.

- Part I: determine the difference in microcirculatory perfusion between three
different prime fluid strategies in patients undergoing elective cardiac
surgery with cardiopulmonary bypass.
- Part II: To determine the effect of limiting hemodilution and hemolysis on
reduction of CPB induced microcirculatory perfusion disturbances in cardiac
surgery.

Two randomized controlled trials, double blind

- Part I: Prime fluid strategies containing gelofusine and ringers (A), albumin
and ringers (B) or ringers with retrograde autologous priming (C).
- Part II: The best prime fluid to preserve microcirculatory perfusion from
Part I combined with either administration of additional human albumin (T) or
ringers (C) during CPB.

The investigation of the effect of different prime fluid strategies on
microcirculatory perfusion is justified because it serves a greater social
interest in relation to the load and the risks. The different priming
strategies are used by various centers in the Netherlands as standard care,
whereby the standards of safe cardiac surgery are met in the Netherlands. It is
of greater importance to investigate whether the priming strategy can
contribute to the prevention of microcirculatory dysfunction during cardiac
surgery. In addition, whether the effect of hemolysis can be reduced to prevent
microcirculatory dysfunction. With both pieces, we hope to gain insight into
reducing microcirculatory dysfunction to improve organ perfusion during cardiac
surgical procedures and preserve organ function. It can also contribute to an
evidence-based protocol for priming strategies in cardiac surgical care.