A Cross-over Randomized Controlled Trial; Pulmonary edema detection after fluid loading with blood versus saline in patients after CABG

Transfusion associated cardiac overload (TACO) is now considered the leading
cause of transfusion*related mortality in Europe. TACO is defined in terms of
clinical characteristics. The International Society of Blood Transfusion
defined TACO as the onset of any four of the following symptoms which occur
within six hours of transfusion: acute respiratory distress, tachycardia,
increased blood pressure, acute or worsening pulmonary edema and or evidence of
positive fluid balance. Other definitions use similar markers such as bilateral
infiltrates, ultrasound of the heart, pulmonary wedge pressure or a history of
cardiac decompensation.

The pathophysiology of TACO is poorly understood; current literature describes
TACO as hydrostatic pulmonary edema due to volume overload. This seems
unlikely, since 20% of TACO occurs after only one transfused unit. Moreover,
differences in the incidences of TACO after red blood cell (RBC) compared to
plasma transfusion cannot be explained. Our hypothesis is that the pathogenesis
is a *two hit**entity: the *first hit* is an underlying condition (e.g. cardiac
failure or acute kidney injury) resulting in poor compliance to fluid loading *
the *second hit* being a transfusion. This may explain why especially
critically ill patients are at risk. Furthermore, we hypothesize that TACO is a
combination of hydrostatic pulmonary edema (overload) and pulmonary edema by
protein leakage following exposure to mediators in different types of blood
products (a mechanism similar to transfusion related acute lung injury).

It is paramount to understand the pathophysiology of TACO, as currently no
evidence-based therapy exists for this life-threatening syndrome.

Cardiac surgery patients are often exposed to blood products perioperatively
(18). Due to their underlying cardiac condition and ventricular dysfunction
these patients are at an increased risk for TACO.(19) In a *proof of principle*
approach we will determine whether TACO is solely volume overload or arises
from a combination of volume overload and capillary leakage, by investigating
the difference in change in volume parameters and capillary leakage after
autologous transfusion or saline infusion. Furthermore, we will investigate the
effect of fluid loading on the microcirculation.

Open-label, prospective cross-over randomized controlled trial.

Patients will be allocated to either infusion of 300mL saline with a subsequent
autologous RBC (cell saver) transfusion of 300 mL at a rate of 10mL/min, or the
same in the reversed order. Prior to start of the intervention, 15 minutes
following start of infusion and a the end of infusion, we will measure wedge
pressure (PCWP), as well as extravascular lung water index (EVLWI) and CO
estimation through PICCO® and Pulmonary Artery Catheter. We will identify fluid
responsiveness by performing a passive leg raise test (PLR). We aim to measure
total vessel density (TVD), perfused vessel density (PVD), proportion of
perfused vessels (PPV), microvascular flow index (MFI), and blood vessel
diameters (Øbv) from the oral microcirculation by CytoCam microscope system. We
will estimate the effective circulating blood and plasma volume through
dilutional infusion of indocyanine green prior to initial infusion, between and
at the end of subsequent infusion. In total 6 times measurements will be
performed.

The study provides no benefits for the participants. The study will include
placement of a Swan Ganz catheter. Central line placement is part of standard
care in cardiac surgery. The placement of a Swan Ganz Catheter depends on
patient category, anaesthesiologist and hospital settings. The application of a
Swan Ganz Catheter may result in a better read out of cardiac function. On the
other hand, some studies find a small increase in catheter related side
effects.