Reduced Plasma Volume Response to Crystalloid Fluid in Goal‑Directed Fluid Therapy

• In ICU
• Wed, 25 Jun 2025

Anaesthetists use fluids and drugs during surgery to maintain adequate tissue perfusion pressure and oxygenation. Goal-directed therapy (GDT) is a strategy aimed at optimising cardiovascular function and organ perfusion during the perioperative period by closely monitoring haemodynamic parameters such as cardiac output (CO), blood pressure, oxygen saturation, and fluid responsiveness indicators like stroke volume variation (SVV) or pulse pressure variation (PPV). The objective of GDT is to tailor interventions such as fluid administration, vasopressors, and inotropes based on these monitored parameters to achieve optimal tissue oxygen delivery.

Saugel et al. highlight that the most commonly targeted variables in GDT protocols are dynamic preload variables (e.g., PPV, SVV) and blood flow variables. They also note that GDT is a broad term encompassing different haemodynamic management strategies, but individualised fluid administration is central to most approaches. 
 

A common GDT practice involves repeated fluid bolus infusions (fluid challenges) to increase cardiac preload and test fluid responsiveness, defined as a stroke volume increase of ≥10%. If a patient is non-responsive, further boluses are withheld. This technique relies on the assumption that each standardised bolus expands plasma volume consistently, enabling reliable interpretation of stroke volume responses.

A significant shift in clinical practice over the past decade has been the replacement of colloid solutions (e.g., hydroxyethyl starch, HES) with crystalloid fluids for these boluses, driven by concerns about kidney injury linked to HES in septic patients. However, crystalloids and colloids differ markedly in their pharmacokinetics: colloids remain longer in circulation with minimal distribution losses, whereas crystalloids distribute rapidly out of the vascular space. This raises concerns that sequential crystalloid boluses may not produce consistent plasma volume expansion, thus undermining the reliability of fluid responsiveness testing in GDT protocols.

To better understand these effects, a recent study used pharmacokinetic modelling based on previous fluid administration data to compare plasma and blood volume expansions resulting from repeated fluid boluses of crystalloid versus colloid. The primary hypothesis was that the plasma volume expansion achieved by multiple boluses depends on the fluid’s pharmacokinetic profile. A secondary hypothesis was that crystalloid use would produce lower peak plasma volume expansion and greater variability between boluses compared to colloid. The study also examined how maintenance fluid infusions and surgical blood loss influence plasma volume changes during fluid challenges.

The analysis was based on a database of 103 intravenous infusion experiments in humans. Approximately 1.5 litres of Ringer’s acetate or lactate was infused over 30 to 60 minutes in patients undergoing various surgeries, including laparoscopic cholecystectomies, laparoscopic gynaecologic resections, thyroid surgeries, open gastrointestinal operations, and open hysterectomies. Patient positioning varied depending on the surgery type, with some in Trendelenburg or reverse Trendelenburg positions and others in a flat recumbent position. Minimal surgical bleeding occurred during data collection, and no patients underwent dehydration, blood withdrawal (other than sampling), or received adrenergic drugs. 

Repeated bolus infusions of crystalloid fluid resulted in a progressively reduced plasma volume expansion, with the second and third boluses increasing plasma volume by only 51% and 36% of the first bolus’s effect. This attenuation also occurred when boluses followed a constant-rate crystalloid infusion but was lessened when patients were positioned in Trendelenburg. Surgical bleeding increased plasma volume responses, yet attenuation persisted. In contrast, colloid fluid infusions did not exhibit this attenuation effect.

A key challenge arises when the first crystalloid fluid bolus indicates fluid responsiveness, but subsequent boluses do not. This ambiguity may reflect either that the patient truly lies on the flat part of the Frank-Starling curve (no further preload benefit) or that plasma volume expansion from later boluses is attenuated—too small to meaningfully increase cardiac preload. This dilemma is less likely with colloid fluids because their plasma volume expansion per bolus is more consistent and repeatable, making attenuation less problematic. The attenuation seen with crystalloids may reduce the sensitivity and specificity of dynamic fluid responsiveness measures like PVI, PPV, and SVV, increasing diagnostic uncertainty.

Additionally, the SV measurement following a fluid challenge is affected by the rapid redistribution of crystalloids out of the vascular space. The study’s kinetic model predicts that the plasma volume expansion from a crystalloid bolus is short-lived, with most effects dissipating quickly. Full volume equilibration takes about 30 minutes, but waiting that long is impractical in clinical settings where rapid fluid responsiveness assessment is needed.

The key issue causing attenuation is an acute fluid imbalance between central and peripheral compartments, regardless of whether the patient is dehydrated or hyperhydrated. Even dehydrated patients show similar attenuation patterns after crystalloid infusion. Practically, to compensate for this attenuation when using crystalloids, the volume of the second bolus should be 50% larger than the first, and the third bolus increased by an additional 25%. For a 70-kg patient, achieving equal plasma volume expansion across three boluses requires about 1280 mL of crystalloid versus only 735 mL of colloid. Using identical crystalloid bolus volumes risks overestimating fluid non-responsiveness and results in a shorter duration of haemodynamic effect compared to colloids.

This modelling raises the possibility that replacing colloids with crystalloids for stroke volume optimisation in GDT could influence fluid volumes administered and the use of vasoactive or inotropic drugs to maintain haemodynamics. While it is unclear if this shift reduces the overall efficacy of GDT protocols, it should be considered in evaluating past studies and designing future trials.

The authors recommend that fluid challenges and fluid responsiveness interpretation be more rigorously standardised, not only regarding volume and infusion rate but also in accounting for fluid type effects. They propose that fluid pharmacokinetic analysis may eventually become a valuable clinical tool to better tailor fluid challenges, improve fluid responsiveness assessment, and enhance blood volume management in major surgery patients.

Source: Annals of Intensive Care

Image Credit: iStock 

References:

Hahn RG, O’Brien T (2025) Attenuation of the plasma volume response to crystalloid fluid used for goal-directed fluid therapy. Ann. Intensive Care. 15, 83.