Main findings
This report provides a mathematical description of what happens to the fluid distribution when anesthesia is induced in the middle of a continuous crystalloid infusion. The most apparent effect consists of a marked reduction in the rate constant that governs the distribution of infused fluid (k12) from the central fluid space (Vc, the plasma) to the extravascular space.
The change is probably an illustration of the classical Starling equation, which holds that the transcapillary exchange of fluid is determined by the balance between hydrostatic and oncotic forces across the capillary wall. A lowered crude MAP is likely to decrease the intravascular hydrostatic pressure. This, in turn, would reduce the capillary filtration because the interstitial hydrostatic pressure remains unchanged.
The elimination rate constant that describes urinary excretion (k10) also decreased and to an even greater extent than was observed for the distribution. Both reductions were proportional to the anesthesia-induced decrease in MAP, as shown in Fig. 2D and illustrated in Fig. 3.
Clinical implications
A dependency of the plasma volume expansion on MAP was observed previously in the papers underlying this work (Ewaldsson and Hahn, 2001; 2005; Li et al., 2007). However, the present population kinetic analysis of the pooled data provides a more precise understanding of this relationship. This is achieved by allowing simulations to be made that predict how variations in MAP and the amount and rate of infused fluid affect changes in Hb and the plasma volume expansion.
The following example, based on mass balance calculations (Ho et al., 2017), illustrates the influence of the reported fluid retention as compared to the conventional view of how fluid affects the blood Hb concentration. A widely cited relationship holds that infusion of 1 L of crystalloid increases the blood volume by 150 mL (Jacob et al., 2012), which would reduce blood Hb from 150 g/L to 144 g/L if the baseline blood volume is 5 L. Based on the relationships presented here, infusion of the same amount over 30 min during the induction of anesthesia would reduce Hb to 129 g/L if the MAP is 70 mmHg; i.e., 3.5 times more. Hence, marked Hb changes occur even without hemorrhage when MAP is modulated by regional or general anesthesia.
Some of this difference is not due to MAP but to the fact that crystalloid fluid shows a distribution function that requires 25–30 min for completion. In the example above, as much as 83% of the infused volume remains in the blood, and the patient will be close to being anuric if the anesthesia reduces MAP to 70 mmHg (Fig. 3). However, induction of general or regional anesthesia with unchanged MAP was still associated with a plasma volume expansion amounting to 50% of a Ringer’s infusion over 30 min. This confirms previous findings in volunteers (Hahn, 2010) and is 3 times greater than after the infusion is completed (Jacob et al., 2012).
The excessive intravascular accumulation of infused fluid during induction of anesthesia reduces the blood Hb level more than is expected, and this is relevant for perioperative medicine. For example, the drop in Hb will decrease oxygen delivery if it is unmatched by an increase in the stroke volume. Furthermore, a pre-set Hb used as transfusion trigger will be reached more rapidly than is indicated by the surgical blood loss.
The increased plasma volume expansion due to the MAP-dependent decrease in k12 is likely to remain until the intravascular hydrostatic pressure has increased sufficiently to reach a new Starling equilibrium, and this increase requires a vasoconstrictor, capillary refill, or additional infusion of fluid. The k10 value is known to remain low, despite adequate volume compensation, as long as MAP is low, but the normal value is resumed when the patient awakens from the anesthesia (Hahn, 2020).
Kinetic analysis
Several variables were evaluated that did not receive sufficient strength to be included in the kinetic model. For example, ephedrine administration had only an indirect effect via MAP on the kinetic parameters. Previous work has shown that buffered Ringer’s solution undergoes a more rapid turnover in young subjects than in aged subjects, but the current age span was probably too narrow to distinguish that relationship. No differences in fluid kinetics were found between patients who received spinal, epidural, or general anesthesia. The crude MAP, and not the change from baseline, governed the fluid kinetics, just as occurs during ongoing surgery (Hahn, 2017).
A thorough evaluation was made to determine whether a normal k12 was resumed after a certain amount of fluid had been infused. However, no such “turning point” was found. The reason is probably that the infusion of 1.1 L of Ringer’s did not fill up the vasodilated cardiovascular system sufficiently to allow a resumption of the normal exchange of fluid with the extravascular space. In a previous study, this “turning point” was reached when 16.6 mL kg− 1 of Ringer’s (1.25 L) had been administered (Hahn and Nemme, 2020). This probably corresponds to the anesthesia-induced expansion of the part of the blood volume that is sometimes called “unstressed” and which denotes the amount of venous blood that does not increase the transmural pressure (Gelman, 2008).
Current versus previous models
The excessive accumulation of infused Ringer’s solution during the onset of regional anesthesia was first studied by linear regression and reported in the early 1990s (Hahn, 1992). A later study showed that the decrease in MAP appears a few minutes before the increased hemodilution, and this finding clarified the order of events (Drobin and Hahn, 1996). Subsequent analyses of the fluid kinetics during induction of anesthesia applied a clearance version with a single inter-compartmental clearance parameter (Li et al., 2007), but this is problematic because the Starling forces are changed in the middle of the experiment. The present population kinetic model separates the flows in and out of the plasma volume and shows clearly that no return of fluid to the plasma occurs during the onset of anesthesia as long as fluid loading is ongoing.
The current model also uses micro-constants instead of clearances, which makes it independent of plasma volume and body fluid volumes. The micro-constant model detects a “wall” between a central space, where fluid equilibrates very rapidly with the site of infusion, and a more remote peripheral space. The space with this fast equilibration is very likely to represent the plasma volume contained in blood vessels that are allowed to expand. The exchange of infused fluid between these two body fluid spaces is determined by rate constants (k12 and k21). The volume of the infused fluid residing in the two body fluid spaces is obtained directly in the micro-constant model, while their dilution must be multiplied by the volume of distribution to obtain volume expansion in the clearance model.