^{1–4}whereas technical difficulties explain why less is known about this during surgery.

^{5,6}There is a relative lack of data regarding the influence of anesthetic techniques on volume kinetics in humans. The kinetics of infusion fluids might actually be changed by anesthesia itself.

^{7}Recently, a crystalloid fluid load was followed by excessive extravascular retention during isoflurane anesthesia in sheep.

^{8}Most of the model-predicted elimination of fluid did not appear as urine and was therefore considered to have been sequestrated into body fluid spaces without any functional exchange with the plasma volume. A follow-up study confirmed that these fluid losses were due to isoflurane and not to the mechanical ventilation used during the anesthesia.

^{9}

^{10,11}This term originally denoted an isotope-verified reduction of the extracellular fluid space during surgery which should be replaced by crystalloid fluid to maintain cardiovascular stability. The term

*third space*is sometimes used less strictly today, and therefore, we use the phrase extravascular retention to imply fluid that is functionally unavailable.

#### Materials and Methods

*via*sealed envelopes, to receive one of two methods of anesthesia, isoflurane (n = 15) or propofol (n = 15), both supplemented by fentanyl. One patient in the propofol group was excluded because of excessive blood loss (1,700 ml).

##### Anesthesia

^{−1}· h

^{−1}propofol (Propofol-Lipuro; B. Braun, Melsungen, Germany). Analgesia was ensured by boluses of fentanyl up to 300–500 μg (table 1) and rocuronium as required to maintain a train-of-four less than 25%. To increase anesthetic depth, a bolus injection of fentanyl was the primary intervention rather than an adjustment of the isoflurane or propofol dosage.

^{+}, 4 mm K

^{+}, 2 mm Ca

^{2+}, 1 mm Mg

^{2+}, 110 mm Cl

^{−}, and 30 mm acetate

^{−}). No fluid was infused during the induction of anesthesia or after the 30-min infusion of acetated Ringer’s solution except for the injected anesthetics, which amounted to approximately 17 ml in the isoflurane group and 32 ml in the propofol group. The study period was 150 min, but the anesthesia was prolonged until the protocol was finished in the event that surgery had been completed earlier. The mean operating time was 143 min (table 1).

##### Measurements

##### Volume Kinetic Analysis

Equation 1 Image Tools |
Equation 2 Image Tools |
Fig. 1 Image Tools |

*k*

_{i}is distributed between one central (

*V*

_{1}) and one peripheral (

*V*

_{2}) body fluid space, the sizes of which then increase to

*v*

_{1}and

*v*

_{2}at a later time (

*t*). The net rate of fluid exchange between

*v*

_{1}and

*v*

_{2}is proportional to the relative difference in deviation from

*V*

_{1}and

*V*

_{2}by a constant,

*k*

_{t}(fig. 1). Elimination occurs by virtue of a zero-order parameter,

*k*

_{b}, and a first-order elimination rate constant,

*k*

_{r}. The volume changes in

*v*

_{1}and

*v*

_{2}are described by the following differential equations:

^{2}were fitted to the data from each patient separately by using a nonlinear least-squares regression routine, based on a modified Gauss-Newton method and programmed in the Matlab version 4.2 (The MathWorks, Inc., Natick, MA), which was repeated until no parameter changed by more than 0.001 (0.1%) in each iteration. No weight was applied because the residual errors were constant throughout the range of the studied dilutions. A correction for sampled hemoglobin and surgical losses of hemoglobin was applied (see appendix).

*k*

_{b}and estimating this parameter from the kinetic model. In this case,

*k*

_{r}was taken as the total urinary excretion divided by the area under the curve (AUC), as obtained by the linear trapezoid method, for the dilution–time profile as follows:

*V*

_{1}and the fluid volume eliminated from the kinetic model were based on the numerical solutions to equations 1 and 2. The best estimate of the model parameters (table 2) were inserted into the solutions, which had been programmed into the Matlab software.

^{2}A time-stepping method was then used to generate the predicted dilution–time curve. The volumes of

*v*

_{1}and

*v*

_{2}were taken as the product of the simulated dilution and the baseline volume (

*V*

_{1}or

*V*

_{2}).

*v*

_{1}. The translocation of albumin was taken as the product of the albumin concentration at any time

*t*and the simultaneous difference between the volume of

*v*

_{1}as obtained by the hemoglobin tracer and the volume of

*v*

_{1}as obtained by the albumin tracer.

##### Intracellular Fluid Shift

^{12,13}which is based on a mass balance equation implying that the number of sodium ions (Na) and the water in the extracellular fluid (ECF) remain constant over time except for additions and losses that can be quantified. Because Na is distributed throughout the ECF space, the plasma Na concentration at time (

*t*) during or after an intravenous infusion of fluid (PNa(

*t*)) equals the amount of Na in the ECF volume divided by the current ECF volume. This relation can be expressed as

*t*) is the change in the water content of the intracellular fluid compartment from baseline to time (

*t*). Because ECF corresponds to approximately 20% of the body weight,

^{14}ΔICF could be calculated from the following rearrangement:

##### Statistics

*k*

_{b}by

*P*< 0.01 with 90% confidence,

^{15}the SD for this estimate being 2 ml/min as obtained for sheep.

^{9}Changes were evaluated by repeated-measures analysis of variance, and correlations were evaluated by simple and multiple linear regression, where

*R*

^{2}is the coefficient of determination. The median (interquartile range) was used where distribution was skewed. The Wilcoxon matched-pair test was used for pairwise comparisons, and the Mann–Whitney test was used for nonpairwise comparisons. Incidence data were compared by using the chi-square test.

*P*< 0.05 was considered significant.

#### Results

*vs.*four), but this difference did not reach statistical significance.

##### Volume Kinetic Analysis

*V*

_{1}) of 2.34 l in the isoflurane group and of 2.73 l in the propofol group. The size of

*V*

_{2}was also slightly larger, and the exponential rate constants (

*k*

_{t}and

*k*

_{r}) were higher in the propofol group, but the differences from the isoflurane group were not statistically significant (table 2). However, the actual volume expansion over time, which is obtained as the product of the measured dilution of

*v*

_{1}and the calculated dilution of

*v*

_{2}and their corresponding baseline volumes

*V*

_{1}and

*V*

_{2}, were virtually identical in the isoflurane and propofol groups.

*V*

_{2}(

*P*< 0.02),

*k*

_{t}(

*P*< 0.001), and

*k*

_{r}(

*P*< 0.003, Wilcoxon test; table 2). This implied that albumin molecules entered

*v*

_{1}(fig. 3, right). The translocated amount was approximately 5–6 g, which corresponds to the albumin content of 150 ml plasma.

##### Extravascular Retention

*k*

_{b}during the curve-fitting procedure. This value averaged 2.0 ml (isoflurane) and 2.2 ml (propofol) per minute (table 2), the point estimate for the difference being 0.2 ml/min (95% confidence interval, −1.5 to +2.0). After accounting for minimal evaporation and bled plasma, approximately 160 ml (9% of the infused fluid) no longer participated in the volume equilibration between

*v*

_{1}and

*v*

_{2}at the end of the study and was considered to have been retained extravascularly (fig. 4, top).

*k*

_{r}and

*V*

_{2}, typically when the elimination phase lacked an apparent slope (5 in the isoflurane and 3 in the propofol group). The 21 successful analyses showed that elimination amounted to 681 ml (255–869 ml), 39% (21–58%) of which could be accounted for as urine, with no differences between the groups. When calculated in this way,

*k*

_{b}averaged 2.9 ml/min, corresponding to 435 ml during the 150-min study. After accounting for minimal evaporation and bled plasma, approximately 270 ml (15% of the infused fluid) no longer participated in the volume equilibration between

*v*

_{1}and

*v*

_{2}at the end of the study (fig. 4, middle). Slightly lower values were obtained on excluding those patients who received ephedrine (fig. 4, bottom).

##### Hemodynamics, Urine, and Sodium

*P*< 0.01) and during anesthesia (repeated-measures analysis of variance,

*P*< 0.05; fig. 5, top). The mean arterial pressure was lower during isoflurane anesthesia (

*P*< 0.001; fig. 5, middle).

*P*< 0.001) and low mean arterial pressure during surgery (

*P*< 0.002) accounted for 53% of the interpatient variability in urinary excretion. Patients with a low arterial pressure also tended to have a lower sodium excretion (

*R*

^{2}= 0.32,

*P*< 0.002). The urinary sodium concentration decreased with the urinary osmolality (

*R*

^{2}= 0.46,

*P*< 0.001); this correlation indicates that isotonic urine corresponded to a sodium concentration of 40 mm.

*P*< 0.04, Mann–Whitney test).

##### Nomograms

#### Discussion

*V*

_{2}). However, between 300 and 435 ml of the infused volume could not be accounted for. This figure may seem to be small, considering that it includes fluid losses through accumulation in wounded tissue, breathing, and evaporation from surgical wound and body surfaces as well as bled plasma (sampled plasma was replaced).

*v*

_{1}) and a peripheral (

*v*

_{2}) body fluid space. Eliminated fluid that did not appear as urine was considered to have been “lost” from the kinetic system, by evaporation, bleeding, or sequestration within the body (extravascular retention). By definition, lost fluid was irreversibly removed from

*v*

_{1}, part of which is the sampled plasma.

^{16}The baseline evaporation in adults is usually taken to be 0.5 ml/min,

^{17}or 75 ml of water during the present operations, although the low-flow breathing system reduces evaporation losses from the airway because the circulating gases become saturated with humidity within a few minutes of anesthesia.

^{18}If we assume that exudation into the surgical wound was negligible, between 160 (9%) and 270 ml (15%) of the infused fluid still remains that might be considered to have been retained extravascularly.

^{8,9}The current study contrasts with these findings by the more intravascular distribution of infused fluid and also less extravascular retention. A factor contributing to this difference might be that that both isoflurane and propofol combined with fentanyl induced arterial hypotension in our patients, whereas the blood pressure was unchanged or slightly increased in the animals.

*Isoflurane* versus *Propofol*

^{8,9}If inhaled isoflurane exerts this effect in humans, it would appear as a difference in extravascular fluid retention compared with intravenous (propofol) anesthesia. However, isoflurane was not associated with any greater retention than propofol anesthesia in the current study. When estimated directly as

*k*

_{b}in the kinetic model, the sum of water losses by evaporation and in extravascular fluid retention occurred at a rate of 2.0–2.2 ml/min, or 300–330 ml during the entire study period. The similar results in the groups indicate that isoflurane does not promote extravascular accumulation of fluid in humans undergoing surgery. Slight sequestration of fluid within the body probably occurred as a result of both forms of anesthesia, but even so, it seems to be less pronounced in humans than in sheep.

*V*

_{1},

*k*

_{t}, and

*k*

_{r}during isoflurane anesthesia, which is the same direction in which these parameters change when spinal or general anesthesia is induced.

^{7}Anesthesia with isoflurane, using conventional dosing, caused a larger decrease in arterial pressure than propofol, and these patients also tended to receive ephedrine more often. Isoflurane increases the heart rate by stimulating catecholamine release,

^{19}which might also be relevant. For both forms of anesthesia, however, the plasma dilution was much more pronounced than previously found in awake volunteers (fig. 3, left).

^{20}These factors make it difficult to directly compare the current results with the previous studies in sheep,

^{8,9}but isoflurane does not seem to play a unique role as an anesthetic that increases extravasation during clinical anesthesia, at least not during routine thyroid surgery.

##### Modeling and Fluid Retention

*V*

_{2}and

*k*

_{r}in cases where the terminal part of the elimination curve is close to horizontal. This can be solved by letting

*k*

_{r}be determined by the urinary excretion,

^{21}but this is not justified when extravascular fluid retention is anticipated, as during surgery, because then the model-predicted elimination of fluid is not the same as the urinary excretion. This became an issue when the sum of evaporation and extravascular fluid retention was estimated by our second approach. Completely horizontal elimination curves were sometimes associated with injections of ephedrine, which might have caused a slight upward shift due to the β-adrenergic properties of this drug.

^{22}In the patients without horizontal elimination curves, fluid losses occurred at a rate of 2.9 ml/min, or 435 ml during the study, rather than the average of 2.0–2.2 ml/min, which is based on all patients (table 2). Although open to debate, 435 ml, of which 270 ml represents extravascular fluid retention, is probably the most correct figure. Overall, however, there were only quite limited differences in fluid distribution, depending on how the calculations were made (fig. 4).

^{5}as well as glucose-containing fluid,

^{6}is quite slow during anesthesia. During the current 2.5-h study period, urinary excretion amounted to 11% of the infused volume. By comparison, healthy volunteers excrete between 43% and 75% of an isotonic fluid load within 3-4 h after starting an infusion.

^{3,23,24}Despite the fact that additional fluid losses occurred as a result of evaporation and extravascular fluid retention, the poor urine output explains why the patients, even with a small blood loss, attained a long-lasting hemodilution after fluid therapy was completed. From a practical point of view, the slow elimination reduced the need for liberal crystalloid infusion during both forms of anesthesia, and only 7 ml/min would be necessary to maintain a steady state plasma dilution of 10% (fig. 6).

##### Protein Transport

*v*

_{1}. In the current study, the difference in volume kinetics based on hemoglobin and albumin was used to indicate the direction and possibly also the magnitude of the translocation of albumin.

^{25}which might be mediated by the atrial natriuretic peptide.

^{26,27}Such extravasation of albumin can be indicated as a greater plasma dilution when measured by serum albumin as compared with hemoglobin.

^{2}During both isoflurane and propofol anesthesia in humans, however, the hemoglobin–albumin gradient was reversed. Our data indicate that, despite a marked dilution of the serum albumin concentration, there was a net transport

*from*the interstitial space

*to*plasma (fig. 3). Translocation of albumin in this direction is more consistent with the capillary refill after hemorrhage.

^{28,29}Perioperative blood loss was hardly the cause, however, because bled volumes were small. Furthermore, the albumin–hemoglobin gradient in fractional dilution was much greater in the current study than in experimental hemorrhage in volunteers followed by infusion of acetated Ringer’s solution.

^{24}Increased lymph flow could boost the albumin content of plasma after hemorrhage, but this seems to be a later phenomenon.

^{30}Anesthesia

*per se*and the reduction of the arterial pressure are more likely causes.

^{5}This endogenous plasma dilution was excluded from all further calculations because it may represent an adaptation of the plasma volume to a new baseline due to the hypotension. Interestingly, the percentage reduction of hemoglobin and serum albumin were almost identical from before to after the induction (table 1), but the plasma dilution based on hemoglobin was 40% greater because the percentage reduction should be divided by (1 − hematocrit). This indicates that albumin was translocated to the plasma also during the induction of anesthesia.

##### Sodium

^{12}However, the sodium balance has also been applied to nearly isotonic solutions

^{13}and corroborated volume kinetic results obtained during intravenous administration of glucose solution.

^{6}The model is based on the assumption that sodium ions are evenly distributed throughout the extracellular space, whereas evaporation losses create a false indication of intracellular volume expansion by increasing serum sodium (see equation 5). The current results show that no significant fluid shifts occurred between the extracellular and intracellular spaces, and the 2–3 ml/min that was detected as the sum of evaporation and extravascular retention of fluid can hardly have accumulated intracellularly.

^{13}but this effect does not become apparent in the current study because of the small urinary excretion. The body normally excretes urine with a much lower sodium concentration than near-isotonic saline, and the linear relation between urinary sodium and urinary osmolality,

^{13}which was also observed in the current study, suggests that the urine must be quite concentrated before acetated Ringer’s solution can be excreted without being coupled with sodium retention. This probably contributes to the protracted difficulties connected to excreting a crystalloid volume load (up to 1 week) that has been reported after colonic surgery.

^{31}

#### Conclusion

##### Appendix

##### Hemoglobin-derived Plasma Dilution

*v*

_{1}(

*t*) −

*V*

_{1})/

*V*

_{1}. The reference equation for this relation is

*v*

_{1}is the size of the expanded central body fluid space,

*V*

_{1}is the same body fluid space at baseline, Hct is the hematocrit, and Hb is the hemoglobin concentration in whole blood. Symbols without an index denote baseline values, and (

*t*) indicates those obtained at a later point in time.

Equation (Uncited) Image Tools |
Equation (Uncited) Image Tools |
Equation (Uncited) Image Tools |

*et al.*,

^{32}from which losses are subtracted, and the expanded blood volume is then obtained at a later time (BV(

*t*)):

Equation (Uncited) Image Tools |
Equation (Uncited) Image Tools |

Equation (Uncited) Image Tools |
Equation (Uncited) Image Tools |

*t*)). Thus, the dilution of

*V*is calculated as

*t*) in the reference equation, whereas the inverse relation is used when the calculations use an assumed blood volume based on the weight and height of the subjects.

##### Albumin Dilution

Equation (Uncited) Image Tools |
Equation (Uncited) Image Tools |
Equation (Uncited) Image Tools |

Equation (Uncited) Image Tools |

*V1*based on the serum albumin concentration between baseline (no index) and time (

*t*) were the following, in which Malbumin is the albumin mass: Cited Here...