The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water (TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment (mainly sodium salts) and in the intracellular compartment (mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume (EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.

Extracellular water (ECW), a relevant molecular level component for clinical assessment, is commonly obtained by 2 methods that rely on assumptions that may not be possible to test at the time the measurements are made.

The aim of the current study was to evaluate the degree of agreement between ECW assessment by the sodium bromide dilution (ECW(NaBr)) and total body potassium (TBK; whole-body (40)K counting) to total body water (TBW; isotope dilution) methods (ECW(TBK-TBW)) in an ethnically mixed group of children and adults.

ECW was measured with the ECW(NaBr) and ECW(TBK-TBW) methods in 526 white and African American males and females (86 nonobese children, 193 nonobese adults, and 247 obese adults). Fat mass was assessed with dual-energy X-ray absorptiometry. Multiple regression analysis was used to examine the variables related to between-ECW method differences.

Significant but generally small group mean (+/-SD) differences in ECW were found in the obese adults (1.28 +/- 2.54 kg) and children (-0.71 +/- 1.78 kg). The magnitude of the differences was related to mean ECW in obese adults, children, and nonobese adults, and the relations between these variables were modified by sex for nonobese adults. ECW differences were also dependent on age, weight, sex, and race or on interactions between these variables.

Overall, although good between-method agreement was found across the 3 groups, the degree of agreement varied according to subject characteristics, particularly at the extremes of ECW and body weight. We advance a possible mechanism that may link subject characteristics with the degree of agreement between ECW measurement methods and their underlying assumptions.

To determine whether impaired cell membrane permeability exists in critically ill patients with "sick cell" type hyponatraemia.

A 36 year old male patient was identified in an intensive care unit (ICU) with liver disease and multi-organ failure. His initial serum sodium (Na) was 101 mmol/L and osmolar gap + 35 mmol/L. A flow cytometric system was used to assess lymphocyte membrane integrity using fluorescein diacetate (FDA) and propidium iodide (PI). Following this, similar studies were carried out in 17 hyponatraemic (Na < 130 mmol/L) and 19 normonatraemic (Na > 136 mmol/L) ICU patients.

Flow cytometry in the index patient showed two clear populations of cells-one was normal (with identical characteristics to a healthy control) and the other had dysfunctional cell membrane integrity. The extended patient series, however, revealed only 2 other patients with similar flow cytometric patterns-one hyponatraemic and one normonatraemic.

Cell membrane studies in the index patient demonstrated supportive evidence for the "sick cell syndrome" in critically ill patients. The extended series revealed that 3/37 (8%) had this abnormality, which was however not consistently associated with hyponatraemia.

Postoperative hyponatremia is a frequent metabolic disturbance that may cause life-threatening complications. It results from both a positive electrolyte-free water (EFW) balance and an antidiuretic hormone release. During surgery, intracellular solutes may leak out of cells because of an increased membrane permeability leading to increased osmolality, cellular water shift, and redistribution hyponatremia, a concept coined the sick cell syndrome. Because of release of osmotically active solutes, plasma or urinary osmolar gap should increase. Therefore, we tested the hypothesis that postoperative hyponatremia may be related to a translocational mechanism evidenced by a postoperative increase of the osmolar gap rather than to a positive EFW balance.

An anesthesiology department in a 1,200-bed university hospital.

A 5-month prospective observational study.

Thirty-three consecutive patients undergoing elective hip arthroplasty under general anesthesia. They were divided into two groups whether the postoperative plasma sodium concentration decrease was > or = 2 mmol/L (group 1) or <2 mmol/L (group 2).

Plasma sodium concentration ([Na+]p) and plasma osmolality were measured before induction of anesthesia and at skin closure. Osmolality was calculated at the same times. Plasma osmolar gap (OG(p)) was calculated as the difference between measured and calculated osmolality. Postoperative urinary osmolar gap (OG(u)) was calculated in the same way. EFW balance was calculated as the ratio of (infused EFW - excreted urinary EFW) to total body water.

In 33 patients, a significant [Na+]p decrease of -2.0 was observed. No relationship was demonstrated between EFW balance and perioperative [Na+]p variation (r =.28; p=.12). A relationship was observed between perioperative OG(p) variation and perioperative [Na+]p variation (r =.74; p<.0001). In the 19 group 1 patients, [Na+]p decreased by -3.0 mmol/L. EFW balance did not differ between group 1 and group 2 patients. No statistical relationship was observed between EFW balance and perioperative [Na+]p variation in group 1 (r =.20; p=.40) and in group 2 (r =.43; p=.14). OG(p) increased only in group 1 but not in group 2 patients, and postoperative OG(u) was greater in group 1 than in group 2 patients. A relationship was observed between perioperative OG(p) variation and perioperative [Na+]p variation in group 1 (r =.53; p=.02) but not in group 2 (r =.32; p=.26).

Hyponatremia after hip arthroplasty may not be related to a positive EFW balance. The postoperative increase of the OG(p) and the greater postoperative OG(u) in patients developing postoperative hyponatremia suggest the release of osmotically active solutes leading to cellular water shift from intracellular to extracellular spaces. These data may support the clinical relevance of the sick cell syndrome in the postoperative context.

Accumulation of nondiffusible solutes in plasma leads to redistribution hyponatremia with an increased osmolar gap (i.e., the difference between measured and calculated osmolality). In critically ill patients, intracellular solutes may leak out of the cell because of an increased membrane permeability and may lead to redistribution hyponatremia with increased osmolar gap, a concept called the "sick cell syndrome." The aims of this prospective study were to determine whether an increased osmolar gap related to endogenous solutes accumulation was present in intensive care patients with true hyponatremia and to identify the solutes accounting for this increased osmolar gap.

A 14-bed medical intensive care unit in an 821-bed university hospital.

A 20-wk prospective observational study.

Fifty-five consecutive patients with a measured plasma sodium concentration <or=130 mmol/L (mean +/- sd, 126 +/- 6 mmol/L) were automatically identified by the Biochemistry Department. Patients were excluded in the case of reduced plasma water content resulting from hyperlipidemia or hyperproteinemia, in the case of hyperglycemia, or if exogenous compounds known to increase the osmolar gap were present.

Plasma osmolar gap was calculated.

Plasma osmolar gap was considered significant if >10 mosm/kg. Total plasma amino acid concentration also was measured. Organ dysfunctions were assessed with the Sequential Organ Failure Assessment. Thirty of the 55 patients (54%) had an osmolar gap >10 mosm/kg (17.2 +/- 7.1 mosm/kg). Sequential Organ Failure Assessment score was significantly higher in the osmolar gap patients (6.4 +/- 3.2 vs. 4.5 +/- 2.0; p =.015). No difference of amino acids concentration was observed between osmolar gap and non-osmolar gap patients, and no correlation was observed between osmolar gap and amino acid concentration. Accumulation of ketone bodies and lactic acid was also unlikely. During correction of hyponatremia in osmolar gap patients, a significant decrease of plasma osmolar gap was observed and a statistically significant inverse relationship was demonstrated between osmolar gap decrease and plasma sodium concentration increase.

Hyponatremia with increased osmolar gap related to endogenous solutes accumulation is observed frequently in hyponatremic intensive care patients, especially in patients with the most severe organ dysfunctions. The nature of the endogenous solutes accounting for the increased osmolar gap remains to be determined. Simultaneous correction of sodium and osmolar gap suggests a causal link between increased osmolar gap and hyponatremia and may support the concept of sick cell syndrome.

There is considerable evidence that the extracellular fluid volume (ECV) may change in disease states or during longitudinal Intervention studies. Therefore, the measurement of ECV is Important for studying body composition in patients and laboratory animals. We present a modified plasma bromide (Br-, non-radioactive) assay using anion-exchange chromatography, in which a small blood sample of 200 microL (100 microL of plasma) appeared to be enough to reproducibly measure ECV. The inter- and intra-assay accuracy of the Br- analysis ranged from -1.6% to 0.9% and from -0.5% to 0%, respectively. The inter- and intra-assay precision ranged from 1.3% to 1.7% and from 0.6% to 1.2%, respectively. This modified precise and accurate Br- analysis in a small blood sample was applied to investigate whether the ECV changed in rats after ovariectomy. Ovariectomy significantly (P < .05) reduced the ECV as compared with results in SHAM rats. This observation indicates that a change in clinical condition may change ECV, which has consequences for the determination of, for example, the fractional absorption and the relative bioavailability of compounds principally distributed through the ECV.

Bioelectrical impedance spectroscopy (BIS) may provide a noninvasive, rapid method for the assessment of total body water (TBW), extracellular water (ECW), and intracellular water (ICW). Few studies, however, have examined the accuracy of BIS in pediatric populations.

Our objective was to evaluate the accuracy of BIS for the measurement of TBW, ECW, and ICW in healthy children.

Dual-energy X-ray absorptiometry (DXA), total body potassium (TBK), and BIS measurements were performed in 347 children (202 males and 145 females aged 4-18 y). The reference values for TBW, ECW, and ICW were defined by using a DXA+TBK model. BIS values were evaluated by using the method of Bland and Altman. A randomly selected calibration group (n = 231) was used to derive new BIS constants that were tested in the remaining group (n = 116).

BIS values were highly correlated with the reference values (r(2) = 0.94-0.97, P < 0.0001), but differences between the BIS and DXA+TBK models for individuals were significant (P < 0.001). Use of new BIS constants reduced the mean differences between the BIS and DXA+TBK models; the SDs of the mean differences were improved (1.8 L for TBW, 1.4 L for ICW, and 1.0 L for ECW) for the total population.

On a population basis, BIS can be calibrated to replace the DXA+TBK model for the assessment of TBW, ECW, and ICW in healthy children. The accuracy of the BIS measurement in individual children may be refined further by using age- and sex-specific adjustments for the BIS calibration constants.

Resting energy expenditure (REE) was investigated by indirect calorimetry in relation to body composition and to different degrees of obesity in order to assess if a defective energy expenditure contributes to extra body fat accumulation. Differences were found between control subjects (group C; BMI 23 +/- 0.5 kg/m2, REE 5890 +/- 218 kJ/day; mean +/- SEM) and obese subjects (group O; BMI 34.2 +/- 0.9 kg/m2, REE 7447 +/- 360 kJ/day; P < 0.0001) and between group C and morbidly obese subjects (group MO; BMI 49.9 +/- 1.6 kg/m2, REE 8330 +/- 360 kJ/day; P < 0.0001); REE was not significantly different between groups O and MO. Body composition data were obtained by means of body impedance analysis. Even though group MO had a fat mass higher than group O, body cell mass, the metabolically active body compartment, was similar in groups O and MO, and this fact may have contributed to the similar REE in the two groups. Multiple regression analysis gave the following equation as the best predictor of REE: REE (kJ/day) = 1591 +/- 49BW + 74BCM - 737G (R2 = 0.88), where BW is body weight, BCM is body cell mass and G is a dummy variable coding group membership (group C = 1; group O = 2; group MO = 3). Thus the analysis showed a negative impact of obesity on REE beyond body composition variables.

The bromide-82 dilution space (extracellular space, ECS) and blood volume (BV) were measured in 21 patients with esophageal and gastric cancer and in 27 patients 18-96 months after total gastrectomy. Resistance (R) and reactance (Xc) from bioelectrical impedance measurements were used to obtain multiple regression equations for ECS and BV. The variables weight, gender, and height 2/Xc were independent predictors of ECS (r = 0.767; P less than 0.0001). Height 2/R and gender were predictors of blood volume (r = 0.856; P less than 0.0001). The mean difference between the Br space and the ECS predicted from impedance measurements was 0 +/- 1.54 (mean +/- SD). The limits of agreement (+/- 2 SD) were therefore +/- 3.08 l or 19.6% of the mean Br space of 15.7 l. The limits of agreement for BV were +/- 789 ml or +/- 19.7% of the average BV of 4008 ml. It is concluded that bioelectrical impedance plethysmography using a single frequency can be used for the estimation of ECS and BV. The wide limits of agreement, however, may limit its used in clinical practice.

Extracellular space and blood volume were measured using 82Br dilution and 51Cr-tagged erythrocytes in 24 tumor-free patients after total gastrectomy. Eleven of the patients suffered from early dumping. Age, blood volume, and extracellular space were significantly smaller in dumpers (P less than 0.05). The dumping score could be predicted by a multiple regression model considering blood volume per lean body mass and extracellular space (r = 0.637; P = 0.0039). Rapid (t1/2 less than 360 seconds) emptying of the gastric substitute, assessed using a 99Tc-labeled solid test meal, was significantly associated with dumping in addition to extracellular space and blood volume (r = 0.876; P = 0.0018). Both rapid emptying and a narrow extracellular space seem to contribute to the early dumping syndrome.

Continuous infusion of 15O-labeled water allows a quantitative measurement of the total water pool in the chest region by positron emission tomography (PET). By subsequent inhalation of 11CO the intravascular space (blood pool) can be quantitated as well. After a suitable normalization of the intravascular activities the extravascular water can be determined by subtraction of the blood pool from the water pool. The regional extravascular lung water distribution can be visualized in tomographic slices. The method was validated in an animal experiment using five dogs. They were measured before and after induction of a lung edema by IV injection of oleic acid. The increase of extravascular lung water was monitored by the thermo-dye-dilution method (TDD). The correlation of extravascular lung water as measured by TDD with PET measurements is good (r = 0.94). The PET values agree also with gravimetric lung water determinations. An absolute quantitation of regional extravascular lung water is possible after absorption correction of the PET data via transmission measurements and calibration of the camera system. The uncertainty in the absolute quantification is +/- 20%. In the experiments described here the mean extravascular lung water was 0.13 g/cm3 before and 0.25 g/cm3 after induction of lung edema.

The total body potassium (TBK), serum potassium, and the number of red blood cell ouabain-binding sites was studied in 94 patients with Crohn's disease. TBK was measured by counting the endogenous 40K in a whole body counter. TBK was 87% +/- 13% in 94 patients with Crohn's disease, while in control subjects, it was 97% +/- 12% (n = 24). This significant reduction in TBK was accompanied by normal serum potassium levels (4.4 +/- 0.5 mM). TBK was significantly correlated with the Crohn's disease activity index (r = 0.79, n = 113, P less than 0.01). The number of red cell ouabain binding sites measured by equilibrium binding of 3H-ouabain showed a significant increase in the number of Na-K pumps in Crohn's disease (396 +/- 65, n = 27) compared with the control group (290 +/- 45; n = 24). These results support the suggestion that changes in TBK may regulate the synthesis of Na-K pump molecules. The total body potassium depletion and the need for a preoperative nutritional support in Crohn's disease are discussed.