The study was approved by the regional ethics committee in Linköping, Sweden (Dnr 2010/241-31) and registered at ClincalTrials.com with identifier NCT01360333. Data was collected during 2011. Ten healthy volunteers, seven males and three females, aged 33 ± 10 years (mean ± standard deviation [SD]; range 21–48 years) and with a body weight of 77 ± 13 kg (range 58–95 kg), were recruited for the three experiments. After being informed about the study both orally and in writing, each volunteer gave his/her consent for participation.
The participants arrived at the Department of Intensive Care at Linköping University Hospital between 7:30 and 8:30 a.m. The volunteers had fasted since midnight, but to ensure that they were euhydrated prior to the study, they were told to eat one sandwich and drink one glass (2 dL) of clear liquid shortly prior to 6:00 a.m. All participants voided prior to beginning of the study and were then randomised to ingest one of three beverages. To achieve a haemodynamic steady state, volunteers rested for 30 min before the experiments began. During this time, a cannula was placed in the cubital vein of one arm to sample blood. In every case, the first blood sample was collected more than 2 h after any previous ingestion of liquid. The volunteers rested on a bed below an OPN Thermal Ceiling radiant warmer (Aragon Medical, River Vale, NJ) placed about 1 m above them, and the heat was adjusted to achieve optimal comfort.
Ingested fluids
Each volunteer underwent the following three experiments in random order, separated by at least seven days:
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A.
Tap water, 0.5 L (orally).
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B.
Carbohydrate-containing soft drink (90 g carbohydrates/L), 0.5 L (orally).
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C.
Saline, NaCl (9 g/L), 0.5 L (orally).
The tap water contained an average of 0.009 g/L of sodium, 0.002 g/L of potassium and 0.019 g/L of calcium.
Measurements
Venous blood (1–3 mL per tube) was withdrawn from the venous cannula using a vacuum tube just before and at 5, 10, 15, 20, 30, 45, 60, 90 and 120 min after the ingestion of the beverage. The baseline sample was drawn in duplicate, and the mean was used in all calculations. Before each sampling, a small volume of blood was drawn, and the volume was replaced by 2 mL of 0.9 % saline to prevent clotting.
All blood samples were analysed in the hospital’s central laboratory. The blood haemoglobin (Hb) concentration and the haematocrit (Hct) were analysed in EDTA tubes on a Cell-Dyn Sapphire (Abbott Diagnostics, Abbott Park, IL). The coefficient of variation (CV) for these analyses, based on the duplicate baseline samples, was 0.8 %. Plasma was used for measurement of the sodium, potassium (litium-heparine plasma gel tube) and glucose concentrations (Na-fluorid/oxalat-tube) on an ADVIA® 1800 Chemistry System (Siemens, Eschborn, Germany) with a CV of 1.0, 1.5 and 1.5 %, respectively. At the end of the study, all participants voided and the volume was measured.
Calculations
The following volume kinetic calculations are derived from pharmacokinetics.
The absorption, volume of distribution and elimination of fluid were analysed by a one-volume kinetic model.
Fluid was absorbed at a rate determined by a rate constant ka to increase the volume of central body fluid space V to v. The rate of elimination was given as the product of the dilution V and the clearance CL. The differential equation is as follows:
$$ \mathrm{d}v/dt={k}_aD{e}^{-{k}_at}{\textstyle\ \hbox{-}\ }CL\left(v{\textstyle\ \hbox{-}\ }V\right)/V $$
where D is the volume of ingested drink. The Hb-derived fractional plasma dilution was used to indicate the volume expansion V resulting from the infusion [11]:
$$ \left(v{\textstyle\ \hbox{-}\ }V\right)/V=\left(\left[\mathrm{H}\mathrm{b}/\mathrm{h}\mathrm{b}\right]\ {\textstyle \hbox{-}\ }1\right)/\left(1{\textstyle\ \hbox{-}\ }\mathrm{H}\mathrm{c}\mathrm{t}\right) $$
Symbols in capital letters denote baseline values. The minor artificial dilution due to the blood sampling was corrected mathematically [11]. Elimination of fluid by evaporation was disregarded.
The structural parameters in the model (k
a
, V and CL) were estimated using population modelling in Phoenix software for non-linear mixed effects, NLME version 1.3 (Pharsight, St Louis, MO). The possibility to stabilise the analyses by using the renal clearance CLR as CL was used:
$$ CL=\frac{{\displaystyle \sum}\mathrm{urine}\ \mathrm{volume}\ }{AUC\kern0.5em for\ \left(v-V\right)/V} $$
where AUC = area under the curve. The half-life was obtained as ln 2 * V / Cl.
Simulations were performed with programs developed by us for the Matlab R2012b software (Math Works Inc., Natick, MA).
The plasma volume expansion was obtained as the product of the simulated plasma dilution, that is, ((v–V)/V) and the estimated plasma volume at baseline. The latter was obtained as (1–haematocrit) x 7 % of the body mass.
The amount of absorbed fluid that remained in the body at any time t was calculated as the product of the plasma dilution and V.
Statistics
Data are given as the mean, or best estimate, and SD. Differences were evaluated by the Wilcoxon matched-pair test.