Clinical pharmacokinetics of intravenous ethanol : relationship between the ethanol space and total body water

Introduction: Total body water (TBW) is an important parameter in pathological states where the normal regulation of fluid balance is impaired (e.g., during critical illness, congestive heart failure, bum injury and renal insufficiency). Dilution of water isotopes, such as deuterium oxide (D2O), is considered die gold standard method for measuring TBW in humans. However this procedure requires skilled staff, expensive equipment and the results are seldom available in a timely fashion, which makes it less suitable for clinical applications. Ethanol is completely miscible with water and is thought to distribute into the TBW. The ethanol volume of distribution at steady state (Vss) can be estimated by pharmacokinetic analysis of the concentration-time profile. Ethanol can be measured in expired breath with high precision and this non- invasive method of analysis could provide an attractive alternative with the prospect of bedside monitoring of Vss within 4-6 hours. The aim. of this thesis was to develop an appropriate pharmacokinetic model for intravenous ethanol administration and to identify experimental factors that impact on the results. With this background, we compared Vss. determined by ethanol dilution with TBW determined by D20 dilution. The complicated absorption kinetics of ethanol (e.g. variable gastric emptying and first-pass metabolism) was avoided by use of the intravenous route of administration. Material and Methods: Forty-six healthy volunteers (20 women and 26 men) received intravenous infusions of ethanol (0.4- 0.6 g/kg body weight) in 15-60 minutes. The concentration of ethanol was measured in end-expired breath by infrared spectrometry and in blood and urine by headspace gas chromatography. Specimens of blood and breath were obtained at 5-15 min intervals for 3-6 hours post-dosing. The concentration of D20 in plasmawater was measured with isotope ratio mass spectrometry. Subjective feelings of inebriation were measured with a visual analogue scale