Population Kinetics of 0.9% Saline Distribution in Hemorrhaged Awake and Isoflurane-anesthetized Volunteers

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Volume kinetic modeling is an adaptation of pharmacokinetic modeling that characterizes the disposition of intravenously administered fluids using hemoglobin concentration as a natural tracerPopulation-based pharmacokinetic analysis enables assessment of variability between individuals and across populations and permits inclusion of covariates such as the presence or absence of anesthetization, body weight, and sex in the data analysis WHAT THIS ARTICLE TELLS US THAT IS NEW: The distribution of infused fluid after hemorrhage (7 ml/kg during 20 min) in a randomized crossover study of 12 healthy volunteers while awake and while isoflurane-anesthetized was described by a two-fluid space model that included study arm, body weight, and sex as covariatesOnly sex had a statistically significant effect on the area under the plasma dilution curve and maximum plasma dilution, both of which were increased by a median of 17% in females (95% CIs, 1.08 to 1.38 and 1.07 to 1.39, respectively) compared with males BACKGROUND:: Population-based, pharmacokinetic modeling can be used to describe variability in fluid distribution and dilution between individuals and across populations. The authors hypothesized that dilution produced by crystalloid infusion after hemorrhage would be larger in anesthetized than in awake subjects and that population kinetic modeling would identify differences in covariates. METHODS: Twelve healthy volunteers, seven females and five males, mean age 28 ± 4.3 yr, underwent a randomized crossover study. Each subject participated in two separate sessions, separated by four weeks, in which they were assigned to an awake or an anesthetized arm. After a baseline period, hemorrhage (7 ml/kg during 20 min) was induced, immediately followed by a 25 ml/kg infusion during 20 min of 0.9% saline. Hemoglobin concentrations, sampled every 5 min for 60 min then every 10 min for an additional 120 min, were used for population kinetic modeling. Covariates, including body weight, sex, and study arm (awake or anesthetized), were tested in the model building. The change in dilution was studied by analyzing area under the curve and maximum plasma dilution. RESULTS: Anesthetized subjects had larger plasma dilution than awake subjects. The analysis showed that females increased area under the curve and maximum plasma dilution by 17% (with 95% CI, 1.08 to 1.38 and 1.07 to 1.39) compared with men, and study arm (anesthetized increased area under the curve by 99% [0.88 to 2.45] and maximum plasma dilution by 35% [0.71 to 1.63]) impacted the plasma dilution whereas a 10-kg increase of body weight resulted in a small change (less than1% [0.93 to 1.20]) in area under the curve and maximum plasma dilution. Mean arterial pressure was lower in subjects while anesthetized (P < 0.001). CONCLUSIONS: In awake and anesthetized subjects subjected to controlled hemorrhage, plasma dilution increased with anesthesia, female sex, and lower body weight. Neither study arm nor body weight impact on area under the curve or maximum plasma dilution were statistically significant and therefore no effect can be established.