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Synthesis of plasma proteins is an important function of the liver that has sparsely been investigated by modern techniques in patients with advanced chronic liver disease (CLD). Twenty-eight well-characterized patients with CLD under evaluation for liver transplantation were included. Albumin and fibrinogen synthesis rates were measured by the flooding dose technique using stable isotope-labeled phenylalanine. Transcapillary escape rate of albumin and plasma volume were assessed by radioiodinated human serum albumin. The absolute albumin synthesis rates were low (65 mg/kg/day, range: 32-203) and were associated with impaired liver function, as reflected by the risk-scores Child-Pugh (P = 0.025) and model for end-stage liver disease (rs = -0.62, P = 0.0005). The fibrinogen synthesis rate (12.8 mg/kg/day, range: 2.4-52.9) was also negatively associated with liver function. The synthesis rates of albumin and fibrinogen were positively correlated. Plasma volume was high (51 ± 9 mL/kg body wt), which contributed to an almost normal intravascular albumin mass despite low plasma concentration. Autoimmune inflammatory etiologies to CLD were associated with higher fibrinogen synthesis. De novo synthesis rates of albumin and fibrinogen in advanced chronic liver failure were negatively correlated to prognostic scores of liver disease. Albumin synthesis rate was low and associated with both liver failure and autoimmune inflammation, whereas fibrinogen synthesis was often normal and positively associated with chronic inflammation. This is different from acute inflammatory states in which both albumin and fibrinogen synthesis rates are high. [ABSTRACT FROM AUTHOR]

Background: Esophagectomy is a major surgical intervention and a cornerstone in the treatment of esophageal cancer. There is clinical experience that blood lactate concentration often is elevated in the period following esophagectomy, but the incidence and clinical consequences are sparsely studied. Methods: We extracted data from all patients undergoing esophagectomy at Karolinska University Hospital 2016–2018, n = 153. Most were performed with minimally invasive technique, n = 130. Blood lactate values directly after surgery, highest value during the first night, and morning level on postoperative day one were recorded. Primary outcome was hospital length of stay and secondary outcome was a composite of postoperative infection, additional surgery, or intensive care during the hospital stay. Development of anastomotic leak was analyzed separately. Results: Postoperative hyperlactatemia was common as 93% of patients had peak lactate concentration >1.6 mmol/L and 27% >3.5 mmol/L in the first night following operation. Median hospital length of stay was 14 days. Blood lactate showed a weak correlation to hospital stay and intensive care the morning following surgery, but not at arrival to postoperative ward. There were no statistical differences between those with and without anastomotic leak at any of the time points. Elevated lactate in the first 12–16 h postoperatively was related to surgical factors (open technique, surgery time, and perioperative bleeding) but not to patient related factors (ASA‐class, Charlson comorbidity index, sex, age) or cumulative fluid balance. Conclusion: In conclusion, elevated blood lactate in the immediate time following esophagectomy showed a weak association to intensive care and length of stay but not anastomotic leak. [ABSTRACT FROM AUTHOR]

Introduction:  Early differentiation between perforated and nonperforated acute appendicitis (AA) in children is of major benefit for the selection of proper treatment. Based on pilot study data, we hypothesized that plasma sodium concentration at hospital admission is a diagnostic marker for perforation in children with AA.Materials and Methods:  This was a prospective diagnostic accuracy study, including previously healthy children, 1 to 14 years of age, with AA. Blood sampling included plasma sodium concentration, plasma glucose, base excess, white blood cell count, plasma arginine vasopressin (AVP), and C-reactive protein.Results:  Eighty children with histopathologically confirmed AA were included in the study. Median plasma sodium concentration on admission in patients with perforated AA (134 mmol/L, [interquartile range 132-136]) was significantly lower than in children with nonperforated AA (139 mmol/L, [137-140]). The receiver operating characteristic curve of plasma sodium concentration identifying patients with perforated AA showed an area under the curve of 0.93 (95% confidence interval, 0.87-0.99), with a sensitivity and specificity of 0.82 (0.70-0.90) and 0.87 (0.60-0.98), respectively. Plasma sodium concentrations ≤136 mmol/L resulted in an odds ratio of 31.9 (6.3-161.9) for perforation. The association between low plasma sodium concentration and perforated AA was confirmed in a multivariate logistic regression analysis. Median plasma AVP on admission was higher in patients with perforated (8.6 pg/mL [5.0-14.6]) as compared with nonperforated AA (3.4 pg/mL [2.5-6.6]).Conclusion:  In children with AA, there is a strong association between low plasma sodium concentration and perforation, a novel and not previously described finding. [ABSTRACT FROM AUTHOR]

Background: Plasma lactate concentrations and their trends over time are used for clinical prognosis, and to guide treatment, in critically ill patients. Although heavily relied upon for clinical decision-making, lactate kinetics of these patients is sparsely studied.Aim: To establish and validate a feasible method to study lactate kinetics in critically ill patients.Methods: Healthy volunteers (n = 6) received a bolus dose of 13C-labeled lactate (20 μmol/kg body weight), and 43 blood samples were drawn over 2 h to determine the decay in labeled lactate. Data was analyzed using non-compartmental modeling calculating rates of appearance (Ra) and clearance of lactate. The area under the curve (AUC) was calculated using a linear-up log-down trapezoidal approach with extrapolation beyond 120 min using the terminal slope to obtain the whole AUC. After evaluation, the same protocol was used in an unselected group of critically ill patients (n = 10).Results: Ra for healthy volunteers and ICU patients were 12.8 ± 3.9 vs 22.7 ± 11.1 μmol/kg/min and metabolic clearance 1.56 ± 0.39 vs 1.12 ± 0.43 L/min, respectively. ICU patients with normal lactate concentrations showed kinetics very similar to healthy volunteers. Simulations showed that reducing the number of samples from 43 to 14 gave the same results. Our protocol yielded results on lactate kinetics very similar to previously published data using other techniques.Conclusion: This simple and user-friendly protocol using an isotopically labeled bolus dose of lactate was accurate and feasible for studying lactate kinetics in critically ill ICU patients.Trial Registration: ANZCTR, ACTRN12617000626369, registered 8 March 2017. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372507&isReview=true. [ABSTRACT FROM AUTHOR]

Comment on: Linde H, Bartusevicius V, Norberg Å, Klevebro F, Grip J. Frequency of blood lactate elevation following esophagectomy and its association to postoperative complications. The stress hyperglycemia ratio, a novel index of relative hyperglycemia, predicts short-term mortality in critically ill patients after esophagectomy. [Extracted from the article]

Background: Patients with multiple organ failure (MOF) often receive large amounts of resuscitation fluid, making them at high risk of fluid overload (FO). Our main objective was to investigate if the ability to achieve a negative fluid balance during the first 3 continuous renal replacement therapy (CRRT) days was associated with mortality in children with MOF.Methods: Retrospective cohort study in a tertiary multidisciplinary academic paediatric hospital. The study included 63 patients (age 0-18 years) with 3 or more failing organs receiving CRRT due to acute kidney injury and/or fluid overload.Results: The median age was 4 months, and PICU mortality was 29%. Survivors had significantly lower degree of FO at CRRT initiation, (median 15% (Interquartile range 9-22)) than non-survivors (24% (17%-37%), P = 0.002). On PICU admission, PIM-3 score was significantly higher in non-survivors (P = 0.01), but at CRRT initiation there was no difference in PELOD-2 score (P = 0.98). Mortality in patients achieving a cumulative net negative fluid balance during the first 3 days after CRRT initiation was 12%, compared to 86% in those not achieving this (P < 0.0001). In multivariate analysis, the inability to achieve a net negative fluid balance during 3 days after CRRT initiation (P < 0.0001) and FO >20% at CRRT initiation (P = 0.0019) remained associated with mortality.Conclusion: Our results suggest that early fluid removal is associated with improved patient outcome in critically ill children receiving CRRT, and that prompt measures should be taken to prevent fluid overload in critical illness. These results need to be verified in further, prospective studies. [ABSTRACT FROM AUTHOR]

Background: A decrease in lactate concentration over time during septic shock is associated with favourable outcomes. However, if this applies to hourly intervals during the initial time period in the ICU is unknown. The aim of this study was to investigate whether there is an early hourly reduction rate of lactate that is related to clinical outcome in septic shock patients treated in the ICU.Methods: A cohort of adult septic shock patients admitted to the ICU with an initial lactate level >2 mmol/L and receiving vasopressor was retrospectively analysed. Mean hourly reduction rate of lactate (ΔLact/h) was calculated individually from all lactate concentrations measured from inclusion until normalization of lactate (≤1.5 mmol/L) within 24 hours. The mortality at 30 days following ICU admission was evaluated.Results: Among 1405 ICU admissions during 2 years, 104 patients were eligible. Mortality rate at 30 days was 34%. The optimal cut-off values of baseline lactate and ΔLact/h for 30-day mortality were 4 mmol/L and 2.5%/h. When stratifying the patients by these cut-points, those with baseline lactate > 4 mmol/L and ΔLact/h < 2.5%/h had lowest probability of survival (27%). Multivariable logistic regression showed that ΔLact/h <2.5%/h, baseline lactate >4 mmol/L and high Simplified Acute Physiology Score III were independent risk factors of 30-day mortality.Conclusions: In this retrospective pilot cohort, a mean reduction rate of lactate <2.5%/h within the first 24 hours of ICU stay was associated with an increased risk of 30-day mortality in septic shock patients. [ABSTRACT FROM AUTHOR]

Background: Providing supplemental amino acids to ICU patients during a 3-h period results in improved whole-body net protein balance, without an increase in amino acid oxidation. The primary objective was to investigate if a 24-h intravenous amino acid infusion in critically ill patients has a sustained effect on whole-body protein balance as was seen after 3 h. Secondary objectives were monitoring of amino acid oxidation rate, urea and free amino acid plasma concentrations.Methods: An infusion of [1-13C]-phenylalanine was added to ongoing enteral nutrition to quantify the enteral uptake of amino acids. Primed intravenous infusions of [ring-2H5]-phenylalanine and [3,3-2H2]-tyrosine were used to assess whole-body protein synthesis and breakdown, to calculate net protein balance and to assess amino acid oxidation at baseline and at 3 and 24 hours. An intravenous amino acid infusion was added to nutrition at a rate of 1 g/kg/day and continued for 24 h.Results: Eight patients were studied. The amino acid infusion resulted in improved net protein balance over time, from -1.6 ± 7.9 μmol phe/kg/h at 0 h to 6.0 ± 8.8 at 3 h and 7.5 ± 5.1 at 24 h (p = 0.0016). The sum of free amino acids in plasma increased from 3.1 ± 0.6 mmol/L at 0 h to 3.2 ± 0.3 at 3 h and 3.6 ± 0.5 at 24 h (p = 0.038). Amino acid oxidation and plasma urea were not altered significantly.Conclusion: We demonstrated that the improvement in whole-body net protein balance from a supplemental intravenous amino acid infusion seen after 3 h was sustained after 24 h in critically ill patients.Trial Registration: This trial was prospectively registered at Australian New Zealand Clinical Trials Registry. ACTRN, 12615001314516 . Registered on 1 December 2015. [ABSTRACT FROM AUTHOR]

The high fashion in nutrition for the critically ill is to recommend a high protein intake. Several opinion leaders are surfing on this wave, expanding the suggested protein allowance upwards. At the same time, there is no new evidence supporting this change in recommendations. Observational data show that in clinical practice protein intake is most often far below current ESPEN recommendations of 1.2-1.5 g/kg/day. Therefore, it may be in the best interests of our patients just to adhere to that guideline, and not to stretch them upwards for protein intake? Here we give arguments to stay conservative. [ABSTRACT FROM AUTHOR]

The possibility of using two different isotopomers, for the incorporation of isotopically labeled amino acids, was explored to enable longitudinal studies of de novo synthesis of two export liver proteins, albumin and fibrinogen. The agreement of the synthesis rates between the two different labels was evaluated along with the reproducibility of repeated experiments using different time intervals. Healthy volunteers were studied in a standardized fed state. Protocol A (n = 10) involved two measurements 48 hours apart. Protocol B (n = 6) involved three measurements at baseline and five hours and then seven days after the initial measurement. De novo synthesis of albumin and fibrinogen by the incorporation of D5-phenylalanine or D8-phenylalanine were measured using the flooding dose technique. Albumin and fibrinogen were isolated from plasma using standard techniques. Fractional and absolute synthesis rates were calculated. Repeated measurements employing the two isotoptomers showed good agreement for albumin fractional synthesis rate after 48 hours (p = 0.92) and after 7 days (p = 0.99), with a coefficient of variation of 5.9% when using the same isotopic label. For fibrinogen, the coefficient of variation for the fractional synthesis rate employing the same isotopic label was 16.6%. Repeated measurements after 48 hours and seven days showed less agreement although there was no statistical difference (P = 0.32 and P = 0.30 respectively). Repeated measurement after five hours showed a statistical significant difference for the fractional synthesis rate of fibrinogen (p = 0.008) but not for albumin (p = 0.12). Repeated measurements of albumin de novo synthesis more than 48 hours apart show acceptable agreement using either one or two different isotopic labels. For fibrinogen the larger intra-individual scatter necessitates larger study groups to detect changes in longitudinal studies. Repeated measurements within 48 hours need to be validated further. [ABSTRACT FROM AUTHOR]

Background: The time course of plasma albumin concentration (P-alb) and cumulative perioperative albumin shift as a measure of albumin extravasation in major abdominal surgery is not well described. Knowledge of these indices of the vascular barrier and vascular content are important for our understanding of fluid physiology during surgery and anesthesia.Methods: Patients (n = 10) were studied during esophageal or pancreatic surgery. P-alb was repeatedly measured over 72 h, and the mass balance of albumin and hemoglobin were obtained from measures of P-alb, blood hemoglobin and hematocrit.Results: P-alb decreased rapidly from baseline (32.8 ± 4.8 g/L) until the start of surgical reconstruction (18.7 ± 4.8 g/L; p < 0.001), and was thereafter stable until postoperative day 3. Cumulative perioperative albumin shift increased until 1 h after the end of surgery, when 24 ± 17 g (p < 0.001) had been lost from the circulation.Conclusions: The rapid fall in P-alb of more than 40 % consistently occurred during the first part of the surgical procedure, but albumin leakage progressed until 1 h after the end of surgery. After the initial drop, P-alb was stable for 72 h. [ABSTRACT FROM AUTHOR]

Background: Indirect calorimetry allows the determination of energy expenditure in critically ill patients by measuring oxygen consumption (VO2) and carbon dioxide production (VCO2). Recent studies have demonstrated variable performance of "breath-by-breath" instruments compared to mixing chamber technology. The aim of this study was to validate two modern devices (E-sCOVX and Quark RMR) against a reference method (Deltatrac II).Method: Measurements of VO2/VCO2 with the test and reference devices were performed simultaneously over a 20-min period in mechanically ventilated adult intensive care unit patients. Accuracy and precision of instruments were analyzed using Bland-Altman plots.Results: Forty-eight measurements in 22 patients were included for analysis. Both E-sCOVX and Quark RMR overestimated VO2 and VCO2 compared to Deltatrac II, corresponding to a 10% higher mean resting energy expenditure. Limits of agreement of resting energy expenditure within ± 2 standard deviations were ± 461 kcal/24 h (± 21% expressed as percentage error) for ΔE-sCOVX-Deltatrac II and ± 465 kcal/24 h (± 22%) for ΔQuark RMR-Deltatrac II.Conclusion: Both test devices overestimate VO2 and VCO2 compared to Deltatrac II. The observed limits of agreement are comparable to those commonly accepted in evaluations of circulatory monitoring, and significantly less than results from predictive equations. We hypothesize that the discrepancy between methods is due to patient/ventilator-related factors that affect the synchronization of gas and spirometry waveforms.Trial Registration: Australian New Zealand Clinical Trials Registry, Trial ID ACTRN12615000205538. Date registered 3 March 2015. [ABSTRACT FROM AUTHOR]

Background: Higher than normal plasma glutamine concentration at admission to an intensive care unit is associated with an unfavorable outcome. Very high plasma glutamine levels are sometimes seen in both acute and chronic liver failure. We aimed to systematically explore the relation between different types of liver failure and plasma glutamine concentrations. Methods: Four different groups of patients were studies; chronic liver failure (n = 40), acute on chronic liver failure (n = 20), acute fulminant liver failure (n = 20), and post-hepatectomy liver failure (n = 20). Child-Pugh and Model for End-stage Liver Disease (MELD) scores were assessed as indices of liver function. All groups except the chronic liver failure group were followed longitudinally during hospitalisation. Outcomes were recorded up to 48 months after study inclusion. Results: All groups had individuals with very high plasma glutamine concentrations. In the total group of patients (n = 100), severity of liver failure correlated significantly with plasma glutamine concentration, but the correlation was not strong. Conclusion: Liver failure, regardless of severity and course of illness, may be associated with a high plasma glutamine concentration. Further studies are needed to understand whether high glutamine levels should be regarded as a biomarker or as a contributor to symptomatology in liver failure. [ABSTRACT FROM AUTHOR]

Background: The drop in plasma albumin concentration following surgical trauma is well known, but the temporal pattern of the detailed mechanisms behind are less well described. The aim of this explorative study was to assess changes in albumin synthesis and transcapillary escape rate (TER) following major surgical trauma, at the time of peak elevations in two well-recognized markers of inflammation. Methods: This was a clinical trial of radiolabeled human serum albumin for the study of TER and plasma volume. Ten patients were studied immediately preoperatively and on the 2nd postoperative day after major pancreatic surgery. Albumin synthesis rate was measured by the flooding dose technique employing incorporation of isotopically labelled phenylalanine. Results: Fractional synthesis rate of albumin increased from 11.7 (95% CI: 8.9, 14.5) to 15.0 (11.7, 18.4) %/day (p = 0.027), whereas the corresponding absolute synthesis rate was unchanged, 175 (138, 212) versus 150 (107, 192) mg/kg/day (p = 0.21). TER was unchanged, 4.9 (3.1, 6.8) %/hour versus 5.5 (3.9, 7.2) (p = 0.63). Plasma volume was unchanged but plasma albumin decreased from 33.5 (30.9, 36.2) to 22.1 (19.8, 24.3) g/L. (p<0.001). Conclusion: Two days after major abdominal surgery, at the time-point when two biomarkers of generalised inflammation were at their peak and the plasma albumin concentration had decreased by 33%, we were unable to show any difference in the absolute synthesis rate of albumin, TER and plasma volume as compared with values obtained immediately pre-operatively. This suggests that capillary leakage, if elevated postoperatively, had ceased at that time-point. The temporal relations between albumin kinetics, capillary leakage and generalised inflammation need to be further explored. Trial Registration: clinicaltrialsregister.eu: EudraCT ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Glutamine transport between tissues is important for the outcome of critically ill patients. Investigation of glutamine kinetics is, therefore, necessary to understand glutamine metabolism in these patients in order to improve future intervention studies. Endogenous glutamine production can be measured by continuous infusion of a glutamine tracer, which necessitates a minimum measurement time period. In order to reduce this problem, we used and validated a tracer bolus injection method. Furthermore, this method was used to measure the glutamine production in healthy volunteers in the post-absorptive state, with extra alanine and with glutamine supplementation and parenteral nutrition. Healthy volunteers received a bolus injection of [1-13C] glutamine, and blood was collected from the radial artery to measure tracer enrichment over 90 minutes. Endogenous rate of appearance (endoRa) of glutamine was calculated from the enrichment decay curve and corrected for the extra glutamine supplementation. The glutamine endoRa of healthy volunteers was 6.1±0.9 µmol/kg/min in the post-absorptive state, 6.9±1.0 µmol/kg/min with extra alanyl-glutamine (p = 0.29 versus control), 6.1±0.4 µmol/kg/min with extra alanine only (p = 0.32 versus control), and 7.5±0.9 µmol/kg/min with extra alanyl-glutamine and parenteral nutrition (p = 0.049 versus control). In conclusion, a tracer bolus injection method to measure glutamine endoRa showed good reproducibility and small variation at baseline as well as during parenteral nutrition. Additionally, we showed that parenteral nutrition including alanyl-glutamine increased glutamine endoRa in healthy volunteers, which was not attributable to the alanine part of the dipeptide. [ABSTRACT FROM AUTHOR]

Glutamine depletion is demonstrated to be an independent predictor of hospital mortality in ICU (intensive care unit) patients. Today glutamine supplementation is recommended to ICU patients on parenteral nutrition. In addition to glutamine, glutathione may be a limiting factor in ICU patients with MOF (multiple organ failure). To study the prevalence of glutamine and glutathione depletion an observational study was performed. The results were analysed in relation to mortality and the conventional predictors of mortality outcome, APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment). Consecutive patients admitted to the ICU at Karolinska University Hospital Huddinge were studied. Patient admission scoring of APACHE II and SOFA were registered as well as mortality up to 6 months. Plasma glutamine concentration and whole blood glutathione status at admittance were analysed. The admission plasma glutamine concentrations were totally independent of the conventional risk scoring at admittance, and a subnormal concentration was an independent predictor of mortality. In addition, glutathione redox status was also an independent mortality predictor, but here a normal ratio was the risk factor. In both cases the mortality risk was mainly confined to the post-ICU period. A low plasma concentration of glutamine at ICU admission is an independent risk factor for post-ICU mortality. The possible benefit of extending glutamine supplementation post-ICU should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

A novel bioactive form of neurotensin post-translationally modified at a Glu residue was isolated from porcine intestine. Purification of the peptide was guided by detection of intracellular Ca2+ release in SK-N-SH neuroblastoma cells. Using high resolution accurate mass analysis on an ion trap Fourier transform mass spectrometer, the post-translational modification was identified as arginine linked to the y-carboxyl of Glu via an isopeptide bond, and we named the newly identified peptide ‘arginylated neurotensin’ (R-NT, N-(neurotensin-C5-4-yl)arginine). Although arginylation is a known modification of N-terminal amino groups in proteins, its presence at a Glu side chain is unique. The finding places neurotensin among the few physiologically active peptides that occur both in post-translationally modified and unmodified forms. Pharmacologically, we characterized R-NT for its ligand activity on three known neurotensin receptors, NTR1, -2, and -3, and found that R-NT has similar pharmacological properties to those of neurotensin, however, with a slightly higher affinity to all three receptors. We expressed the intracellular receptor NTR3 as a soluble protein secreted into the cell culture medium, which allowed characterization of its R-NT and neurotensin binding properties. The creation of soluble NTR3 also provides a potential tool for neutralizing neurotensin action in vivo and in vitro. We have shown that SK-N-SH neuroblastoma cells express NTR1 and NTR3 but not NTR2, suggesting that the Ca2+ mobilization elicited by R-NT is via NTR1. [ABSTRACT FROM AUTHOR]

Extracts from Gynostemma pentaphyllum Makino (Cucurbitaceae), a Southeast Asian herb, has been reported to affect numerous activities resulting in antitumor, cholesterol-lowering, immunopotentiating, antioxidant, and hypoglycemic effects. We have isolated one active compound by ethanol extraction, distribution in n-butyl alcohol/water, solid phase extraction/separation, and several rounds of reverse phase high pressure liquid chromatography. We have shown by NMR and mass spectrometry that this active compound is a novel saponin, a gypenoside, which we have named phanoside (21-,23-epoxy-,3β-,20-,21-trihydroxydammar-24-ene-3-O-([α-D-rhamnopyranosyl(1→2)]-[ β-D-glycopyranosyl(1→3)]-β-D-lyxopyranoside)), with a molecular mass of 914.5 Da. Phanoside is a dammarane-type saponin, and four stereoisomers differing in configurations at positions 21 and 23 were identified, each of which were found to stimulate insulin release from isolated rat pancreatic islets. We have also found that the stereoisomers are interconvertible. Dose-dependent insulin-releasing activities at 3.3 and 16.7 mM glucose levels were determined for the racemic mixture containing all four stereoisomers. Phanoside at 500 μM stimulates insulin release in vitro 10-fold at 3.3 mM glucose and potentiates the release almost 4-fold at 16.7 mM glucose. At these glucose levels, 2 μM glibenclamide stimulates insulin release only 2-fold. Interestingly, β-cell sensitivity to phanoside is higher at 16.7 mM than at 3.3 mM glucose, although insulin responses were significantly increased by phanoside below 125 μM only at high glucose levels. Also when given orally to rats, phanoside (40 and 80 mg/ml) improved glucose tolerance and enhanced plasma insulin levels at hyperglycemia. [ABSTRACT FROM AUTHOR]

Background: The volume of distribution at steady state for ethanol (Vss) is thought to be identical to the total body water (TBW). We compared a two-compartment pharmacokinetic model with parallel Michaelis-Menten and first-order renal elimination with the classical one-compartment zero-order elimination model. Ethanol concentration-time profiles were established for breath, venous blood, and urine. The values of Vss obtained for ethanol were compared with TBW determined by deuterium oxide dilution. Methods: Sixteen healthy volunteers each received a 30-min intravenous infusion of ethanol on two occasions. Ethanol was measured in breath by a quantitative infrared analyzer and in blood and urine by headspace gas chromatography. Deuterium oxide was given as an intravenous injection and measured in serum by isotope-ratio mass spectrometry. Components of variation were calculated by ANOVA to determine the precision of the estimates of Vss and TBW. Results: Mean TBW, determined by deuterium oxide dilution, was 44.1 ± 3.9 liters (±SD) for men, corresponding to 0.61 liters/kg, and 37.4 ± 3.2 liters for women, or 0.54 liters/kg. Estimates of Vss from blood-ethanol pharmacokinetics were 87.6% of TBW according to isotope dilution and 84.4% for breath analysis with the two-compartment model. This compares with 95.1% and 95.4% for blood and breath alcohol, respectively, when the classical zero-order kinetic analysis is used. The precision of the estimates of Vss and TBW was between ±1.56 and ±2.19 liters (95% confidence interval). Conclusions: Ethanol does not distribute uniformly into the TBW. The precision of measuring Vss by ethanol dilution was comparable to estimates of TBW by isotope dilution. Results of noninvasive breath ethanol analysis compared well with use of venous blood for estimating Vss. The sophisticated two-compartment model was much superior to the classical one-compartment model in explaining the total concentration-time course of intravenously given ethanol. [ABSTRACT FROM AUTHOR]

The time required for ethanol to distribute between the systemic circulation and the rest of the body water results in an ‘overshoot’ of the blood-alcohol concentration (BAC) during the first 30 min after intravenous infusion. To investigate whether a similar distribution phenomenon occurs when ethanol is given by the oral route, we compared BACs after intravenous infusion and oral intake under strictly controlled conditions by giving a 0.4 g/kg dose of ethanol over 15 min to six fasting female volunteers. The results show an ‘overshoot’ in three volunteers who had the shortest time to BACmax, which indicates rapid absorption, and the time-course was similar to the distribution phase seen during the intravenous experiments. We conclude that BAC is sometimes higher than expected shortly after alcohol has been ingested rapidly. This finding can probably be explained by the fact that ethanol is distributed more slowly throughout the total body water than it is absorbed from the gut. [ABSTRACT FROM PUBLISHER]