Robert G. Hahn

Role of variability in explaining ethanol pharmacokinetics: Research and forensic applications

Variability in the rate and extent of absorption, distribution and elimination of ethanol has important ramifications in clinical and legal medicine. The speed of absorption of ethanol from the gut depends on time of day, drinking pattern, dosage form, concentration of ethanol in the beverage, and particularly the fed or fasting state of the individual. During the absorption phase, a concentration gradient exists between the stomach, portal vein and the peripheral venous circulation. First-pass metabolism and bioavailability are difficult to assess because of dose-, time- and flow-dependent kinetics.Ethanol is transported by the bloodstream to all parts of the body. The rate of equilibration is governed by the ratio of blood flow to tissue mass. Arterial and venous concentrations differ as a function of time after drinking. Ethanol has low solubility in lipids and does not bind to plasma proteins, so volume of distribution is closely related to the amount of water in the body, contributing to sex- and age-related differences in disposition.The bulk of ethanol ingested (95–98%) is metabolised and the remainder is excreted in breath, urine and sweat. The rate-limiting step in oxidation is conversion of ethanol into acetaldehyde by cytosolic alcohol dehydrogenase (ADH), which has a low Michaelis-Menten constant (Km) of 0.05–0.1 g/L. Moreover, this enzyme displays polymorphism, which accounts for racial and ethnic variations in pharmacokinetics. When a moderate dose is ingested, zero-order elimination operates for a large part of the blood-concentration time course, since ADH quickly becomes saturated. Another ethanol-metabolising enzyme, cytochrome P450 2E1, has a higher Km (0.5–0.8 g/L) and is also inducible, so that the clearance of ethanol is increased in heavy drinkers.Study design influences variability in blood ethanol pharmacokinetics. Oral or intravenous administration, or fed or fasted state, might require different pharmacokinetic models. Recent work supports the need for multicompartment models to describe the disposition of ethanol instead of the traditional one-compartment model with zero-order elimination. Moreover, appropriate statistical analysis is needed to isolate between- and within-subject components of variation. Samples at low blood ethanol concentrations improve the estimation of parameters and reduce variability.Variability in ethanol pharmacokinetics stems from a combination of both genetic and environmental factors, and also from the nonlinear nature of ethanol disposition, experimental design, subject selection strategy and dose dependency. More work is needed to document variability in ethanol pharmacokinetics in real-world situations.

Volume kinetics of Ringer solution, dextran 70, and hypertonic saline in male volunteers

Background: A knowledge of the distribution of different fluids given by intravenous infusion is basic to the understanding of the effects of fluid therapy. Therefore, a mathematical model was tested to analyze the volume kinetics of three types of fluids. Methods: The authors infused 25 ml/kg of Ringer acetate solution, 5 ml/kg of 6% dextran 70 in 0.9% NaCl, and 3 ml/kg of 7.5% NaCl over 30 min in 8 male volunteers aged from 25 to 36 years (mean, 31 years) and measured the changes in total hemoglobin, serum albumin, and total blood water over time. The changes were expressed as fractioned dilution and then plotted against time. The curves were fitted to a one‐volume and a two‐volume model, which allowed an estimation of the size of the body fluid space expanded by the fluid (V) and the elimination rate constant (kr) to be made. Results: The changes in blood water concentration indicated a mean size of V of 5.9 l (+/‐ 0.8, SEM) for Ringers solution, 2.6 (+/‐ 0.3) l for dextran, and 1.2 (+/‐ 0.1) l for hypertonic saline. The corresponding values of kr were 94 (+/‐ 42), 12 (+/‐ 6), and 30 (+/‐ 4) ml/min, respectively. Blood hemoglobin indicated a degree of dilution similar to that indicated by blood water. Serum albumin indicated a more pronounced dilution, which resulted in a larger expandable volume and a greater mean square error for the curvefitting. The larger volume obtained for serum albumin can probably be explained by a loss of intravascular albumin into the tissues along with the infused fluid. Conclusions: The distribution of intravenous fluids can be analyzed by a kinetic model adapted for fluid spaces, but slightly different results are obtained, depending on the marker used to indicate dilution of the primary fluid space. Analysis and simulation of plasma volume expansion by this model is a tool that can help the anesthetist to better plan fluid therapy.

Volume Kinetics of Ringer's Solution in Hypovolemic Volunteers

BACKGROUND The amount of Ringers solution needed to restore normal blood volumes is thought to be three to five times the volume of blood lost. This therapy can be optimized by using a kinetic model that takes accounts for the rates of distribution and elimination of the infused fluid. METHODS The authors infused 25 ml/kg Ringers acetate solution into 10 male volunteers who were 23 to 33 yr old (mean, 28 yr) when they were normovolemic and after 450 ml and 900 ml blood had been withdrawn. One-volume and two-volume kinetic models were fitted to the dilution of the total venous hemoglobin and plasma albumin concentrations. RESULTS Withdrawal of blood resulted in a progressive upward shift of the dilution-time curves of both markers. The two-volume model was statistically justified in 56 of the 60 analyzed data sets. The hemoglobin changes indicated that the body fluid space expanded by the infused fluid had a mean total volume of 10.7 l(+/-0.9 SEM). The elimination rate constant (kr) decreased with the degree of hypovolemia and was 133 ml/min (22 ml/min [SEM]), 100 ml/min (39 ml/min [SEM]), and 34 ml/min (7 ml/min [SEM]), respectively (P < 0.01). Plasma albumin indicated a slightly larger body fluid space expanded by the infused fluid, but kr was less (P < 0.02). Hypovolemia reduced the systolic and diastolic blood pressures by approximately 10 mmHg (P < 0.05). CONCLUSIONS The dilution of the blood and the retention of infused Ringers solution in the body increases in the presence of hypovolemia, which can be attributed chiefly to a reduction of the elimination rate constant.

Kinetics of isotonic and hypertonic plasma volume expanders.

Background Major differences in plasma volume expansion between infusion fluids are fairly well known, but there is a lack of methods that express their dynamic properties. Therefore, a closer description enabled by kinetic modeling is presented. Methods Ten healthy male volunteers received, on different occasions, a constant-rate intravenous infusion over 30 min consisting of 25 ml/kg of 0.9% saline, lactated Ringers solution, acetated Ringers solution, 5 ml/kg of 7.5% saline, or 3 ml/kg of 7.5% saline in 6% dextran. One-, two-, and three-volume kinetic models were fitted to the dilution of the total venous hemoglobin concentration over 240 min. Osmotic fluid shifts were considered when hypertonic fluid was infused. Results All fluids induced plasma dilution, which decreased exponentially after the infusions. The ratio of the area under the dilution-time curve and the infused fluid volume showed the following average plasma-dilution dose-effect (efficiency), using 0.9% saline as the reference (= 1): lactated Ringers solution, 0.88; acetated Ringers solution, 0.91; hypertonic saline, 3.97; and hypertonic saline in dextran, 7.22 (“area approach”). Another comparison, based on kinetic analysis and simulation, showed that the strength of the respective fluids to dilute the plasma by 20% within 30 min was 0.94, 0.97, 4.44, and 6.15 (“target dilution approach”). Between-subject variability was approximately half as high for the latter approach. Conclusions The relative efficiency of crystalloid infusion fluids differs depending on whether the entire dilution-time profile or only the maximum dilution is compared. Kinetic analysis and simulation is a useful tool for the study of such differences.

Relation between myelin sheath thickness and axon size in spinal cord white matter of some vertebrate species

The relation between number of myelin lamellae and axon size in the CNS was examined by electron microscopy of spinal cord white matter fibres in different vertebrate species (cat, rabbit, guinea pig, rat, mouse, frog and perch). The results show that the number of myelin lamellae increases with increasing axon size in a non-linear fashion. Below an axon size of 4--5 micron the relation follows a fairly straight line but above this size rectilinearity is lost. The mouse and the frog differ from the pattern shared by the other animals. In the mouse the lamellar number increases more slowly with axon size and the relation is close to linear. In the frog the number of lamellae increases very slowly with axon size and the relation is markedly curvilinear. Measurements of the myelin repeating period show that in the mammals and the frog the average period of thick sheaths is about 85% of that in thin sheaths, in accordance with previous findings in the cat. In the perch a clearcut difference in this respect between thick and thin sheaths is not found. Calculations of the g-ratio on the basis of the findings indicate that it increases with increasing fibre size. This is most pronounced in the perch and the frog in which the g-ratio for the largest fibres far exceeds the functionally optimal value defined in theoretical analyses on impulse propagation.

Central and regional hemodynamics during crystalloid fluid therapy after uncontrolled intra-abdominal bleeding.

OBJECTIVE To study the effect of graded crystalloid fluid resuscitation on central hemodynamics and outcome after intra-abdominal hemorrhage. METHODS Ten minutes after a 5-mm long laceration was produced in the infrarenal aorta, 32 pigs were randomized to receive either no fluid or Ringers solution in the proportion 1:1, 2:1, or 3:1 to the expected amount of blood lost per hour (26 mL kg[-1]) over 2 hours. The hemodynamics were studied using arterial and pulmonary artery catheters and four blood flow probes placed over major blood vessels. RESULTS During the first 40 minutes after the injury, the respective blood flow rates in the distal aorta were 39% (no fluid), 41% (1:1), 56% (2:1), and 56% (3:1) of the baseline flow. Fluid resuscitation increased cardiac output but had no effect on arterial pressure, oxygen consumption, pH, or base excess. Rebleeding occurred only with the 2:1 and 3:1 fluid programs. Survival was highest with the 1:1 and 2:1 programs. CONCLUSIONS Crystalloid fluid therapy improved the hemodynamic status but increased the risk of rebleeding. Therefore, a moderate fluid program offered the best chance of survival.

Volume Kinetics for Infusion Fluids

Volume kinetics is a method used for analyzing and simulating the distribution and elimination of infusion fluids. Approximately 50 studies describe the disposition of 0.9% saline, acetated and lactated Ringers solution, based on repeated measurements of the hemoglobin concentration and (sometimes) the urinary excretion. The slow distribution to the peripheral compartment results in a 50–75% larger plasma dilution during an infusion of crystalloid fluid than would be expected if distribution had been immediate. A drop in the arterial pressure during induction of anesthesia reduces the rate of distribution even further. The renal clearance of the infused fluid during surgery is only 10–20% when compared with that in conscious volunteers. Some of this temporary decrease can be attributed to the anesthesia and probably also to preoperative psychologic stress or dehydration. Crystalloid fluid might be allocated to “nonfunctional” fluid spaces in which it is unavailable for excretion. This amounts to approximately 20–25% during minor (thyroid) surgery.

Central and regional hemodynamics during acute hypovolemia and volume substitution in volunteers.

OBJECTIVES To study the central and regional hemodynamics and oxygen consumption during acute hypovolemia and volume replacement with crystalloid and colloid solutions. DESIGN Prospective, randomized, laboratory investigation. SETTING Clinical physiology department at a university hospital. SUBJECTS Eighteen healthy male volunteers, between 21 and 35 yrs of age (mean 26). INTERVENTIONS Catheters were inserted in the cubital vein, brachial artery, pulmonary artery, thoracic aorta, right hepatic vein, and left renal vein for measurements of systemic arterial and pulmonary arterial pressures, total and central blood volumes, extravascular lung water, and the splanchnic (liver) and renal blood flow rates. The exchange of respiratory gases was measured, using the Douglas bag technique. Measurements were made before and after a venesection of 900 mL and again after the subjects had been randomized and received volume replacement with either 900 mL of Ringers acetate solution 900 mL of albumin 5%, or 900 plus 900 mL of Ringers solution. MEASUREMENTS AND MAIN RESULTS Withdrawal of 900 mL of blood decreased cardiac output and the splanchnic and renal blood flow rates by between -16% and -20%. The oxygen uptake decreased by 13% in the whole body, while it remained unchanged in the liver and kidney. The systemic and pulmonary vascular resistances increased, while the extravascular lung water decreased. Autotransfusion of fluid from tissue to blood was indicated by hemodilution, which was most apparent in subjects showing only a minor change in peripheral resistance. Cardiac output, blood volume, and systemic vascular resistance were significantly more increased by infusion of 900 mL of albumin 5% than by 900 mL of Ringers solution. However, infusion of 1800 mL of Ringers solution increased the extravascular lung water and the pulmonary arterial pressures to significantly above baseline, while no significant difference from baseline was found after 900 mL of Ringers acetate solution. CONCLUSIONS Withdrawal of 900 mL of blood induces similar reductions in cardiac output as in the splanchnic and renal blood flow rates. A fluid shift from the extravascular to the intravascular fluid compartment might restore up to 50% of the blood loss. Optimal volume substitution with Ringers solution can be effectuated by infusing between 100% and 200% of the amount of blood lost.

The transurethral resection syndrome

The transurethral resection syndrome (“TUR syndrome”) is caused by absorption of electrolyte‐free irrigating fluid, and consists of symptoms from the circulatory and nervous systems. The clinical picture is inconsistent and the syndrome is easily confused with other acute disorders. Mild forms are common and often go undiagnosed, while severe forms of the TUR syndrome are rare and potentially life‐threatening. The pathophysiology is complex but includes four mechanisms: circulatory distress from the rapid absorption of electrolyte‐free irrigating fluid, adverse effects of glycine, dilution of the protein and electrolyte concentrations of the body fluids, and disturbance of renal function. The treatment of the TUR syndrome consists of general life support and in specific treatment directed towards hypotension, hyponatraemia and anuria. Methods to lower the uptake of irrigating fluid are widely used and probably reduce the incidence of the TUR syndrome. However, patient safety can be guaranteed only if the absorption is monitored. An irrigating fluid containing tracer amounts of ethanol can be used for this purpose. This permits the uptake of fluid to be indicated by measuring the concentration of ethanol in the patients exhaled breath.

Symptoms of the transurethral resection syndrome using glycine as the irrigant

We evaluated signs and symptoms of the transurethral resection syndrome recorded during and after 273 transurethral prostatic resections performed at 2 hospitals between 1984 and 1993. Glycine solution was used as the irrigant and ethanol served as a tracer for fluid absorption. The incidence and severity of symptoms that could possibly be related to the syndrome increased progressively as more glycine solution was absorbed. Patients who absorbed 0 to 300 ml. of glycine solution had an average of 1.3 such symptoms. This number increased to 2.3 when 1,001 to 2,000 ml. were absorbed, 3.1 when 2,001 to 3,000 ml. were absorbed and 5.8 for volumes greater than 3,000 ml. Nausea and vomiting occurred significantly more often when 1,001 to 2,000 ml. were absorbed compared to no absorption. Confusion and arterial hypotension were other prominent signs of fluid absorption, whereas hypertension was not. The severity of symptoms was markedly aggravated when more than 3,000 ml. were absorbed. Extravasation resulted in higher risks of bradycardia, hypotension and failed spontaneous diuresis postoperatively than absorption by the intravascular route.