The serum pharmacokinetic findings are summarized in Table 3. The median Vd was 41 mL/kg and was 72 mL/kg corrected for whole blood. The median T1/2 of HES within the first 8 h was 4.2 h (range, 1.9–17.7 h), and the median T1/2 for the 7-day observation period was 38.2 h (range, 11.0–145.4 h). HES elimination was faster during the first hours after the termination of IV infusion than in the later phase.
Most of the HES administered was eliminated through the kidneys. Consistent with the rapid initial decrement in the serum concentration of HES, the cumulative urine excretion during the first 24 h was 64% of the infused dose. Detectable HES concentrations were observed in urine samples for every subject 1 wk after dosing at 0.20–2.72 mg/mL.
Pharmacodynamic analysis showed hemodilution resulting in decreases in hemoglobin concentration, hematocrit, and red blood cell count lasting for 24 to 48 h. Platelet counts returned to near baseline levels in less than 24 h (Table 4).
The activated partial thromboplastin time, but not prothrombin time, increased during infusion and peaked 6 h after infusion. The thrombin time decreased immediately after Hextend® infusion and remained so for 48 h. Fibrinogen, factor VIII, and vWFAg demonstrated mild to moderate reductions for 48 h. The platelet function analyzer showed moderate and transient increases in closure times (Table 5).
Bilirubin, total protein, alanine aminotransferase, and γ-glutamyl transferase activities exhibited reductions slightly more than expected for that volume infusion alone (Table 6). Albumin, alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase, and creatine phosphokinase showed even greater decreases. In contrast, amylase activity increased at 6 h, reached values four times higher than control at 24 h, and returned to near baseline values after 7 days. Plasma sodium, potassium, calcium, magnesium, chloride, urea, and creatinine remained within their respective reference ranges during and after the infusion of Hextend®.
This open-label study was designed to describe the pharmacokinetic and pharmacodynamic profiles of Hextend®. The serum concentration-time curves indicated a mixed pharmacokinetic behavior. The pharmacokinetic profile for most subjects agreed with a two-compartment model. They had a brief distribution phase (a few hours), followed by a long elimination phase (days or weeks). Some subjects’ data suggested a single-compartment behavior, with a few others indicating a three-compartment pattern. It is reasonable to derive pharmacokinetic indices by using noncompartment methods with some additional analyses focusing on clinically relevant treatment periods (e.g., the first eight hours).
Because the mean values of most pharmacokinetic variables may be skewed by some outliers, medians are used in the summary and discussion. Large variations in observed pharmacokinetic indices were expected, because Hextend®, like all HES, is a heterogeneous compound with 80% of its polymer units occurring within the range of 20–2500 kDa. Traditional pharmacokinetic modeling may be applied, but the interpretation of measured or derived variables should take into account the polydisperse nature of HES solutions. The degree of substitution with hydroxyethyl groups, the sites of those substitutions, and the molecular size determine the pharmacokinetic characteristics of the compound. HES fractions below the renal threshold are rapidly eliminated, whereas larger fractions are either broken down by amylase and then excreted mainly through the kidneys or taken up by body tissues and stored in the reticuloendothelial system before being metabolized and excreted (11).
Serum levels of HES did not reach steady state during the short infusion. Peak serum concentrations were observed approximately at the end of IV infusion. Immediately after the infusion, serum HES concentrations decreased rapidly compared with the later phase, resulting in a T1/2 of 4.2 hours within the first 8 hours. This time frame of eight hours represents the clinically relevant period after the administration of a single dose of HES. The overall T1/2 of 38.2 hours for the 7-day observation period describes the actual fate of the compound.
For HES solutions, the biological T1/2 changes as a function of the period of elimination studied (11–13). These unique properties are related to the fact that some degradation-resistant molecule populations remain in the plasma longer than their more vulnerable counterparts. As a result, their T1/2 values seem to increase with time. T1/2 values ranging from 9 hours to 48 days have been reported for HES, but narrower ranges can be calculated if the period of elimination is specified (12,14).
The corrected median Vd of 72 mL/kg was equivalent to the estimated circulating blood volume, indicating that Hextend® was mainly confined to the intravascular space. The median serum clearance was only 0.98 mL/min. Small levels of HES were detected in both serum and urine samples collected 7 days postdose for every study participant. In our study, 64% of the administered dose of Hextend® was eliminated by the kidneys in the first 24 hours, compared with 40%–46% of the administered dose of HES in two similar studies (15,16). In healthy patients, the potential for accumulation after repeat doses is small (16). It has been suggested that the administration of HES to kidney donors may impair renal function in transplant recipients (17), but one study showed no differences in sensitive markers of renal function after HES administration (18). In our study, none of the indices of renal function demonstrated statistically significant or clinically relevant changes.
Further pharmacodynamic analysis showed that the infusion of Hextend® 10 mL/kg produced decreases in some plasma components consistent with the infusion of that volume of fluid. The duration of these changes mirrored the persistence of plasma volume expansion. Hemodilution was observed for 24–48 hours after the infusion of Hextend® and was consistent with the T1/2 of 38.2 hours for the 7-day observation period. Other plasma components, such as plasma chloride, sodium, potassium, calcium, and magnesium, remained virtually unchanged throughout the study period, reflecting the benefit of a balanced electrolyte formulation (19). The increase in plasma bicarbonate is notable and may support suggestions that the administration of Hextend® avoids the risk of producing an iatrogenic metabolic acidosis (9).
Effects of HES on fibrinogen, factor VIII, and vWFAg as a result of binding of coagulation factors to colloid macromolecules have been described (1,2,20), although the administration of clinical volumes seems not to be associated with significant hemostatic defects or hemorrhage (21,22). In this study, Hextend® showed only moderate increases in the activated partial thromboplastin time, whereas the prothrombin time remained unchanged. The shortening of the thrombin time is consistent with previous observations after the administration of HES (23). Changes in platelet function were of a similar magnitude compared with a study of patients who received 10 mL/kg of HES with a molecular weight of 200 kDa (24).
Whereas other enzymes remained unchanged or decreased, a fourfold increase in serum amylase was observed. The infusion of HES stimulates amylase activity in serum, because it is the main enzyme responsible for the elimination of hetastarch (13,15). Hulse and Yacobi (11) suggested that unchanged lipase activity indicated that HES did not affect pancreatic function.
The inhibition of endothelial activation and prevention of neutrophil adhesion during sepsis syndrome may be a benefit of the intravascular presence of HES (25,26). The mechanism seems to be related to a reduced interaction between endothelium and activated white cells in the presence of medium-molecular-weight starch molecules. In an animal model, Hextend® decreased multiple organ failure and xanthine oxidase release after hepatoenteric ischemia-reperfusion (27).
Hextend® is the first colloidal plasma volume expander suspended in a physiologically balanced medium of electrolytes, glucose, and lactate. The pharmacokinetic data suggest that the new balanced electrolyte formulation does not change the distribution, metabolism, or excretion of HES from that expected from the structure and composition of the starch. The pharmacodynamic data confirm that Hextend® infusion results in expansion of plasma volume that decreases over the following 24 to 48 hours. Most biochemical indices remain stable after the infusion of Hextend®, demonstrating the benefits of the balanced formulation of the suspension medium. This may give Hextend® a position where plasma volume expansion is required and biochemical stability is desirable.
The authors thank Abbott Laboratories, Chicago, IL, and BioTime Inc., Berkeley, CA, for the provision of study fluids and all other support to complete this study.
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© 2002 International Anesthesia Research Society
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