Differences in antithrombin III activities by administration method in critical patients with disseminated intravascular coagulation: A pharmacokinetic study

Pharmacokinetic (PK) data for antithrombin III (AT) are limited in the critical patients. We therefore performed PK analysis using a two-compartment model and also examined whether plasma AT activity would change depending on two administration methods, AT agent at 500 U/8 h (divided group) or 1,500 U/24 h (combined group) for 3 days, a regulated dosage for disseminated intravascular coagulation (DIC) treatment in Japan, in critical patients with DIC. Clinical prospective randomized study. A high care unit in a university hospital. Twenty-four consecutive critical patients with DIC. Ages ranged from 34 to 91 years. Acute physiology age and chronic health evaluation II scores were 25 to 35. Antithrombin III activities in the combined group caused remarkable transient increases but returned to near the preadministration level 24 h after the infusion. Antithrombin III level in the divided group showed small elevations on each session; therefore, steady increases were found after serial administrations of the agent. On the third day, AT trough activities in the divided group were significantly higher than those in the combined group (P = 0.005). However, peak AT activities in the combined group after AT administration were higher than those in the divided group throughout the study (P = 0.024). Aggravation of bleeding tendency occurred more frequently in the combined group (P = 0.03). Half-life times on the distribution phase in both groups were remarkably shorter than those of previously reported control in congenital AT deficiency. This suggests an increased vascular permeability in the critical patients in this study. Distribution volume in the patients here increased significantly as compared with the previous controls. This is the first PK report using a two-compartment model to demonstrate that remarkable increases in vascular permeability and distribution volume occur in critical patients with DIC, and if the same dose is administered intermittently in such PK situation, AT administration in divided manner can maintain plasma AT trough activity higher than that in the combined method.