Intensive Care Med (1990) 16:303-306 IntensiveCare Medicine 9 Springer-Verlag1990 Gentamicin volume of distribution in critically ill septic patients C. Triginer 1, I. Izquierdo 2, R. Fernfindez 1, J. Rello 1, J. Torrent 2, S. Benito 1 and A. Net 1 1Intensive Care Unit, 2Clinical Pharmacology Unit, Hospital de la Santa Creu i Sam Pau, Universitat Aut6noma de Barcelona, Barcelona, Spain Received: 7 December 1989; accepted: 8 February 1990 Abstract. Gentamicin intrapatient pharmacokinetics variations were studied in 40 critically ill medical pa- tients, suffering gram-negative sepsis. These patients were studied in two phases throughout gentamicin treatment: firstly, on the second day of treatment~ when aggressive fluid therapy was required, and secondly, five days later, when patients had achieved a more stable clinical condi- tion. Pharmacokinetic parameters were determined using least squares linear regression analysis assuming a one- compartment model using the Sawchuk-Zaske method. The apparent volume of distribution (Vd) in the first phase of the study was 0.43 _+0.12 L/kg, while on the sev- enth day of treatment it was 0.29_+0.17 L/kg (p<0.001). Statistically significant differences were also observed for peak serum concentration (p<0.001), total dosage rec- ommended (p<0.001) and half-life (p < 0.05), whilst dif- ferences were not found for trough levels. From the analy- sis of the results obtained, we recommend increasing the initial dosage and monitoring plasma levels within the first days of therapy in critically ill patients treated with gentamicin, since important variations in aminoglycoside Vd related to disease, fluid balance and renal function, commonly occur in these patients. Key words: Gentamicin - Volume distribution - Sepsis Critically ill patients constitute a unique challenge in drug dosage due to the physiological alterations that ac- company severe illness and the rapidly changing condi- tion of these patients. Knowledge of the pharmacokinetic implications of physiological changes in critically ill pa- tients and the impact on pharmacodynamics is useful for selecting an initial dosage regimen and for further drug dosage adjustments. Changes in cardiac output, renal and hepatic func- tion, and circulating serum proteins, commonly seen in critically ill septic patients [1, 2], can alter the rate and ex- tent of drug elimination and consequently its plasma lev- els. Aminoglycosides are an important group of an- timicrobials currently used in the treatment of serious gram-negative infections. Their effectiveness is closely re- lated to their ability to rapidly achieve plasma levels with- in the therapeutic range [3]. However, standard doses fail to reach desired therapeutic levels in septic patients [4]. As these antimicrobials are eliminated almost exclu- sively by the renal route they constitute a good model for demonstrating pharmacokinetic variations. Interindivid- ual differences in aminoglycoside pharmacokinetics have been widely documented, and many variables (age, sex, haematocrit, weight, renal function, body temperature) have been shown to correlate with aminoglycoside clear- ance [5, 6]. The intraindividual variations due to sepsis [7, 8] and mechanical ventilation [9] have been recently described although not extensively evaluated. Aminogly- coside pharmacokinetics in critically ill patients are ex- tremely variable, and dosage requirements may vary widely despite normal renal function [5, 6]. Microcomputers have enabled rapid and accurate cal- culations using the one compartmental pharmacokinetic model of Sawchuck and Zaske. Further, fluorescent po- larization immunoassay (TDx, Abbott) has allowed rapid determination of plasma concentrations individualizing drug requirements. The aim of the study was: 1) to describe the intrapa- tient variations of gentamicin pharmacokinefics in criti- cally ill septic patients, and 2) to evaluate the relationship between changes in physiological variables and the in- trapatient variability in gentamicin pharmacokinetic pro- files. Material and methods Patient population Criticallyill patients aged 18 or over,admittedto our intensivecare unit were enrolled into a prospective study. The protocol met the ethical standards of the institution's commiteeof researchwith humans. Each patient received gentamicin for known or suspectedgram-negativesep- sis including soft tissue or intra-abdominalinfectionor septicaemia, di-