No abstract

Purpose We studied the pharmacokinetics of paracetamol and determine the incidence of hypotension after intravenous administration in medium-(MCU) and intensive care (ICU) patients. Methods All patients on the ICU/MCU starting with paracetamol i.v. were included, yielding 38 patients. Blood samples were collected at predetermined time points to determine paracetamol serum concentration. The number of patients with a clinically relevant reduction in systolic blood pressure (SBP) and the number of patients that needed intervention to regain an acceptable blood pressure level were assessed. Results Overall, pharmacokinetic data were roughly comparable with earlier publications, but differences were noted in the subgroup ICU patients. Also, there was a trend to a larger peak serum concentration (p=0.052) and a significantly smaller volume of distribution (p=0.033) in MCU patients compared with ICU patients. Twenty-two percent (22%) and 33% of patients had a clinically relevant reduction in systolic blood pressure (SBP) 15 and 30 min after start of paracetamol infusion, respectively. In six patients (16%), an intervention was needed to correct blood pressure. Overall, SBP was significantly reduced at T=15 min and 30 min postinfusion (p<0.003 at both time points) when compared with SBP at the start of paracetamol infusion. Conclusions Further research on differences in paracetamol pharmacokinetics between ICU and MCU patients is warranted, as these differences might result in differences in efficacy. Furthermore, administration of paracetamol i.v. as potential cause of hypotension in the critically ill patient must not be overlooked.

BackgroundPharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled.MethodsThis pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models.ResultsParacetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51).ConclusionsSize and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored.

Objectives To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies. Patients and methods Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR. Results The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of &gt;2.5 mg/L (100% fT&gt;5×MIC, MIC = 0.5 mg/L). Conclusions Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.