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Meropenem Pharmacokinetics and Target Attainment in Critically Ill Patients Are Not Affected by Extracorporeal Membrane Oxygenation: A Matched Cohort Analysis.

ABSTRACT: Existing evidence is inconclusive whether meropenem dosing should be adjusted in patients receiving extracorporeal membrane oxygenation (ECMO). Therefore, the aim of this observational matched cohort study was to evaluate the effect of ECMO on pharmacokinetic (PK) variability and target attainment (TA) of meropenem. Patients admitted to the intensive care unit (ICU) simultaneously treated with meropenem and ECMO were eligible. Patients were matched 1:1, based on renal function and body weight, with non-ECMO ICU patients. Meropenem blood sampling was performed over one or two dosing intervals. Population PK modelling was performed using NONMEM7.5. TA was defined as free meropenem concentrations >2 or 8 mg/L (i.e., 1 or 4× minimal inhibitory concentration, respectively) throughout the whole dosing interval. In total, 25 patients were included, contributing 27 dosing intervals. The overall TA was 56% and 26% for the 2 mg/L and 8 mg/L target, respectively. Population PK modelling identified estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology equation and body weight, but not ECMO, as significant predictors. In conclusion, TA of meropenem was confirmed to be poor under standard dosing in critically ill patients but was not found to be influenced by ECMO. Future studies should focus on applying dose optimisation strategies for meropenem based on renal function, regardless of ECMO.

SUBMITTER: Gijsen M

PROVIDER: S-EPMC8234236 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeCritically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function.Patients and methodsA single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation <70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4.ResultsIn total, 58 patients were included, contributing 345 plasma samples over 70 dosing intervals. The 2 mg/L and 8 mg/L targets were successfully attained in 46% and 11% of all dosing intervals, respectively. A two-compartment population PK model with linear elimination and interindividual variability on clearance best described meropenem PK. The estimated creatinine clearance according to the Cockcroft-Gault equation was the only covariate retained during population PK analysis.ConclusionThis study provided detailed insight into meropenem PK in critically ill patients with preserved or increased renal function. We observed poor PK/PD target attainment, for which renal function was the only significant covariate.Trial registrationThis study is registered at ClinicalTrials.gov (NCT03560557).

Project description:BACKGROUND:Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations. METHODS:This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96?h during infusion and 72?h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses. RESULTS:A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL?=?37.8?×?EXP (0.207?×?(temperature?-?36.9))?L h-1, central volume of distribution (V1)?=?229?L, V2?=?1640?×?(total plasma protein/4.5)2.46?L, and intercompartmental clearance (Q)?=?41?L?h-1. Based on Monte Carlo simulation results, an infusion of 17.5??g?h-1 seems to reach target sufentanil concentration (0.3-0.6??g?L-1) in most ECMO patients except hypothermic patients (33?°C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low. CONCLUSIONS:This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery. TRIAL REGISTRATION:Clinicaltrials.gov NCT02581280 , December 1st, 2014.

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Meropenem Pharmacokinetics and Target Attainment in Critically Ill Patients Are Not Affected by Extracorporeal Membrane Oxygenation: A Matched Cohort Analysis.

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