Dataset Information

Population Pharmacokinetics and Dosing Simulations of Ceftriaxone in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (An ASAP ECMO Study).

ABSTRACT:

Background

Despite the surge in use of extracorporeal membrane oxygenation (ECMO) in the adult intensive care unit, little guidance is available on the appropriate dosing of antimicrobials in this setting. Ceftriaxone is an antimicrobial with a high affinity to plasma protein, a property identified in the literature as susceptible to sequestration into extracorporeal circuits and hypothesised to require dosage adjustments in this setting.

Objective

The aim of this study was to describe the pharmacokinetics of ceftriaxone and identify the best dosing regimen for critically ill adult patients receiving ECMO.

Methods

Serial blood samples were taken from patients receiving both ECMO and ceftriaxone. Total and unbound drug concentrations were measured in plasma by chromatographic assay and analysed using a population pharmacokinetic approach with Pmetrics^®. Dosing simulations were performed to identify the optimal dosing strategy: 60 and 100% of time with free (unbound) drug concentration exceeding the minimum inhibitory concentration (fT_>MIC).

Results

In total, 14 patients were enrolled, of which three were receiving renal replacement therapy (RRT). Total and unbound ceftriaxone was best described in a two-compartment model with total body weight, serum albumin concentrations, creatinine clearance (CrCL), and the presence of RRT included as significant predictors of pharmacokinetics. Patients not on RRT generated a mean renal clearance of 0.90 L/h, non-renal clearance of 0.33 L/h, and central volume of distribution of 7.94 L. Patients on RRT exhibited a mean total clearance of 1.18 L/h. ECMO variables were not significant predictors of ceftriaxone pharmacokinetics. Steady-state dosing simulations found that dosages of 1 g every 12 h and 2 g every 24 h achieved >90% probabilities of target attainment in patients with CrCL of 0 mL/min with RRT and 30 and 100 mL/min and various serum albumin concentrations (17 and 26 g/L).

Conclusions

Dosing recommendations for critically ill adult patients not on ECMO appear to be sufficient for patients on ECMO. Patients exhibiting augmented renal clearance (> 130 mL/min) or treatment of less susceptible pathogens may require higher doses, which requires further investigation.

SUBMITTER: Cheng V

PROVIDER: S-EPMC9249724 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objectives: This study aimed to identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps, and inform future pharmacology studies. Data Sources: We systematically searched the databases MEDLINE, CINAHL, and Embase from earliest publication until November 2018 using a controlled vocabulary and keywords related to "ECMO" and "pharmacokinetics," "pharmacology," "drug disposition," "dosing," and "pediatrics." Study Selection: Inclusion criteria were as follows: study population aged <18 years, supported on ECMO for any indications, received any medications while on ECMO, and reported pharmacokinetic data. Data Extraction: Clearance and/or volume of distribution values were extracted from included studies. Data Synthesis: Forty-one studies (total patients = 574) evaluating 23 drugs met the inclusion criteria. The most common drugs studied were antimicrobials (n = 13) and anticonvulsants (n = 3). Twenty-eight studies (68%) were conducted in children <1 year of age. Thirty-three studies (80%) were conducted without intra-study comparisons to non-ECMO controls. Increase in volume of distribution attributable to ECMO was demonstrated for nine (56%) drugs: cefotaxime, gentamicin, piperacillin/tazobactam, fluconazole, micafungin, levetiracetam, clonidine, midazolam, and sildenafil (range: 23-345% increase relative to non-ECMO controls), which may suggest the need for higher initial dosing. Decreased volume of distribution was reported for two drugs: acyclovir and ribavirin (50 and 69%, respectively). Decreased clearance was reported for gentamicin, ticarcillin/clavulanate, bumetanide, and ranitidine (range: 26-95% decrease relative to non-ECMO controls). Increased clearance was reported for caspofungin, micafungin, clonidine, midazolam, morphine, and sildenafil (range: 25-455% increase relative to non-ECMO controls). Conclusions: There were substantial pharmacokinetic alterations in 70% of drugs studied in children on ECMO. However, studies evaluating pharmacokinetic changes of many drug classes and those that allow direct comparisons between ECMO and non-ECMO patients are still lacking. Systematic evaluations of pharmacokinetic alterations of drugs on ECMO that incorporate multidrug opportunistic trials, physiologically based pharmacokinetic modeling, and other methods are necessary for definitive dose recommendations. Trial Registration Prospero Identifier: CRD42019114881.

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.