Drug Monitoring in Critically Ill Patients During Extracorporeal Life Support

Study Overview
=================
Brief Summary
-----------------
About 70% of critically ill patients require antiinfective therapy. Optimal antibiotic dosing is key to improve patient survival, reduce toxic effects and minimise the emergence of bacterial resistance. There is a growing body of evidence demonstrating the existence of significant changes in pharmacokinetics (PK) in intensive care patients, particularly those with extracorporeal therapy (extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT)). To characterize the effects of extracorporal therapy for critically ill patients, we designed a prospective pilot observational study using a drug monitoring to derive relevant effects of extracorporeal therapy and clinical patient characteristics for the treatment with meropenem, teicoplanin, linezolid, piperacillin/tazobactam, levofloxacin and acyclovir.

Detailed Description
-----------------
About 70% of critically ill patients require antiinfective therapy. Optimal antibiotic dosing is key to improve patient survival, reduce toxic effects and minimise the emergence of bacterial resistance. However, there is a growing body of evidence demonstrating the existence of significant changes in pharmacokinetics (PK) in intensive care patients, particularly those with extracorporeal therapy (extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT)). Existing antiinfectivedosing regimens assume a normal PK; currently there are no evidence-based antiinfective dosing guidelines for critically ill patients available. The current recommendations of the Paul-Ehrlich Society and the Surviving Sepsis Campaign therefore recommend explicitly appliance of a therapeutic drug monitoring (TDM) for intensive care patients to individually adjust dosing and to avoid potential over- or underdosing. To characterize the effects of extracorporal therapy for critically ill patients, we designed a prospective pilot observational study using a drug monitoring. Six antiinfectives (meropenem, teicoplanin, linezolid, piperacillin / tazobactam, levofloxacin and aciclovir) will be investigated as index substances for the various antiinfective groups. A total of 100 patients, divided into 5 groups of 20 patients, will be examined in this study: 1. venovenous (vv)-ECMO, 2. venoarterial (va)-ECMO, 3. vv-ECMO + CRRT, 4. va-ECMO + CRRT, 5. control group. Sampling for determination of trough and peak levels of the study substances will take place during the different dosing intervals. Patients will be included at the beginning of ECMO therapy within 24-48h after start of an antiinfective therapy with at least one of the index-substances; observation period will be a total of 5 days. The collected data will be analyzed to identify covariates associated with changes in PK for the 6 different antiinfectives in critically ill patients receiving extracorporeal therapy. Using the comprehensive data set collected, the pharmacokinetic profile of the 6 antiinfectives as well as other influencing factors will be constructed to assess the need for dose adjustment of antiinfective agents in these patients. This prospective observational trial addresses the current knowledge deficiency with the aim to derive relevant effects of extracorporeal therapy and clinical patient characteristics for the treatment with meropenem, teicoplanin, linezolid, piperacillin/tazobactam, levofloxacin and acyclovir. With these relevant results, adapted dosing of antiinfectives can probably be improved in critically ill patients with extracorporeal therapy in future.

Official Title
-----------------
Drug Monitoring of Antiinfectives in Critically Ill Patients Receiving Extracorporeal Life Support - a Prospective Observational Pilot Study

Conditions
-----------------
Drug Monitoring of Antiinfectives in Critically Ill Patients Receiving Extracorporeal Life Support

Intervention / Treatment
-----------------
* Other: No Intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age > 18 Informed consent Clinical infection indicated for intravenous therapy with at least one of the following index anti-infectives: meropenem, teicoplanin, linezolid, piperacillin/tazobactam, levofloxacin and/oraciclovir Application of an ECLS procedure with an expected duration of at least five days Exclusion Criteria: Pregnancy Massive Hemorrhage

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| VA ECMO<br>Patients will be included at the beginning of VA ECMO therapy within 24-48h after start of an antiinfective therapy | Other: No Intervention<br>* No Intervention<br>|
| VA EMCO + RRT<br>Patients with RRT will be included at the beginning of VA ECMO therapy within 24-48h after start of an antiinfective therapy | Other: No Intervention<br>* No Intervention<br>|
| VV ECMO<br>Patients will be included at the beginning of VV ECMO therapy within 24-48h after start of an antiinfective therapy | Other: No Intervention<br>* No Intervention<br>|
| VV ECMO + RRT<br>Patients with RRT will be included at the beginning of VV ECMO therapy within 24-48h after start of an antiinfective therapy | Other: No Intervention<br>* No Intervention<br>|
| Control<br>Patients will be included within 24-48h after start of an antiinfective therapy | Other: No Intervention<br>* No Intervention<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of antiinfective agents | pharmacokinetic profile of 6 antiinfectives (meropenem, teicoplanin, linezolid, piperacillin / tazobactam, levofloxacin and aciclovir) as well as other influencing factors will be constructed to assess the need for dose adjustment of antiinfective agents | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
drug monitoring, antiinfectives, intensive care, ECMO