title: Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood.
abstract: BACKGROUND
  As a result of drug sequestration and increased volume of distribution, the extracorporeal membrane oxygenation (ECMO) procedure might lead to a decrease in drug concentrations during a patient's treatment. The aim of this study was to evaluate sedative, antibiotic and immunosuppressive drug loss in ECMO circuit using ex-vivo and in-vitro experiments.
  
  
  METHODS
  Blood concentrations of propofol, midazolam, cyclosporine and vancomycin were measured in an ex-vivo ECMO circuit primed with whole human blood, and compared to controls stored in polypropylene tubes. In vitro experiments were also conducted to further explore the role of temperature, oxygen exposure and polyvinylchloride surfaces on propofol loss in the ECMO circuit.
  
  
  RESULTS
  Propofol concentration decreased rapidly; 70% of its baseline concentration was lost after only 30 minutes, and only 11% remained after five hours (P <0.001 for the comparison with control polypropylene tube propofol concentration). Further experiments demonstrated that oxygen exposure and contact with polyvinylchloride tubing were respectively responsible for 70% and 85% of propofol loss after 45 minutes. Midazolam concentration also rapidly decreased in the ECMO circuit, with only 54% and 11% of baseline concentration being detected at 30 minutes and 24 hours respectively (P = 0.01 versus control). Alternatively, cyclosporine concentration remained stable for the five first hours, then decreased to 78% and 73% of the baseline value after 24 hours and 48 hours, (P = 0.35 versus control). Lastly, vancomycin concentration remained stable in the ECMO circuit for the 48-hour experimental protocol.
  
  
  CONCLUSIONS
  We observed important losses of propofol and midazolam, while cyclosporine concentration decreased slowly and moderately, and vancomycin concentration remained unchanged in the ex-vivo ECMO circuit primed with whole human blood. These data might help intensive care unit physicians planning clinical trials with a final objective to better adapt doses of these drugs while treating critically ill ECMO patients.
authors.affiliation: Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Paris Sud University, Châtenay-Malabry, France. florian.lemaitre@chu-rennes.fr.|Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes University Hospital, Rennes, France. florian.lemaitre@chu-rennes.fr.|Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes 1 University, Rennes, France. florian.lemaitre@chu-rennes.fr.|Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France. florian.lemaitre@chu-rennes.fr.
authors.forename: Florian
authors.initials: F
authors.lastname: Lemaitre
authors.affiliation: Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Paris Sud University, Châtenay-Malabry, France. nesrinehasni@yahoo.fr.
authors.forename: Nesrine
authors.initials: N
authors.lastname: Hasni
authors.affiliation: Paris 6 University Pierre et Marie Curie, 91-105 Boulevard de l'Hôpital, 75013, Paris, France. pascal.leprince@psl.aphp.fr.|Cardiovascular Surgery department, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, AP-HP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France. pascal.leprince@psl.aphp.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Leprince
authors.affiliation: Cardiovascular Surgery department, Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, AP-HP, 47-83 Boulevard de l'Hôpital, 75013, Paris, France. emmanuel.corvol@psl.aphp.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Corvol
authors.affiliation: Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Paris Sud University, Châtenay-Malabry, France. belhabib.ghassen@yahoo.fr.
authors.forename: Ghassen
authors.initials: G
authors.lastname: Belhabib
authors.affiliation: Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes University Hospital, Rennes, France. pierre.fillatre@chu-rennes.fr.|Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes 1 University, Rennes, France. pierre.fillatre@chu-rennes.fr.|Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France. pierre.fillatre@chu-rennes.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fillâtre
authors.affiliation: Service de Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, iCAN, Institute of Cardiometabolism and Nutrition, 47, Boulevard de l'Hôpital, 75651, Paris, Cedex 13, France. charles-edouard.luyt@psl.aphp.fr.|Paris 6 University Pierre et Marie Curie, 91-105 Boulevard de l'Hôpital, 75013, Paris, France. charles-edouard.luyt@psl.aphp.fr.
authors.forename: Charles-Edouard
authors.initials: CE
authors.lastname: Luyt
authors.affiliation: Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes University Hospital, Rennes, France. cyril.leven@gmail.com.|Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes 1 University, Rennes, France. cyril.leven@gmail.com.|Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France. cyril.leven@gmail.com.
authors.forename: Cyril
authors.initials: C
authors.lastname: Leven
authors.affiliation: Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Paris Sud University, Châtenay-Malabry, France. robert.farinotti@u-psud.fr.
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.affiliation: Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Paris Sud University, Châtenay-Malabry, France. christine.fernandez@u-psud.fr.|Pharmacy Department, Saint-Antoine Hospital, Assistance Publique Hôpitaux de Paris, AP-HP, 184 rue du faubourg Saint-Antoine, 75012, Paris, France. christine.fernandez@u-psud.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.affiliation: Service de Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, iCAN, Institute of Cardiometabolism and Nutrition, 47, Boulevard de l'Hôpital, 75651, Paris, Cedex 13, France. alain.combes@psl.aphp.fr.|Paris 6 University Pierre et Marie Curie, 91-105 Boulevard de l'Hôpital, 75013, Paris, France. alain.combes@psl.aphp.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Combes
mesh_terms: D000890:Anti-Infective Agents / Q000097:blood* / Q000627:therapeutic use; D001769:Blood; D016638:Critical Illness; D016572:Cyclosporine / Q000097:blood* / Q000627:therapeutic use; D016903:Drug Monitoring; D015199:Extracorporeal Membrane Oxygenation / Q000295:instrumentation*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood* / Q000627:therapeutic use; D008874:Midazolam / Q000097:blood* / Q000627:therapeutic use; D008954:Models, Biological; D011143:Polyvinyl Chloride / Q000009:adverse effects; D015742:Propofol / Q000097:blood* / Q000627:therapeutic use; D014640:Vancomycin / Q000097:blood* / Q000627:therapeutic use
chemical_list: D000890:Anti-Infective Agents; D006993:Hypnotics and Sedatives; D014640:Vancomycin; D016572:Cyclosporine; D011143:Polyvinyl Chloride; D008874:Midazolam; D015742:Propofol