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A Population Pharmacokinetic Analysis to Study the Effect of Extracorporeal Membrane Oxygenation on Cefepime Disposition in Children

Zuppa, Athena F., MD, MSCE1,2; Zane, Nicole R., PharmD, PhD1; Moorthy, Ganesh, PhD1,2; Dalton, Heidi J., MD, MCCM3; Abraham, Alan, MBA; Reeder, Ron W., PhD5; Carcillo, Joseph A., MD4; Yates, Andrew R., MD6; Meert, Kathleen L., MD7; Berg, Robert A., MD2; Sapru, Anil, MD8; Mourani, Peter, MD9; Notterman, Daniel A., MD10; Dean, J. Michael, MD5; Gastonguay, Marc R., PhD11 for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN)

Pediatric Critical Care Medicine: January 2019 - Volume 20 - Issue 1 - p 62–70
doi: 10.1097/PCC.0000000000001786
Extracorporeal Support

Objectives: Limited data exist on the effects of extracorporeal membrane oxygenation on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with extracorporeal membrane oxygenation using population pharmacokinetic modeling.

Design: Multicenter, prospective observational study.

Setting: The pediatric and cardiac ICUs of six sites of the Collaborative Pediatric Critical Care Research Network.

Patients: Seventeen critically ill children (30 d to < 2 yr old) on extracorporeal membrane oxygenation who received cefepime as standard of care between January 4, 2014, and August 24, 2015, were enrolled.

Interventions: None.

Measurements and Main Results: A pharmacokinetic model was developed to evaluate cefepime disposition differences due to extracorporeal membrane oxygenation. A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data. The typical value of clearance in this study was 7.1 mL/min (1.9 mL/min/kg0.75) for a patient weighing 5.8 kg. This value decreased by approximately 40% with the addition of renal replacement therapy. The typical value for V1 was 1,170 mL. In the setting of blood transfusions, V1 increased by over two-fold but was reduced with increasing age of the extracorporeal membrane oxygenation circuit oxygenator.

Conclusions: Cefepime clearance was reduced in pediatric patients treated with extracorporeal membrane oxygenation compared with previously reported values in children not receiving extracorporeal membrane oxygenation. The model demonstrated that the age of the extracorporeal membrane oxygenation circuit oxygenator is inversely correlated to V1. For free cefepime, only 14 of the 19 doses (74%) demonstrated a fT_minimum inhibitory concentration of 16 mg/L, an appropriate target for the treatment of pseudomonal infections, for greater than 70% of the dosing interval. Pediatric patients on extracorporeal membrane oxygenation might benefit from the addition of therapeutic drug monitoring of cefepime to assure appropriate dosing.

1Center for Clinical Pharmacology, The Children’s Hospital of Philadelphia, Philadelphia, PA.

2Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA.

3Adult and Pediatric ECLS, INOVA Fairfax Hospital, Falls Church, VA.

4Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA.

5Department of Pediatrics, University of Utah, Salt Lake City, UT.

6Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH.

7Department of Pediatrics, Children’s Hospital of Michigan, Wayne State University, Detroit, MI.

8Division of Critical Care, UCLA Mattel Children’s Hospital, Los Angeles, CA.

9Section of Critical Care, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO.

10Department of Molecular Biology, Princeton University, Princeton, NJ.

11Metrum Research Group, Tariffville, CT.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network (CPCCRN) members are as follows: Children’s Hospital of Michigan: Kathleen L. Meert, MD, Sabrina M. Heidemann, MD; Children’s Hospital of Philadelphia: Robert A. Berg, MD, Athena F. Zuppa, MD, MSCE; Children’s National Medical Center: Murray M. Pollack, MD, Michael Bell, MD, David L. Wessel, MD, John T. Berger, MD, Randall Burd, MD, PhD; Children’s Hospital Colorado: Peter M. Mourani, MD, Todd C. Carpenter, MD; Nationwide Children’s Hospital: Mark W. Hall, MD, Andrew R. Yates, MD; Mattel Childrens Hospital: Anil Sapru, MD, MBBS, MAS; Benioff Children’s Hospital: Patrick McQuillen, MD; Children’s Hospital of Pittsburgh: Joseph A. Carcillo, MD, Ericka L. Fink, MD, MS; University of Utah School of Medicine Data Coordinating Center: J. Michael Dean, MD, MBA, Richard Holubkov, PhD, Katherine Sward, PhD, RN, Ron W. Reeder, PhD, John VanBuren, PhD; Eunice Kennedy Shriver National Institute for Child Health and Human Development: Robert F. Tamburro, MD, MSc, Tammara L. Jenkins, MSN, RN, PCNS-BC, Valerie Maholmes, PhD; Princeton University: Daniel A. Notterman, MD.

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Supported, in part, by the following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Health and Human Services: U10HD063108 (to Drs. Zuppa and Berg), 5R01HL112745 (to Dr. Zuppa), U10HD063114 (to Dr. Dalton), U10HD049983 and UG1HD049983 (to Mr. Abraham and Dr. Carcillo), U01HD049934 and UG01HD049934 (Drs. Reeder and Dean), UG1HD083170 (to Dr. Yates), U10HD050096 and UG1HD050096 (to Dr. Meert), UG1HD63108 (to Dr. Berg), UG1HD083116 and U10HD050012 (to Dr. Sapru), and UG1HD083171 (to Dr. Mourani).

Drs. Zuppa, Moorthy, Dalton, Reeder, Carcillo, Yates, Meert, Berg, Sapru, Mourani, and Dean received support for article research from the NIH. Drs. Dalton’s, Reeder’s, Meert’s, Berg’s, and Mourani’s institutions received funding from the NIH. Dr. Dalton received funding from Innovative Extracorporeal Membrane Oxygenation Concepts. Drs. Carcillo's, Sapru's, and Dean's institutions received funding from the NICHD. Dr. Yates’ institution received funding from a NIH/NICHD/Collaborative Pediatric Critical Care Research Network grant. Dr. Mourani disclosed off-label product use of cefipime. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Athena F. Zuppa, MD, MSCE, Center for Clinical Pharmacology, The Children’s Hospital of Philadelphia, 3500 Civic Center Blvd, Philadelphia, PA 19104. E-mail:

©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies