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Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine–Defined Acute Kidney Injury in Infants After Cardiac Surgery

Gist, Katja, M., DO, MSCS*; Cooper, David, S., MD, MPH; Wrona, Julia, BS*; Faubel, Sarah, MD; Altmann, Christopher, BS; Gao, Zhiqian, MSPH, PhD§; Marino, Bradley, S., MD, MPP, MSCE; Alten, Jeffrey, MD; Hock, Kristal, M., RN, MSN, CNL, BS; Mizuno, Tomoyuki, PhD**; Vinks, Alexander, A., PharmD, PhD**; Joy, Melanie, S., PharmD, PhD††; Wempe, Michael, F., PhD††; Bennett, Michael, R., PhD‡‡; Goldstein, Stuart, L., MD†,§,‡‡

doi: 10.1097/FTD.0000000000000496
Original Article

Background: Milrinone, an inotropic agent used ubiquitously in children after cardiac surgery, accumulates in acute kidney injury (AKI). We assessed if urinary AKI biomarkers are predictive of an increase in milrinone concentrations in infants after cardiac surgery.

Methods: Multicenter prospective pilot study of infants undergoing cardiac surgery. Urinary AKI biomarkers were measured in the urine at specific time intervals after cardiopulmonary bypass initiation. AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Serum milrinone concentrations were measured at specific intervals after drug initiation, dose changes, and termination. Excessive milrinone activity was defined as a 20% increase in serum concentration between 6 and 36 hours after initiation. The temporal relationship between urinary AKI biomarker concentrations and a 20% increase in milrinone concentration was assessed.

Results: AKI occurred in 31 (33%) of infants. Milrinone clearance was lower in patients with AKI (4.2 versus 5.6 L/h/70 kg; P = 0.02). Excessive milrinone activity was associated with development of serum creatinine–defined AKI [odds ratio (OR) 3.0; 95% confidence interval (CI), 1.21–7.39; P = 0.02]. Both tissue inhibitor metalloproteinase type 2 and insulin-like growth factor–binding protein type 7 (TIMP-2*IGFBP-7) ≥0.78 at 12 hours (OR 2.72; 95% CI, 1.01–7.38; P = 0.04) and kidney injury molecule 1 (KIM-1) ≥529.57 at 24 hours (OR 2.76; 95% CI, 1.06–7.17; P = 0.04) predicted excessive milrinone activity before a diagnosis of AKI.

Conclusions: In this pilot study, urine TIMP-2*IGFBP-7 and KIM-1 were predictive of AKI and excessive milrinone activity. Future studies that include a pharmacodynamics assessment of patient hemodynamics, excessive milrinone activity, and AKI biomarker concentrations may be warranted to integrate this concept into clinical practice.

*Division of Pediatric Cardiology, Department of Pediatrics, The Heart Institute, The University of Colorado, Children's Hospital Colorado, Aurora, Colorado;

Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;

Department of Internal Medicine, Division of Renal Disease and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado;

§Heart Institute Research Core, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;

The Heart Center, Divisions of Cardiology and Critical Care Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois;

Department of Pediatrics, Pediatric Cardiac Critical Care Medicine, University of Alabama, Children's of Alabama, Birmingham, Alabama;

**Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;

††Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and

‡‡Department of Pediatrics, Center for Acute Care Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Correspondence: Katja M. Gist, DO, MSCS, The Heart Institute, Children's Hospital Colorado, 13123 E 16th Avenue, B100, Aurora, CO 80045 (e-mail:

Supported by Thrasher Pediatric Research Foundation, Early Career award. K. M. Gist received grant funding from the E.W. Thrasher Foundation, The Center for Acute Care Nephrology, the Heart Institute Research Core, and the Division of Critical Care Medicine at Cincinnati Children's Hospital Medical Center also provided internal grant support for the study. Urinary TIMP-2*IGFBP-7 processing was supported by a pilot grant from the Children's Hospital Colorado Research Institute.

S. L. Goldstein has the following disclosures to report: Baxter/Gambro Renal Products—Grant support/expert panel/consultant; Akebia—consultant; Bellco—consultant; Otsuka—steering committee for a clinical trial; La Jolla Pharmaceuticals—steering committee for a clinical trial; Astute Medical Inc—Consultant; AM Pharma—Consultant; Bioporto Inc—Consultant; Reata Medical Inc—DSMB member for a study. The remaining authors declare no conflict of interest.

Clinical Trials Information: NCT01966237, October 17, 2013.

Received August 07, 2017

Accepted January 22, 2018

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