Milrinone Pharmacokinetics and Acute Kidney Injury (MIL-PK)

USE OF ACUTE KIDNEY INJURY BIOMARKERS TO PREDICT IMPAIRED MILRINONE PHARMACOKINETICS IN CHILDREN FOLLOWING CARDIAC SURGERY

Acute kidney injury (AKI) occurs in 40% of children following heart surgery. Serum creatinine (Scr) is a late biomarker of AKI, rising 24-48 hours after surgery. Thus, for medicines excreted in the urine, AKI could potentially lead to toxic levels in the blood. Urinary biomarkers have the ability to detect AKI earlier. Whether early detection of AKI through urinary biomarkers can predict altered drug levels is unknown.

Milrinone is used to improve heart function after surgery, but accumulates in AKI resulting in low blood pressure. Dose adjustments are not currently possible because of the late rise in SCr, and are based on clinical parameters that may lead to clinically relevant over or under-dosing. Thus, this study will address an important knowledge gap being the first to use elevations of AKI biomarker concentrations to anticipate increased milrinone levels.

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury; Congenital Heart Disease

• Study Type: Observational
• Enrollment (Actual): 92

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All patients less than or equal to 1 year who present for cardiac surgery at Cincinnati Children's Hospital Medical Center who meet the eligibility criteria.

Description

Inclusion Criteria:

• Undergoing cardiothoracic surgery with cardiopulmonary bypass
• weight greater than 2500 grams (5 pounds 8 ounces) at the time of surgery
• gestational age > 36 weeks
• age less < to 1 year
• infants with complex congenital heart disease
• use of milrinone in the intra-operative and post-operative period.

Exclusion Criteria:

• Pre-existing kidney disease (structural and functional abnormalities) as determined by the Principal Investigator
• use of aminoglycosides within 48 hours of planned surgery
• cardiac arrest prior to cardiac surgery
• extracorporeal membrane oxygenation prior to cardiac surgery
• urinary tract infection prior to surgery
• repair of an isolated atrial or ventricular septal defect

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Acute kidney injury; AKI defined by an elevation in urinary AKI biomarkers
No acute kidney injury; No AKI defined by normal urinary AKI biomarkers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker elevation and milrinone clearance	The primary outcome variables for Aim 1 are an elevation in urinary AKI biomarkers to predict a 25% reduction in milrinone clearance.	By 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Creatinine elevation and milrinone clearance	The secondary outcome variables for Aim 2 include a 50-75% increase in SCr to predict a 25% reduction in milrinone clearance	by 72 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemodynamic parameters and AKI	Parameters of hemodynamic function defined by a decrease in central venous pressure of > 5cmH20, and/or a decrease in superior vena cava saturation by >10% at 12-36 hours after cardiopulmonary bypass. These surrogate markers of clinical outcome will be correlated with the following: operative mortality, longer time to achieve negative fluid balance, higher vasoactive inotrope score and longer intensive care and hospital length of stay.	by 72 hours

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Thrasher Research Fund
• Investigators: Principal Investigator: Katja M Gist, DO, MSCS, University of Colorado, Denver

Publications and helpful links

General Publications

• Mizuno T, Gist KM, Gao Z, Wempe MF, Alten J, Cooper DS, Goldstein SL, Vinks AA. Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery. Clin Pharmacokinet. 2019 Jun;58(6):793-803. doi: 10.1007/s40262-018-0729-3.
• Gist KM, Cooper DS, Wrona J, Faubel S, Altmann C, Gao Z, Marino BS, Alten J, Hock KM, Mizuno T, Vinks AA, Joy MS, Wempe MF, Bennett MR, Goldstein SL. Acute Kidney Injury Biomarkers Predict an Increase in Serum Milrinone Concentration Earlier Than Serum Creatinine-Defined Acute Kidney Injury in Infants After Cardiac Surgery. Ther Drug Monit. 2018 Apr;40(2):186-194. doi: 10.1097/FTD.0000000000000496.
• Gist KM, Goldstein SL, Wrona J, Alten JA, Basu RK, Cooper DS, Soranno DE, Duplantis J, Altmann C, Gao Z, Faubel S. Kinetics of the cell cycle arrest biomarkers (TIMP-2*IGFBP-7) for prediction of acute kidney injury in infants after cardiac surgery. Pediatr Nephrol. 2017 Sep;32(9):1611-1619. doi: 10.1007/s00467-017-3655-y. Epub 2017 Apr 5.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): July 31, 2017
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: October 17, 2013
• First Submitted That Met QC Criteria: October 17, 2013
• First Posted (Estimate): October 21, 2013

Study Record Updates

• Last Update Posted (Actual): June 22, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Renal Insufficiency; Cardiovascular Abnormalities; Heart Diseases; Wounds and Injuries; Acute Kidney Injury; Heart Defects, Congenital
• Other Study ID Numbers: 2013-2507