Evaluating Precision of Therapy - Milrinone

Children with congenital heart disease have significant morbidity including low cardiac output syndrome and subsequent organ dysfunction that may be prevented by optimization of circulatory function. More than half of these children receive milrinone. Clinical evaluation cannot distinguish between patients with sub-therapeutic, therapeutic, and toxic milrinone drug levels. Consequently children who require pharmacologic circulatory support may be receiving sub-optimal dosing, and children who do not need milrinone may be receiving milrinone unnecessarily. The primary objective of this study is to determine if optimizing milrinone levels with therapeutic drug monitoring in critically ill children following cardiac surgery improves clinical outcomes and reduces the duration of milrinone infusion. This study hypothesizes that optimizing milrinone levels with therapeutic drug monitoring in critically ill children following cardiac surgery will improve clinical outcomes and reduce the duration of milrinone infusion.

Study Overview

• Status: Completed
• Conditions: Congenital Heart Disease
• Intervention / Treatment: Drug: Milrinone

Detailed Description

The proposed trial is a pilot of an open label, randomized trial of milrinone therapeutic drug monitoring in patients < 18 years treated with milrinone following open-heart surgery for congenital heart disease at the Hospital for Sick Children, Toronto. We will randomize patients to (1) receiving therapeutic drug monitoring or (2) control patients who receive standard care. Standard care involves titration of milrinone infusion based on clinical examination by the treating team. Control patients will have milrinone plasma levels drawn but not analysed until the end of the study. The intervention is (1) regular measurement of milrinone levels; and (2) physician feedback of plasma levels in experimental arm by the ICU pharmacist. After obtaining consent, eligible subjects will be allocated to a trial group by random assignment (sealed envelopes) within 3 strata in a 1:1 allocation. These strata are < 2 years, 2- 10 years and > 10 years to ensure equal distribution of these age ranges in each group for pharmacokinetic analysis. For the intervention group, sampling for milrinone levels will occur at 0 hours (upon arrival to ICU with routine admission blood collection) and approximately every 6- 8 hours (whenever the line is accessed for routine blood work). The last sample will be taken 6-8 hours after cessation of infusion, or if the patient leaves the ICU, or the maximum amount of blood sampling has been reached or after 7 days for children weighing more than 8 kgs (or 5 days for children weighing less than 8 kgs), which ever comes first. Follow-up will be exclusively during the period of hospitalization in the ICU until ICU discharge. An optional algorithm with a proposed titration for milrinone will be provided for use at the discretion of the treating team. Clinical outcomes will be measured as a composite outcome of dysrhythmia, LCOS and death.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Admitted to a Pediatric (0 - 18 years) Intensive Care Unit following cardiopulmonary bypass (CPB) and surgery for congenital heart disease.
• Clinical decision by treating team to start milrinone infusion.
• Anticipated to receive milrinone infusion for more than 24hs. This limit will increase the proportion of sicker children in the sample, increasing the power of the study.
• Has an arterial line, and a central venous line defined as radiologically confirmed line
• Informed consent obtained

Exclusion Criteria:

• Premature infants (<36 weeks post-conceptual age) or weight less than 2.0 kg.
• Failure to provide consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Therapeutic Drug Monitoring; The intervention is [1] regular measurement of milrinone levels; [2]physician feedback of plasma levels in experimental arm by the ICU pharmacist ( this process currently occurs for other drugs such as vancomycin).	Drug: Milrinone; Milrinone is a potent selective phosphodiesterase (PDE) type III inhibitor which stimulates myocardial function (inotropy), causes peripheral vasodilatation (afterload reduction) and improves myocardial relaxation (lusitropy).; Other Names: Milrinone Lactate Inj
ACTIVE_COMPARATOR: Standard Care; Standard care involves titration of milrinone infusion based on clinical examination by the treating team. The control group will receive standard care: with milrinone dose modification on clinical assessment. Control patients will have milrinone plasma levels drawn but not analysed until the end of the study.	Drug: Milrinone; Milrinone is a potent selective phosphodiesterase (PDE) type III inhibitor which stimulates myocardial function (inotropy), causes peripheral vasodilatation (afterload reduction) and improves myocardial relaxation (lusitropy).; Other Names: Milrinone Lactate Inj

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LCOS,	Composite outcome	within first 48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Therapeutic Levels	Therapeutic levels at 8-16 hours post CPB measured in ng/mL [to coincide with recognized nadir in CO post cardiopulmonary bypass]	+8, +16 hours
Duration	Duration of milrinone infusion (number of hours in the week)	Duration of ICU stay or maximum of 1 week
Dosage Adjustment	Number of dosage adjustments in control and experimental group after clinical assessment	Duration of infusion or maximum of 1 week
Plasma Milrinone Levels	Plasma milrinone levels in both groups	Duration of infusion or maximum of 1 week

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: Katherine Taylor, MD, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (ACTUAL): August 1, 2020
• Study Completion (ACTUAL): August 1, 2020

Study Registration Dates

• First Submitted: April 23, 2013
• First Submitted That Met QC Criteria: April 23, 2013
• First Posted (ESTIMATE): April 26, 2013

Study Record Updates

• Last Update Posted (ACTUAL): January 6, 2022
• Last Update Submitted That Met QC Criteria: December 16, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Congenital Heart Disease; Pediatrics; Cardiopulmonary Bypass; Therapeutic Drug Monitoring; Milrinone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Milrinone
• Other Study ID Numbers: 1000032365

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO