Ignite Creation Date:
2024-05-06 @ 8:22 AM
Last Modification Date:
2024-10-26 @ 11:59 AM
Study NCT ID:
NCT02728128
Status:
COMPLETED
Last Update Posted:
2020-03-04
First Post:
2016-03-08
Brief Title:
Platelet and Tissue cAMP Novel Biomarkers of Milrinone Efficacy in Children
Sponsor:
University of Colorado Denver
Organization:
University of Colorado Denver
Study Overview
Official Title:
Platelet and Tissue cAMP Novel Biomarkers of Milrinone Efficacy in Children
Status:
COMPLETED
Status Verified Date:
2020-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to identify if circulating platelet cyclic adenosine monophosphate cAMP levels can be used as a biomarker of milrinone efficacy in children following cardiac surgery or undergoing heart transplant
Detailed Description:
Milrinone is a phosphodiesterase type III PDE3 inhibitor with sites of action in cardiac and vascular smooth muscle PDE3 hydrolyzes the critical second messenger cyclic adenosine monophosphate cAMP and PDE3 inhibition PDE3i results in a positive inotropic effect in the heart through an increase in cAMP PDE3i causes relaxation of the vascular smooth muscle and induces vasodilation while concomitantly reducing myocardial oxygen consumption
In adults long term PDE3i results in malignant arrhythmias and an increased risk of sudden death and is therefore not a recommended therapy in this population However in the pediatric Heart Failure HF population long-term outpatient milrinone infusions are safely used as a palliative therapy or as a bridge to transplant without an increased risk of unexpected deaths and results in fewer HF emergency department visits and admissions and improved New York Heart Association NYHARoss classification In addition short term PDE3i ie milrinone is successfully and routinely used in children presenting with decompensated HF following cardiac surgery In children undergoing cardiac surgery with cardiopulmonary bypass there is a predictable fall in cardiac index 6 to 18 hours after cardiac surgery This phenomenon is known as low cardiac output syndrome LCOS and is typified by tachycardia and poor perfusion resulting in end-organ dysfunction and risk for cardiac arrest Milrinone is the only proven drug for prophylactic use in children following cardiac surgery for the prevention of LCOS
While standard dosing of milrinone is routinely used in children the actual dose-response relationship is unknown Indeed the investigators have noted significant variability in serum milrinone concentrations between patients despite weight based dosing strategies This uncertainty in dosing is confounded by differences in patient age size and ontologic maturation of the kidneys Milrinone dose adjustments therefore vary widely among practitioners based on urine output degree of systemic vasodilation and a change in serum creatinine Additional uncertainty resides in the inability to easily identify the most appropriate milrinone dose to produce a biological effect such as an increase in the critical secondary messenger cAMP in the pediatric population
Because milrinone is excreted as unchanged drug in the urine kidney function is a critical factor in milrinone dosing Recently published data demonstrate that 73 of milrinone levels in children with acute kidney injury AKI were outside the therapeutic range Thus children are particularly vulnerable to inappropriate milrinone dosing Currently AKI is diagnosed by an increase in serum creatinine SCr Unfortunately the increase in SCr may not occur until 3 days after AKI occurs Thus in children treated with milrinone undetected AKI would result in significant over-dosing Since milrinone is also a potent vasodilator excess milrinone dosing in AKI could lead to hypotension - and further exacerbation of AKI Therefore early detection of AKI is especially important in children receiving milrinone Preliminary data demonstrate that supra therapeutic milrinone concentrations and urinary AKI biomarkers increase in advance of SCr in patients with AKI In this grant the investigators propose to determine if increases in Tissue inhibitor metalloproteinase and insulin like growth factor binding protein-7 TIMP2xIGFBP7 prior to an increase in SCr will correlate with increased platelet cAMP and supra-therapeutic milrinone levels
In the absence of the ability to identify the optimal dose children are at risk for clinically relevant over or under-dosing with milrinone that can lead to hemodynamic compromise and end organ dysfunction While clinical response to milrinone remains the most important factor in dose titration decisions in order to fully optimize milrinone dosing and minimize drug-related toxicity a biomarker representative of biologic milrinone effect is needed The Investigators recently demonstrated that milrinone treatment results in increased myocardial cAMP levels and augmented phospholamban phosphorylation in children but not in adults with idiopathic dilated cardiomyopathy In addition preliminary data suggest that platelet cAMP levels correlate with tissue levels The purpose of this study is to determine if platelet cAMP levels can serve as a circulating biomarker for end organ cardiac milrinone efficacy and investigate whether changes in this biomarker correlate with clinical efficacy Defining platelet cAMP levels in pediatric patients with heart disease would provide the basis for a personalized approach to milrinone dose titration and allow identification of those most likely to benefit from its use
In adults long term PDE3i results in malignant arrhythmias and an increased risk of sudden death and is therefore not a recommended therapy in this population However in the pediatric Heart Failure HF population long-term outpatient milrinone infusions are safely used as a palliative therapy or as a bridge to transplant without an increased risk of unexpected deaths and results in fewer HF emergency department visits and admissions and improved New York Heart Association NYHARoss classification In addition short term PDE3i ie milrinone is successfully and routinely used in children presenting with decompensated HF following cardiac surgery In children undergoing cardiac surgery with cardiopulmonary bypass there is a predictable fall in cardiac index 6 to 18 hours after cardiac surgery This phenomenon is known as low cardiac output syndrome LCOS and is typified by tachycardia and poor perfusion resulting in end-organ dysfunction and risk for cardiac arrest Milrinone is the only proven drug for prophylactic use in children following cardiac surgery for the prevention of LCOS
While standard dosing of milrinone is routinely used in children the actual dose-response relationship is unknown Indeed the investigators have noted significant variability in serum milrinone concentrations between patients despite weight based dosing strategies This uncertainty in dosing is confounded by differences in patient age size and ontologic maturation of the kidneys Milrinone dose adjustments therefore vary widely among practitioners based on urine output degree of systemic vasodilation and a change in serum creatinine Additional uncertainty resides in the inability to easily identify the most appropriate milrinone dose to produce a biological effect such as an increase in the critical secondary messenger cAMP in the pediatric population
Because milrinone is excreted as unchanged drug in the urine kidney function is a critical factor in milrinone dosing Recently published data demonstrate that 73 of milrinone levels in children with acute kidney injury AKI were outside the therapeutic range Thus children are particularly vulnerable to inappropriate milrinone dosing Currently AKI is diagnosed by an increase in serum creatinine SCr Unfortunately the increase in SCr may not occur until 3 days after AKI occurs Thus in children treated with milrinone undetected AKI would result in significant over-dosing Since milrinone is also a potent vasodilator excess milrinone dosing in AKI could lead to hypotension - and further exacerbation of AKI Therefore early detection of AKI is especially important in children receiving milrinone Preliminary data demonstrate that supra therapeutic milrinone concentrations and urinary AKI biomarkers increase in advance of SCr in patients with AKI In this grant the investigators propose to determine if increases in Tissue inhibitor metalloproteinase and insulin like growth factor binding protein-7 TIMP2xIGFBP7 prior to an increase in SCr will correlate with increased platelet cAMP and supra-therapeutic milrinone levels
In the absence of the ability to identify the optimal dose children are at risk for clinically relevant over or under-dosing with milrinone that can lead to hemodynamic compromise and end organ dysfunction While clinical response to milrinone remains the most important factor in dose titration decisions in order to fully optimize milrinone dosing and minimize drug-related toxicity a biomarker representative of biologic milrinone effect is needed The Investigators recently demonstrated that milrinone treatment results in increased myocardial cAMP levels and augmented phospholamban phosphorylation in children but not in adults with idiopathic dilated cardiomyopathy In addition preliminary data suggest that platelet cAMP levels correlate with tissue levels The purpose of this study is to determine if platelet cAMP levels can serve as a circulating biomarker for end organ cardiac milrinone efficacy and investigate whether changes in this biomarker correlate with clinical efficacy Defining platelet cAMP levels in pediatric patients with heart disease would provide the basis for a personalized approach to milrinone dose titration and allow identification of those most likely to benefit from its use
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None