Milrinone Versus Dobutamine in Critically Ill Patients

Study Overview
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Brief Summary
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The investigators are interested in determining if there is a meaningful difference between two of the most commonly used medications used to improve the pumping function of the heart among critically ill patients admitted to the Coronary Care Unit (CCU) at the University of Ottawa Heart Institute (UOHI). To do this, the investigators will randomly assign patients who are felt to require use of these medications by their treating physicians to one of the two most commonly used agents in Canada: Milrinone or Dobutamine. Each patient will be closely monitored by their healthcare team, and their medication will be adjusted based on each patient's clinical status. Information from blood work (e.g. kidney and liver function, complete blood counts, and other markers of how effectively blood is circulating in the body), assessment of end-organ function (e.g. urine output, mentation), abnormal heart rhythms noted on monitoring and results of imaging studies (e.g. angiogram, echocardiograms.) will be collected for analysis. All patients will be followed for the duration of their hospital stay at UOHI.

Detailed Description
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The use of various inotropes in the care of critically ill cardiac patients has become increasingly widespread: while predominantly used in decompensated heart failure, they have also been used in cardiogenic shock complicating acute coronary syndrome (ACS) and septic shock. Purported mechanisms of efficacy include improved cardiac output, improved end-organ perfusion, and vasodilation of both pulmonary and systemic circulations. Two of the most commonly used agents are Milrinone, a phosphodiesterase 3 inhibitor, and Dobutamine, a synthetic catecholamine with affinity for both beta-1 and 2 receptors. Both the American College of Cardiology (ACC) and the European Society of Cardiology (ESC) support inotropes for acute and chronic heart failure management with low cardiac output states. Furthermore, the ACC recommends consideration of inotropic therapy within the STEMI guidelines when ACS is complicated by cardiogenic shock, heart failure or for hemodynamic support in isolated right ventricle infarctions. Beyond primarily cardiac etiologies, inotropes have been identified as first-line additive therapy for cardiac augmentation to Norepinephrine in patients with septic shock complicated by myocardial dysfunction. Despite the lack of convincing data supporting a morbidity or mortality benefit with the use of inotropes in severe, decompensated heart failure, cardiogenic or septic shock, or in ACS, inotropic therapy is still widely used across various critical care settings. Furthermore, to date, there has been no head to head comparison of the two more commonly used positive inotropes: Dobutamine and Milrinone. Selection of one inotrope over another is often guided by physician and center preference, and consideration of and purported avoidance of possible adverse effects. In this pilot study, the investigators aim to describe that characteristics of patients receiving inotropic support in the CCU setting and identify possible differences in morbidity and mortality between Dobutamine and Milrinone among a heterogeneous population of patients admitted to the CCU at UOHI, which may help to inform a larger clinical trial in the future. The purpose of this pilot study is to: (a) describe the characteristics of patients receiving inotropic support in the coronary care unit (CCU) setting (hemodynamics prior to inotrope initiation, etiology of cardiogenic shock state, use of PA catheter and values if deemed necessary by medical team) and (b) identify possible differences in morbidity [atrial and ventricular arrhythmias, hepatic and renal function, markers of end-organ perfusion (lactate, urine output, mentation status), use of vasopressors, sustained hypotension of systolic blood pressure less than or equal to 90 mmHg for greater than 30 minutes, need for mechanical support, cardiac transplant, total length of CCU stay, length of CCU stay greater than 14 days] and mortality between patients in cardiogenic shock treated with Dobutamine versus Milrinone.

Official Title
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Comparison of Milrinone Versus Dobutamine in a Heterogeneous Population of Critically Ill Patients

Conditions
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Pulmonary Edema, Acute Coronary Syndrome, Low Cardiac Output Syndrome, Cardiogenic Shock

Intervention / Treatment
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* Drug: Milrinone
* Drug: Dobutamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have one or more of the following: Low cardiac output state, evidenced by sustained hypotension (systolic blood pressure <90 mmHg) and end organ dysfunction (altered level of consciousness, elevated lactate, renal or hepatic dysfunction) Clinical evidence of systemic and/or pulmonary congestion despite use of vasodilators and/or diuretics ACS complicated by cardiogenic shock (defined as persistent hypotension with systolic blood pressure <90 mmHg with severe reduction in cardiac index [<1.8 L/min/m2 without support or <2.2 L/min/m2 with support], left ventricular end-diastolic pressure >18 mmHg) Augmentation of cardiac output when patient already on maximal vasopressor therapy Or medical team's decision that patient needs inotropic therapy Exclusion Criteria: Unwillingness or inability to provide informed consent by the patient or substitute decision maker for healthcare decisions Female participants who are currently pregnant Patients presenting with an out-of-hospital cardiac arrest (OOHCA) Healthcare team preference for use of specific inotrope (Milrinone or Dobutamine)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Consecutive patients admitted to the Coronary Care Unit (CCU) at the Ottawa Heart Institute from start of study (tentatively set for August 2017 with anticipated end date of June 2020) and identified by the treating medical team as requiring initiation of inotrope therapy will be screened and randomized based on the healthcare team's clinical assessment of predominantly LV or RV systolic dysfunction (biventricular dysfunction will be assigned to predominantly LV dysfunction). All decisions to initiate inotrope therapy will be made by the primary care team with no involvement from the research team.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Left ventricular [LV] +/- Biventricular dysfunction<br>Assessment of left ventricular [LV] or biventricular dysfunction will be based on clinical assessment, available imaging (echocardiogram, left ventriculogram, MUGA/RNA scan, cardiac MRI, etc.) and known past medical history (if available and contributory). Patients identified as having biventricular dysfunction will be randomized within the LV dysfunction arm of the trial. Patients in this arm will be randomized in a 1:1 fashion to Milrinone or Dobutamine. | Drug: Milrinone<br>* Patients will be initiated on Milrinone at 0.125 mcg/kg/min [stage 1] and will be titrated according to a blinded protocol from stages 2 to 5 [0.250, 0.375, 0.5 and >0.5 ug/kg/min]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be [increased/decreased/maintained] at stage [1-5]' so as to ensure that treating physicians remain blinded to the allocated drug.<br>* Other names: Phosphodiesterase-3 inhibitors [PDE3] Inhibitor;Drug: Dobutamine<br>* Patients will be initiated on Dobutamine at 2.5 mcg/kg/min [stage 1] and will be titrated according to a blinded protocol from stages 2 to 5 [5.0, 7.5, 10 and >10 ug/kg/min]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be [increased/decreased/maintained] at stage [1-5]' so as to ensure that treating physicians remain blinded to the allocated drug.<br>* Other names: Beta 1/2 Agonist;|
| Active Comparator: Right ventricular [RV] dysfunction<br>Assessment of right ventricular [RV] dysfunction will be based on clinical assessment, available imaging (echocardiogram, left ventriculogram, MUGA/RNA scan, cardiac MRI, etc.) and known past medical history (if available and contributory). Patients in this arm will be randomized in a 1:1 fashion to Milrinone or Dobutamine. | Drug: Milrinone<br>* Patients will be initiated on Milrinone at 0.125 mcg/kg/min [stage 1] and will be titrated according to a blinded protocol from stages 2 to 5 [0.250, 0.375, 0.5 and >0.5 ug/kg/min]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be [increased/decreased/maintained] at stage [1-5]' so as to ensure that treating physicians remain blinded to the allocated drug.<br>* Other names: Phosphodiesterase-3 inhibitors [PDE3] Inhibitor;Drug: Dobutamine<br>* Patients will be initiated on Dobutamine at 2.5 mcg/kg/min [stage 1] and will be titrated according to a blinded protocol from stages 2 to 5 [5.0, 7.5, 10 and >10 ug/kg/min]. All orders to initiate and titrate the dose of the allocated inotrope will be written in the chart as follows: 'Study inotrope dose to be [increased/decreased/maintained] at stage [1-5]' so as to ensure that treating physicians remain blinded to the allocated drug.<br>* Other names: Beta 1/2 Agonist;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Primary End Point | Composite of all-cause in-hospital death, non-fatal MI, TIA or CVA diagnosed by a Neurologist, renal failure requiring renal replacement therapy, need for cardiac transplant or new mechanical support, any atrial or ventricular arrhythmia leading to cardiac arrest and resuscitation. | Through duration of hospitalization, up to 12 weeks following admission | 
| All-cause in-hospital death | All-cause in-hospital death | Through duration of hospitalization, up to 12 weeks following admission | 
| Non-fatal myocardial infarction [MI] | As defined by Thygesen et al., 2012 (Circulation) | Through duration of hospitalization, up to 12 weeks following admission | 
| Transient ischemic attack [TIA] or cerebrovascular accident [CVA] | Transient ischemic attack or cerebrovascular accident as diagnosed by a Neurologist either clinically and/or radiographically | Through duration of hospitalization, up to 12 weeks following admission | 
| Stay in CCU greater than or equal to 7 days | Stay in CCU greater than or equal to 7 days | Through duration of hospitalization, up to 12 weeks following admission | 
| Acute kidney injury requiring renal replacement therapy | Acute kidney injury requiring renal replacement therapy (intermittent hemodialysis or continuous renal replacement therapy) | Through duration of hospitalization, up to 12 weeks following admission | 
| Need for advanced mechanical support [specifically, intra-aortic balloon pump, Impella, ventricular assist device or extra-corporeal membrane oxygenation] or cardiac transplant | Need for new mechanical support or cardiac transplant | Through duration of hospitalization, up to 12 weeks following admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time on inotropes | Total time on inotropes (in hours) | Through duration of hospitalization, up to 12 weeks following admission | 
| Non-invasive or invasive mechanical ventilation | Total number of days requiring non-invasive or invasive mechanical ventilation | Through duration of hospitalization, up to 12 weeks following admission | 
| Change in cardiac index ([CI] | Change in cardiac index measured with PA catheter | Through duration of hospitalization, up to 12 weeks following admission | 
| Change in pulmonary capillary wedge pressure [PCWP] | Change in pulmonary capillary wedge pressure measured with PA catheter | Through duration of hospitalization, up to 12 weeks following admission | 
| Change in pulmonary vascular resistance [PVR] | Change in pulmonary vascular resistance measured with PA catheter | Through duration of hospitalization, up to 12 weeks following admission | 
| Change in systemic vascular resistance [SVR] | Change in systemic vascular resistance measured with PA catheter | Through duration of hospitalization, up to 12 weeks following admission | 
| Presence of acute kidney injury | Presence of acute kidney injury (defined by KDIGO as creatinine increased by 26.5 umol/L, 1.5 times baseline within prior 7 days, or urine volume <0.5 mL/kg/hour for greater than or equal to 6 hours | Through duration of hospitalization, up to 12 weeks following admission | 
| Serum lactate | Normalization of serum lactate | Through duration of hospitalization, up to 12 weeks following admission | 
| Arrhythmia requiring medical team intervention | Arrhythmia requiring medical team intervention, either through electrical or chemical cardioversion or any intravenous anti-arrhythmia medication administration | Through duration of hospitalization, up to 12 weeks following admission | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiogenic shock, Inotropes, Low cardiac output syndrome