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Milrinone Versus Dobutamine in Critically Ill Patients

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ClinicalTrials.gov Identifier: NCT03207165
Recruitment Status : Recruiting
First Posted : July 2, 2017
Last Update Posted : October 30, 2018
Sponsor:
Information provided by (Responsible Party):
Ottawa Heart Institute Research Corporation

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Low Cardiac Output Syndrome Cardiogenic Shock Acute Coronary Syndrome Pulmonary Edema Drug: Milrinone Drug: Dobutamine Phase 4

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 192 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The study participants, treating medical team and research team will be blinded to randomization; the pharmacy staff, CCU nurses and allied healthcare team members will not be blinded to the randomization.
Primary Purpose: Treatment
Official Title: Comparison of Milrinone Versus Dobutamine in a Heterogeneous Population of Critically Ill Patients
Actual Study Start Date : August 30, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Left ventricular [LV] +/- Biventricular dysfunction
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
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.
Other Names:
  • Mil
  • Phosphodiesterase-3 inhibitors [PDE3] Inhibitor

Drug: Dobutamine
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.
Other Names:
  • Dob
  • Beta 1/2 Agonist

Active Comparator: Right ventricular [RV] dysfunction
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
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.
Other Names:
  • Mil
  • Phosphodiesterase-3 inhibitors [PDE3] Inhibitor

Drug: Dobutamine
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.
Other Names:
  • Dob
  • Beta 1/2 Agonist




Primary Outcome Measures :
  1. Composite Primary End Point [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    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.

  2. All-cause in-hospital death [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    All-cause in-hospital death

  3. Non-fatal myocardial infarction [MI] [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    As defined by Thygesen et al., 2012 (Circulation)

  4. Transient ischemic attack [TIA] or cerebrovascular accident [CVA] [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Transient ischemic attack or cerebrovascular accident as diagnosed by a Neurologist either clinically and/or radiographically

  5. Stay in CCU greater than or equal to 7 days [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Stay in CCU greater than or equal to 7 days

  6. Acute kidney injury requiring renal replacement therapy [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Acute kidney injury requiring renal replacement therapy (intermittent hemodialysis or continuous renal replacement therapy)

  7. Need for advanced mechanical support [specifically, intra-aortic balloon pump, Impella, ventricular assist device or extra-corporeal membrane oxygenation] or cardiac transplant [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Need for new mechanical support or cardiac transplant


Secondary Outcome Measures :
  1. Time on inotropes [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Total time on inotropes (in hours)

  2. Non-invasive or invasive mechanical ventilation [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Total number of days requiring non-invasive or invasive mechanical ventilation

  3. Change in cardiac index ([CI] [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Change in cardiac index measured with PA catheter

  4. Change in pulmonary capillary wedge pressure [PCWP] [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Change in pulmonary capillary wedge pressure measured with PA catheter

  5. Change in pulmonary vascular resistance [PVR] [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Change in pulmonary vascular resistance measured with PA catheter

  6. Change in systemic vascular resistance [SVR] [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Change in systemic vascular resistance measured with PA catheter

  7. Presence of acute kidney injury [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    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

  8. Serum lactate [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Normalization of serum lactate

  9. Arrhythmia requiring medical team intervention [ Time Frame: Through duration of hospitalization, up to 12 weeks following admission ]
    Arrhythmia requiring medical team intervention, either through electrical or chemical cardioversion or any intravenous anti-arrhythmia medication administration


Other Outcome Measures:
  1. Sustained hypotension of systolic BP [ Time Frame: Through duration of hospitalization in CCU, up to 12 weeks following admission ]
    Sustained systolic blood pressure hypotension of less than or equal to 90 mmHg for greater than or equal to 30 minutes (or requiring medical intervention)

  2. Atrial arrhythmias requiring medical intervention [ Time Frame: Through duration of hospitalization in CCU, up to 12 weeks following admission ]
    Atrial flutter, fibrillation or tachycardia requiring medical intervention

  3. Need for intravenous or oral anti-arrhythmic therapy [ Time Frame: Through duration of hospitalization in CCU, up to 12 weeks following admission ]
    Initiation of intravenous or oral anti-arrhythmic therapy

  4. Ventricular arrhythmias [ Time Frame: Through duration of hospitalization in CCU, up to 12 weeks following admission ]
    Ventricular arrhythmias (monomorphic or polymorphic ventricular tachycardia [VT] greater than 30 seconds or hemodynamically unstable ventricular arrhythmia requiring intervention, or VF)

  5. Need for up-titration or addition of new vasopressor therapy [ Time Frame: Through duration of hospitalization in CCU, up to 12 weeks following admission ]
    Need for up-titration or addition of new vasopressor therapy



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03207165


Contacts
Contact: Benjamin M Hibbert, MD, PhD 613-761-5128 bhibbert@ottawaheart.ca
Contact: Rebecca T Mathew, MD 613-696-7000 rmathew@ottawaheart.ca

Locations
Canada, Ontario
University of Ottawa Heart Institute Recruiting
Ottawa, Ontario, Canada, K1Y 4W7
Contact: Benjamin M Hibbert, MD, PhD    613-761-5128    bhibbert@ottawaheart.ca   
Contact: Rebecca T Mathew, MD    613-696-7000    rmathew@ottawaheart.ca   
Sponsors and Collaborators
Ottawa Heart Institute Research Corporation
Investigators
Principal Investigator: Benjamin M Hibbert, MD, PhD Ottawa Heart Institute Research Corporation

Publications:

Responsible Party: Ottawa Heart Institute Research Corporation
ClinicalTrials.gov Identifier: NCT03207165     History of Changes
Other Study ID Numbers: 20160975-01H
First Posted: July 2, 2017    Key Record Dates
Last Update Posted: October 30, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Ottawa Heart Institute Research Corporation:
Cardiogenic shock
Inotropes
Low cardiac output syndrome

Additional relevant MeSH terms:
Syndrome
Acute Coronary Syndrome
Critical Illness
Shock, Cardiogenic
Pulmonary Edema
Cardiac Output, Low
Disease
Pathologic Processes
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Disease Attributes
Myocardial Infarction
Shock
Lung Diseases
Respiratory Tract Diseases
Signs and Symptoms
Dobutamine
Milrinone
Phosphodiesterase 3 Inhibitors
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents