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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Left ventricular [LV] +/- Biventricular dysfunction | Active Comparator | 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. |
|
| Right ventricular [RV] dysfunction | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Milrinone | Drug | 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. |
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Sustained hypotension of systolic BP | 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) | Through duration of hospitalization in CCU, up to 12 weeks following admission |
| Atrial arrhythmias requiring medical intervention |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Benjamin M Hibbert, MD, PhD | Ottawa Heart Institute Research Corporation | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Ottawa Heart Institute | Ottawa | Ontario | K1Y 4W7 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15992636 | Background | Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, Cheng ML, Wynne J; ADHERE Scientific Advisory Committee and Investigators; ADHERE Study Group. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005 Jul 5;46(1):57-64. doi: 10.1016/j.jacc.2005.03.051. | |
| 12595851 |
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| ID | Term |
|---|---|
| D002303 | Cardiac Output, Low |
| D012770 | Shock, Cardiogenic |
| D054058 | Acute Coronary Syndrome |
| D011654 | Pulmonary Edema |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D020105 | Milrinone |
| C048042 | N(1)-methyl-2-lysergic acid diethylamide |
| D004280 | Dobutamine |
| ID | Term |
|---|---|
| D000676 | Amrinone |
| D000631 | Aminopyridines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D011725 |
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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.
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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.
|
|
| Dobutamine | Drug | 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. |
|
|
| 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 |
| 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 |
Atrial flutter, fibrillation or tachycardia requiring medical intervention |
| Through duration of hospitalization in CCU, up to 12 weeks following admission |
| Need for intravenous or oral anti-arrhythmic therapy | Initiation of intravenous or oral anti-arrhythmic therapy | Through duration of hospitalization in CCU, up to 12 weeks following admission |
| Ventricular arrhythmias | Ventricular arrhythmias (monomorphic or polymorphic ventricular tachycardia [VT] greater than 30 seconds or hemodynamically unstable ventricular arrhythmia requiring intervention, or VF) | Through duration of hospitalization in CCU, up to 12 weeks following admission |
| Need for up-titration or addition of new vasopressor therapy | Need for up-titration or addition of new vasopressor therapy | Through duration of hospitalization in CCU, up to 12 weeks following admission |
| Background |
| Aranda JM Jr, Schofield RS, Pauly DF, Cleeton TS, Walker TC, Monroe VS Jr, Leach D, Lopez LM, Hill JA. Comparison of dobutamine versus milrinone therapy in hospitalized patients awaiting cardiac transplantation: a prospective, randomized trial. Am Heart J. 2003 Feb;145(2):324-9. doi: 10.1067/mhj.2003.50. |
| 8903534 | Background | Karlsberg RP, DeWood MA, DeMaria AN, Berk MR, Lasher KP. Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone-Dobutamine Study Group. Clin Cardiol. 1996 Jan;19(1):21-30. doi: 10.1002/clc.4960190106. |
| 28475215 | Background | King JB, Shah RU, Sainski-Nguyen A, Biskupiak J, Munger MA, Bress AP. Effect of Inpatient Dobutamine versus Milrinone on Out-of-Hospital Mortality in Patients with Acute Decompensated Heart Failure. Pharmacotherapy. 2017 Jun;37(6):662-672. doi: 10.1002/phar.1939. |
| 11717603 | Background | Yamani MH, Haji SA, Starling RC, Kelly L, Albert N, Knack DL, Young JB. Comparison of dobutamine-based and milrinone-based therapy for advanced decompensated congestive heart failure: Hemodynamic efficacy, clinical outcome, and economic impact. Am Heart J. 2001 Dec;142(6):998-1002. doi: 10.1067/mhj.2001.119610. |
| 35261289 | Derived | Marbach JA, Di Santo P, Kapur NK, Thayer KL, Simard T, Jung RG, Parlow S, Abdel-Razek O, Fernando SM, Labinaz M, Froeschl M, Mathew R, Hibbert B. Lactate Clearance as a Surrogate for Mortality in Cardiogenic Shock: Insights From the DOREMI Trial. J Am Heart Assoc. 2022 Mar 15;11(6):e023322. doi: 10.1161/JAHA.121.023322. Epub 2022 Mar 9. |
| 34713704 | Derived | Jung RG, Di Santo P, Mathew R, Abdel-Razek O, Parlow S, Simard T, Marbach JA, Gillmore T, Mao B, Bernick J, Theriault-Lauzier P, Fu A, Lau L, Motazedian P, Russo JJ, Labinaz M, Hibbert B. Implications of Myocardial Infarction on Management and Outcome in Cardiogenic Shock. J Am Heart Assoc. 2021 Nov 2;10(21):e021570. doi: 10.1161/JAHA.121.021570. Epub 2021 Oct 29. |
| 34376218 | Derived | Di Santo P, Mathew R, Jung RG, Simard T, Skanes S, Mao B, Ramirez FD, Marbach JA, Abdel-Razek O, Motazedian P, Parlow S, Boczar KE, D'Egidio G, Hawken S, Bernick J, Wells GA, Dick A, So DY, Glover C, Russo JJ, McGuinty C, Hibbert B; CAPITAL DOREMI investigators. Impact of baseline beta-blocker use on inotrope response and clinical outcomes in cardiogenic shock: a subgroup analysis of the DOREMI trial. Crit Care. 2021 Aug 10;25(1):289. doi: 10.1186/s13054-021-03706-2. |
| 34347952 | Derived | Mathew R, Di Santo P, Jung RG, Marbach JA, Hutson J, Simard T, Ramirez FD, Harnett DT, Merdad A, Almufleh A, Weng W, Abdel-Razek O, Fernando SM, Kyeremanteng K, Bernick J, Wells GA, Chan V, Froeschl M, Labinaz M, Le May MR, Russo JJ, Hibbert B. Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock. N Engl J Med. 2021 Aug 5;385(6):516-525. doi: 10.1056/NEJMoa2026845. |
| D009203 | Myocardial Infarction |
| D017202 | Myocardial Ischemia |
| D014652 | Vascular Diseases |
| D007238 | Infarction |
| D007511 | Ischemia |
| D010335 | Pathologic Processes |
| D009336 | Necrosis |
| D012769 | Shock |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D002395 | Catecholamines |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |