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The investigators are interested in determining if there is a meaningful benefit from the use of medications purported to increase the pumping function of the heart (i.e. inotropes) among critically ill patients admitted to the Cardiac Intensive Care Unit (CICU). To do this, the investigators will conduct a multi-centre, double blind, randomized control trial with patients who are deemed to require these medications by their treating physician to one of the two most commonly used agents in Canada (Milrinone or Dobutamine) or placebo. Each patient will be closely monitored by their healthcare team. The dose of medication will be adjusted according to each patients' clinical status. After 12 hours, the participants will move to open label treatment and any continued use of inotropes will be at the discretion of their treating physician.
Cardiogenic shock (CS) is a state of inadequate end-organ perfusion due to cardiac dysfunction. Acute myocardial infarction (AMI) remains the most prevalent cause of CS, with mortality reaching upwards of 40% despite advances in emergent revascularization and accelerating use of mechanical circulatory support devices. International guidelines support the use of vasopressors and inotropes as a mainstay of medical therapy among this cohort of critically ill patients. Recently, the first head-to-head prospective randomized trial (CAPITAL DOREMI) comparing milrinone and dobutamine in a cohort of CS participants was performed and found no difference between agents.
There is a signal of harm associated with the use of inotropes in both acute, decompensated heart failure and in the longitudinal management of chronic heart failure. Inotrope use has also been associated with longer ICU and in-hospital length of stay, as well as higher in-hospital mortality. A recent network meta-analysis on treatment strategies in CS and found that while milrinone and dobutamine may reduce the risk of mortality compared to placebo, the evidence is of low certainty and the wide confidence intervals do not rule out the possibility of harm.
Despite their frequent use in the management of patients with CS, it remains unknown if inotropes are needed to augment successful initial resuscitation, reduce morbidity and mortality, or if they cause potential harm in this already critically ill patient population.
This study is a multi-centre, double blind, randomized controlled trial designed to examine the efficacy and safety of inotrope therapy against placebo in the initial resuscitation of SCAI class C to D cardiogenic shock. Consecutive patients admitted to an intensive care unit will be identified by the treating medical team as requiring new initiation of inotrope therapy for CS. All decisions to initiate inotrope therapy will be made by the primary care team with no involvement from the research team. The study hypothesis is that inotrope therapy will lead to an overall improvement in the primary outcome as compared to placebo.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Inotrope | Active Comparator | Participants randomized to receive the inotrope will be initiated on inotrope therapy at starting doses and titrated according to standard clinical care. During reassessment, the treating physicians will make a decision about adjustment of the inotrope dose (increase, maintain or decrease) based on hemodynamics, end-organ perfusion, vasopressor support and clinical exam. Dobutamine doses will be 2.5, 5.0, 7.5, 10 and >10 ug/kg/min and milrinone doses will be 0.125, 0.250, 0.375, 0.5 and >0.5 ug/kg/min. These dose stages are identical to those used in Capital Do-Re-Mi and reflect current standard of care. |
|
| Placebo | Placebo Comparator | Participants in the placebo arm will have an intravenous solution of 0.9% NaCl running at a standardized rate, comparable to the infusion rate of the inotrope arm. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dobutamine | Drug | Dobutamine administered according to its clinical dose stage for cardiogenic shock |
|
| Measure | Description | Time Frame |
|---|---|---|
| Primary composite outcome | The primary outcome will be a composite of:
| Through duration of hospitalization, up to 12 weeks following admission |
| Measure | Description | Time Frame |
|---|---|---|
| All-cause in-hospital mortality | Death resulting from any cause during hospitalization | Through duration of hospitalization, up to 12 weeks following admission |
| Renal failure requiring new initiation of renal replacement therapy |
| Measure | Description | Time Frame |
|---|---|---|
| Need for non-invasive or invasive mechanical ventilation | Need for non-invasive or invasive mechanical ventilation after randomization | Through duration of hospitalization, up to 12 weeks following admission |
| Arrhythmia requiring pharmacologic intervention |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Rebecca Mathew, MD | Contact | 613-696-7406 | rmathew@ottawaheart.ca | |
| Baylie Morgan, RN | Contact | 613-696-7000 | 19059 | bmorgan@ottawaheart.ca |
| Name | Affiliation | Role |
|---|---|---|
| Rebecca Mathew, MD | Ottawa Heart Institute Research Corporation | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Not yet recruiting | Rochester | Minnesota | 55905 | United States |
The study data, protocol, SAP, ICF, and CSR will be made available at study completion/publication.
Study completion
The above will be made publicly available
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| ID | Term |
|---|---|
| D012770 | Shock, Cardiogenic |
| D012769 | Shock |
| ID | Term |
|---|---|
| D009203 | Myocardial Infarction |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D004280 | Dobutamine |
| D020105 | Milrinone |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D002395 | Catecholamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D010627 | Phenethylamines |
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Parallel randomized control trial
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Double-blind
| Milrinone | Drug | Milrinone administered according to its clinical dose stage for cardiogenic shock |
|
| Normal Saline | Drug | Normal saline running at a standardized rate |
|
Requiring new initiation of renal replacement therapy
| Through duration of hospitalization, up to 12 weeks following admission |
| Need for cardiac transplant or mechanical circulatory support | Identification of needing a cardiac transplant or mechanical circulatory support | Through duration of hospitalization, up to 12 weeks following admission |
| Atrial or ventricular arrhythmia leading to emergent electrical cardioversion | Requiring emergent electrical cardioversion for atrial or ventricular arrhythmia | Through duration of hospitalization, up to 12 weeks following admission |
| Resuscitated cardiac arrest | Cardiopulmonary arrest requiring chest compressions and/or defibrillation with successful return of spontaneous circulation (ROSC) | Through duration of hospitalization, up to 12 weeks following admission |
| Non-fatal myocardial infarction | Non-fatal myocardial infarction | Through duration of hospitalization, up to 12 weeks following admission |
| Stroke or transient ischemic attack | Defined as an episode of focal or global neurological deficit as diagnosed by a neurologist | Through duration of hospitalization, up to 12 weeks following admission |
Atrial or ventricular arrhythmias requiring initiation of pharmacologic intervention (intravenous or oral anti-arrhythmic therapy)
| Through duration of hospitalization, up to 12 weeks following admission |
| Acute kidney injury | Acute kidney injury | Through duration of hospitalization, up to 12 weeks following admission |
| Hamilton Health Sciences | Recruiting | Hamilton | Ontario | L8L 2X2 | Canada |
|
| University of Ottawa Heart Institute | Recruiting | Ottawa | Ontario | K1Y4W7 | Canada |
|
| D014652 |
| Vascular Diseases |
| D007238 | Infarction |
| D007511 | Ischemia |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009336 | Necrosis |
| D005021 |
| Ethylamines |
| D002396 | Catechols |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D000676 | Amrinone |
| D000631 | Aminopyridines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |