The Influence of Beta Blocker Therapy on the Hemodynamic Response to Inotrope Infusion in Patients With Acute Decompensated Heart Failure
Condition: Acute Decompensated Heart Failure; Heart Failure
MeSH terms: Heart Failure
Study type: Observational

Summary: 
      Purpose: To compare the hemodynamic effects of dobutamine and milrinone in hospitalized
      patients who are receiving Beta Blocker Participants: Patients who are admitted to the
      General Cardiology and Heart Failure Services at the University of North Carolina Hospitals
      with acute decompensated heart failure, who have maintained steady state concentrations of
      beta blocker therapy (carvedilol or metoprolol), and who are deemed by the health care team
      to require pulmonary artery catheter placement and inotropic therapy with dobutamine or
      milrinone by continuous infusion. Patients that are not currently receiving beta blocker
      therapy will be enrolled for comparative purposes; however, any patient not at steady state
      (on or off beta blocker therapy) will not be enrolled.

      Procedures: After obtaining informed consent, patients will be assigned to the appropriate
      sub-study group based on beta blocker use (Study A: patients on stable doses of metoprolol
      and Study B: patients on stable doses of carvedilol). All patients should receive dobutamine
      followed by milrinone as outlined in the dosing algorithm (see inotrope dosing algorithm
      attached, as part of the usual standard of practice). Baseline pulmonary artery catheter
      hemodynamic parameters will be collected prior to administration of inotrope trial of
      dobutamine followed by milrinone. Hemodynamic parameters will be recorded per the dosing
      algorithm following initiation and dose titration. Dose titration will be determined by the
      health care team based upon patient response or lack thereof and tolerability. Changes in
      hemodynamic parameters in response to dobutamine or milrinone will be compared within study
      groups. Additionally, data will continue to be collected on patients receiving not beta
      blocker therapy for comparative purpose.
    

Detailed description: 
      Background:

      First-line management of chronic heart failure includes beta blockers and angiotensin
      converting enzyme (ACE) inhibitors, as these agents have been shown to have significant
      benefits on morbidity and mortality in large clinical trials. Therefore, a substantial number
      of patients with chronic heart failure are receiving chronic beta blocker therapy, most
      commonly metoprolol succinate and carvedilol. However, despite significant advancements in
      the treatment of chronic heart failure, the natural history of the disease remains
      progressive and many patients develop acute decompensations requiring hospitalization. In the
      setting of acute decompensated heart failure, the use of inotropic agents may be required for
      hemodynamic support. The two most widely used inotropes are dobutamine and milrinone.
      Dobutamine primarily acts as a beta-1 receptor agonist with some effects on beta-2 and
      alpha-1 receptors. Milrinone is a phosphodiesterase III inhibitor, thus inhibiting the
      breakdown of cyclic adenosine monophosphate. As such, milrinone works at a site that is
      distal to beta receptors and may be less influenced by chronic beta blocker therapy. As such,
      one may speculate that the presence of a beta blocker would influence the hemodynamic
      response to dobutamine, but to a much lesser extent to milrinone, if at all.

      Two small studies have assessed the hemodynamic response to dobutamine in the presence and
      absence of beta blocker therapy in patients with chronic heart failure. In addition, one of
      these studies assessed the response to enoximone, another phosphodiesterase III inhibitor.
      Both studies demonstrated that metoprolol did not significantly affect the hemodynamic
      response to dobutamine infusion, including its effect on cardiac index, heart rate, stroke
      volume, and systemic vascular resistance. Conversely, carvedilol was shown to have
      significant inhibitory effects on cardiac index, heart rate, and stroke volume during
      dobutamine infusion. In addition, carvedilol appeared to increase mean arterial pressure at
      higher doses of dobutamine. In the setting of an enoximone infusion, metoprolol increased the
      cardiac index and stroke volume responses, while maintaining other hemodynamic parameters.
      There was no significant difference in the hemodynamic response to enoximone infusion in the
      presence of carvedilol.

      Why This Study is Needed:

      Published studies that assessed the hemodynamic response to inotropes in the presence and
      absence of beta blockers included less than 50 patients combined. As such, the replication of
      their results is warranted in order to use this data to drive changes in clinical practice.
      Additionally, and equally as important, no study has been published, to the best of our
      knowledge, which has assessed the hemodynamic response to milrinone in the presence of
      metoprolol. . Although enoximone is a phosphodiesterase III inhibitor and is theoretically
      similar to milrinone, it is not approved for use in the United States, thus making it
      difficult to extrapolate these findings to milrinone. Lastly, the severity of illness in
      patients included in current literature does not reflect individuals who will receive the
      most benefit from therapy i.e. patients with acute decompensated heart failure.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients who are admitted to the General Cardiology and Heart Failure Services at the
        University of North Carolina Hospitals with acute decompensated heart failure, and who are
        deemed by the health care team to require pulmonary artery catheter placement and inotropic
        therapy with either dobutamine or milrinone by continuous infusion.
      
Keywords: Beta Blocker; Inotrope