Analysis of Adenosine on Sinus and Atrioventricular Nodal Conduction in the Pediatric Transplanted Heart
Condition: Sinus Bradycardia; Atrioventricular Block
MeSH terms: Bradycardia; Atrioventricular Block
Study type: Interventional
Phase: Phase 1

Summary: 
      Heart transplants save the lives of nearly 500 children in heart failure per year. Columbia
      is one of the largest pediatric heart transplant centers in the world, averaging 25
      transplants per year, and providing ongoing care to nearly 250 children with transplanted
      hearts. After transplant, children are at increased risk to develop sudden onset of
      abnormally fast heart rates. This research project will study adenosine, a medication that is
      routinely used to slow fast heart rates in non-transplanted children (i.e. normal hearts),
      and its effects on the transplanted heart. Adenosine is often not used in patients with
      transplanted hearts because, based on prior limited research in adult patients, the standard
      adult dose may have a longer medication effect, producing a slower heart rate for an
      undesirable period of time. However, the current alternatives to adenosine treatment are
      either inappropriate for the pediatric age range, or have increased risk of unwanted side
      effects. This research project will answer two questions: is adenosine safe to give a child
      who has had a heart transplant, and will it be effective in treating the fast heart rate?

      All pediatric heart transplant patients undergo regular heart testing, known as a cardiac
      catheterization, one or more times per year. Three days before testing, participants will be
      asked to stop a regular medication, dipyridamole, because it slows the breakdown of adenosine
      in the body, and may increase its effects. (Of note, all patients that are on dipyridamole
      are also on aspirin, which gives a second line of heart protection, and will not be stopped.)
      After regular cardiac catheterization, all patients will already have intravenous (IV) access
      to give medication. Also, this setting allows the opportunity to have a back-up pacing
      catheter in the heart, ensuring that there will not be a longer than desired effect from the
      medication. Adenosine will be given per a low-dose protocol until either the medication
      effect is seen or the maximum dose is reached. There will be no difference in procedure
      recovery period time, and patients will resume regular home medications after finishing the
      test. As Columbia is one of largest pediatric heart transplant centers in the world, studying
      the effects of adenosine at low doses will benefit the investigators population greatly,
      either to find a new recommended medication dose, or to provide evidence that this medication
      is truly inadvisable for the investigators patients.

      The initial study was completed with all 80 patients enrolled and tested. Subsequent testing
      is now ongoing on patients in whom dipyridamole was stopped prior to their initial testing
      with a repeat study without discontinuing the dipyridamole. We anticipate re-testing about 30
      of the 80 patients.
    

Detailed description: 
      After cardiac catheterization, the study protocol will begin with 12.5µg/kg of adenosine (one
      eighth the recommended starting clinical dose), and will double to 25µg/kg, 50µg/kg, 100µg/kg
      and finally 200µg/kg (not to surpass the total maximum dose of 12mg). A pacing catheter will
      be placed within the right ventricle prior to medication administration. Escalating doses
      will stop if ventricular pacing is required due to a ventricular pause greater than 12
      seconds or if atrioventricular block is demonstrated with a ventricular pause less than 12
      seconds. If there is no prolonged pause requiring pacing and no demonstration of medication
      effect the subsequent dose will be given.

      Progression to the next dose of the adenosine will depend on both the primary and secondary
      study outcomes. If the adenosine dose produces clinically significant bradycardia (> 12
      seconds), ventricular pacing will be used to maintain cardiac output, and the dose will be
      considered unsafe to use clinically and testing will end for that patient. If the adenosine
      dose produces atrioventricular block but with a pause of less than 12 seconds (thus does not
      require pacing), the dose will be considered effective and the study will terminate as well.
      However, if the adenosine dose does not produce atrioventricular block or require pacing
      intervention, the dose will be considered safe but ineffective and the study will progress to
      the next higher dose. Before dose progression, the study will pause for additional 30 seconds
      to ensure complete adenosine metabolism, as the half-life of adenosine is less than 10
      seconds and does not exhibit cumulative effects. The subsequent dose will then be
      administered and the ECG observed for clinically significant bradycardia and atrioventricular
      block. This will be repeated until clinically significant bradycardia and/or atrioventricular
      block is observed, or up to the final 200μg/kg (not to surpass the total maximum of 12mg)
      dose.

      The same study protocol is being utilized to retest the subset of patients in whom
      dipyridamole was discontinued prior to the initial testing to further understand the safety
      of administering adenosine to heart transplant patients chronically maintained on
      dipyridamole.
    

Intervention name(s): Adenosine; Cardiac catheterization
Intervention type(s): Drug; Procedure
Intervention description(s): Testing escalating doses of adenosine in pediatric heart transplant patients; (non-experimental) standard procedure
Other intervention name(s): No brand names
Intervention MeSH terms: Adenosine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Heart transplant; Adenosine; Pediatrics