Chylothorax, Congenital Heart Disease, Open Heart Surgery, Postoperative Chylothorax
Conditions
Brief summary
Postoperative chylothorax is a serious complication after open heart surgery for pediatric patients with congenital heart disease (CHD). While it was thought to be mechanical injury to the thoracic duct, recent research demonstrated that there are intrinsically abnormal lung lymphatics in CHD patients, and after open heart surgery, the fluid shifts that occur overwhelms these abnormal lung lymphatics. As a result, postoperative chylothorax occurs. Propranolol has been found to be helpful in resolving postoperative chylothorax very quickly (9 days) in a subset of postoperative chylothorax patients (60%). However, it is not known why some patients respond and some do not. The investigators hypothesize that propranolol is safe to use in this patient population, and that certain clinical factors will predict propranolol response, but more importantly, some clinical factors can be optimize to allow more patients with postoperative chylothorax to respond to and benefit from propranolol. In order to improve the understanding of how propranolol works and to maximize benefit to patients, the investigators propose to perform a prospective, randomized, double-blind clinical trial to learn how to best use propranolol in patients with postoperative chylothorax.
Detailed description
This clinical trial will prospectively enroll eligible patients and randomize them to placebo or propranolol (1:1). This study will aim to enroll 50 patients, randomized to 25 placebo and 25 propranolol treatment. After patients have been consented, registered, and screened, they will be entered into the study. Participants will be randomized to placebo or propranolol in a 1:1 ratio. Randomization will be double-blinded, and each enrolled participant will be given a number and receive coded medication from the research pharmacy. Patients may undergo a screening MR lymphangiogram (MRL) prior to starting treatment. The criteria for an MRL will require that no additional sedation be given, and patient or parent/legal guardian consents to an MRL. Thus, only patients who are already sedated, or who will be able to undergo the MRL without sedation, and who opts in to the MRL will be eligible. Propranolol or placebo will be administered for 9 days after reaching the lowest effective goal dose not to exceed 2mg/kg/day, or maximum tolerated dose, after which the study groups will be unmasked. Participants who have ≥80% reduction in volume of chylothorax drainage after 9 days of treatment and who received propranolol are identified as "responders". They will be taken off the study officially at this point as no more study interventions will be given. They will be tapered off of propranolol gradually as clinically indicated. Participants who have ≥80% reduction in volume of chylothorax drainage but who received placebo will be the "natural history cohort". This will serve to demonstrate, as baseline, the percentage of participants who naturally resolve their chylothorax without intervention. Patients who have \<80% reduction in chylothorax drainage and who received propranolol, will be categorized as initial "non-responders". They will be officially taken off the study. Participants who have \<80% reduction in chylothorax drainage and who received placebo are considered a control group. They will be given propranolol for 9 days as a single-arm, open study and re-evaluated after a 9-day treatment. After 9 days at goal dosing, they will receive the same treatment as the responders and non-responders in the propranolol-treated group.
Interventions
DRUGPropranolol Hydrochloride
Propranolol will be administered as tablets. Participants who are too young to swallow pills will be given propranolol solution.
DRUGPlacebo
Placebo suspension will only have Ora-Blend Medication Flavoring and Suspension Vehicle
Sponsors
June Wu
United States Department of Defense
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Participants will be randomized to propranolol or placebo in a 1:1 ratio
Eligibility
Sex/Gender
ALL
Age
7 Days to 18 Years
Healthy volunteers
No
Inclusion criteria
* ≥7 days and ≤18 years old at time of original cardiac surgery * Congenital structural cardiac anomaly necessitating surgical correction. Examples include but are not limited to: ASD, VSD, single ventricles, HLHS, Tetralogy of Fallot, transposition of great vessels, AV canal, heart transplant * developed high output postoperative chylothorax (≥10mL/kg/day), or * persistent chylous drainage at any volume for ≥7 days after open heart surgery for a congenital cardiac defect * ≥70% lymphocytes, or * pleural triglyeride (TG) ≥ half of serum TG, or chylomicron positive * for patients with lower than normal serum lymphocyte count (agedependent), ≥60% lymphocytes in pleural fluids * Must have measurable output (chylothorax output in mL) * Any level of respiratory support (room air, supplemental oxygen, CPAP/BIPAP, ventilatory support) * Any level of inpatient support (ICUs, step-down units, floor) * Study participants can be on concomitant treatment for postoperative chylothorax started prior to study initiation * Study participants can continue on on-going treatment for their primary cardiac other medical conditions * Study participants can initiate new treatments for their primary cardiac or other medical conditions during trial period * Adequate renal function * Not on dialysis * No hemodynamically unstable bradycardia * No systolic hypotension not corrected by pressor support * Not in 2nd or 3rd degree heart block * No history of asthma * A parent or a legal guardian must sign a written informed consent and HIPAA Form * Patients will be required to also be enrolled in a related study (AAAQ6902) which collects chylothorax fluid for cell isolation and genetic analysis
Exclusion criteria
* Pregnancy * Renal failure at time of enrollment * Hypotension despite pressor support * Unstable bradycardia without capacity for pacing * History of asthma or chronic bronchodilator therapy * Uncontrolled hypoglycemia or hyperglycemia as per investigators' judgment * Study participant will be removed from study if they failed 2 consecutive attempts to initiate propranolol (\>10% drop in BP/HR from age-adjusted normative range) * Study participant experiences ≥ Grade 3 AE (SAE)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days with documented chest tube (# days), CXR | 24 days | Will also measure the daily output (volume) in the chest tube(s) |
| Initial volume of fluid drained (mL, mL/kg/day) | Day 0 | The volume at the initial day of postoperative chylothorax diagnosis |
| Days hospitalized | 6 months | The length of hospital stay, from post-surgery to discharge |
| Expected and unexpected AEs, per patient | 24 days | Safety outcome |
| Daily heart rates recorded in flow chart and 1 hour after each dose | 24 days | Safety outcome |
| Daily blood pressures recorded in flow chart and 1 hour after each dose | 24 days | Safety outcome |
| Daily glucose levels | 24 days | Safety outcome |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| White Blood Cell (WBC) count | 24 days | to be extracted from clinical lab results, if available |
| C-Reactive Protein (CRP) | 24 days | to be extracted from clinical lab results, if available |
| Immunoglobulin level | 24 days | to be extracted from clinical lab results, if available |
| AT3 titer | 24 days | to be extracted from clinical lab results, if available |
| Pre-operative and post-operative echocardiogram anatomic findings for patients with 4-chamber hearts | Pre-operative and up to 24 days | This outcome will be reported as the percent of patients with normal LV function, normal RV function, and normal pulmonary artery pressure. |
| Protein C titer | 24 days | to be extracted from clinical lab results, if available |
| Hours on bypass during CHD surgery | During surgery | The amount of time the participant was on bypass during heart surgery |
| Triglyceride level in chylothorax fluid | 24 days | Triglyceride levels will be measured |
| Thyroglobulin (TG) lymphocyte count | 24 days | The TG count will be analyzed from the postoperative chylothorax fluid. |
| Protein S titer | 24 days | to be extracted from clinical lab results, if available |
| Pre-operative and post-operative echocardiogram anatomic findings for patients with single ventricle (SV) physiology | Pre-operative and up to 24 days | This outcome will be reported as the percent of patients with normal ventricular function and normal pulmonary artery pressure. |
| Percent of patients with Type 1 anatomy | Day 0 | Screening MR lymphangiogram: An optional imaging study to define lymphatic anatomy subtype |
| Percent of patients with Type 2 anatomy | Day 0 | Screening MR lymphangiogram: An optional imaging study to define lymphatic anatomy subtype |
| Percent of patients with Type 3 anatomy | Day 0 | Screening MR lymphangiogram: An optional imaging study to define lymphatic anatomy subtype |
| Percent of patients with Type 4 anatomy | Day 0 | Screening MR lymphangiogram: An optional imaging study to define lymphatic anatomy subtype |
| Serum albumin | 24 days | to be extracted from clinical lab results, if available |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJune Wu, MD
Columbia University Irving Medical Center/ New York Presbyterian hospital
Outcome results
None listed