Single Ventricle
Conditions
Keywords
Fontan, Treprostinil, Remodulin, Single ventricle
Brief summary
The purpose of this study is to test the efficacy of treprostinil (TRE) in the perioperative non-fenestrated, extracardiac Fontan patients in order to reduce duration of chest tube drainage (in days). The Fontan operation is performed for patients with single ventricle physiology as the final palliation to create a series circulation, with passive systemic venous return to the pulmonary arteries and the single ventricle solely providing systemic output. Patients undergoing extracardiac Fontan tend to have elevation of Fontan pressures immediately following the operation with inflammation from surgery requiring additional fluid administration to maintain blood pressure. Increased Fontan pressures and fluid overload lead to prolonged chest tube drainage. The hypothesis is that treprostinil, a prostacyclin drug that dilates the pulmonary arteries, will improve immediate postoperative Fontan pressures. Treprostinil is not FDA approved for this use. Anecdotally and in a small case series, prostacyclin therapy has been shown to assist in transitioning patients off nitric oxide. The investigators believe that this improvement in hemodynamics will decrease duration of chest tube drainage resulting in a shorter length of hospital stay.
Detailed description
In order to understand the effect of treprostinil on Fontan patients, this study has two parts: 1. reactivity testing with inhaled treprostinil in the cardiac catheterization lab for pre-Fontan patients undergoing routine catheterization in anticipation of the Fontan operation; 2. perioperative use of subcutaneous treprostinil starting immediately pre-op until postoperative day #7 to improve immediate postoperative hemodynamics and ultimately reduce overall length of hospital stay. The investigators hope to learn how pulmonary vasodilator therapy affects and/or improves post- operative hemodynamics following the Fontan operation. This knowledge would be very important in the care of single ventricle patients following the Fontan operation if there is improvement of immediate outcomes and reduction of hospital length of stay. On a broader scale, if the use of treprostinil in perioperative Fontan patients can achieve the same results other centers achieve with the use of a fenestration this may have wide scale implications in the nationwide treatment of Fontan patients.
Interventions
DRUGTreprostinil
Administration of drug (treprostinil) vs placebo (saline) in the post-operative period
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric patient undergoing Fontan operation and/or pre-Fontan cardiac catheterization at Lucile Packard Children's Hospital (LPCH)
Exclusion criteria
* Platelet count \< 50K (treprostinil can act as a platelet inhibitor and this may place patient at additional risk of bleeding if already thrombocytopenic) * Dermatologic condition that renders the patient unable to tolerate a subcutaneous infusion (can still take part in inhaled vasodilator testing during cardiac catheterization) * Currently receiving any vasodilator therapy specifically for the purpose of pulmonary vasodilation (phosphodiesterase type 5 inhibitor, endothelia receptor antagonist and/or prostacyclin).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chest Tube Duration | 2-3 wks | This outcome measures the number of days that chest tubes were in place postoperatively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Length of Hospital Stay | 2-3 wks | This outcome measures the hospital length of stays in days. |
| Postoperative Fontan Pressure | postoperative hour 0, 12 and 24 | Patient hemodynamics as measured by invasive postoperative lines were recorded and compared between groups |
| Postoperative Atrial Pressure | postoperative hour 0, 12 and 24 | Patient hemodynamics as measured by invasive postoperative lines were recorded and compared between groups |
| Postoperative Transpulmonary Gradient | postoperative hour 0, 12 and 24 | Patient hemodynamics as measured by invasive postoperative lines were recorded and compared between groups. Transpulmonary pressure gradient is defined as the difference between mean pulmonary artery pressure and left atrial pressure (commonly estimated by a pulmonary artery wedge pressure). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treprostinil Subcutaneous continuous treprostinil infusion starting at 2 ng/kg/min, increased over the first 24 hours to goal 10 ng/kg/min through day five, then decreased by 2 ng/kg/min every 8 hours starting on postoperative day six with plans for discontinuation on postoperative day seven. | 16 |
| Saline Saline administration via subcutaneous infusion. | 18 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Saline | Treprostinil | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 18 Participants | 16 Participants | 34 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 4.51 years | 4.09 years | 4.16 years |
| Baseline Atrial Pressure | 5.0 mmHg | 7.0 mmHg | 5.0 mmHg |
| Baseline Pulmonary Arterial Pressure | 9.0 mmHg | 11.0 mmHg | 10.0 mmHg |
| Baseline Pulmonary Vascular Resistance | 1.25 indexed Wood units (WU*m^2) | 1.12 indexed Wood units (WU*m^2) | 1.2 indexed Wood units (WU*m^2) |
| Baseline Transpulmonary Gradient | 4.0 mmHg | 4.0 mmHg | 4.0 mmHg |
| Baseline ventricular function Mildly depressed function | 3 Participants | 1 Participants | 4 Participants |
| Baseline ventricular function Normal function | 15 Participants | 15 Participants | 30 Participants |
| Congenital Heart Disease Atrioventricular septal defect | 2 Participants | 0 Participants | 2 Participants |
| Congenital Heart Disease Double inlet left ventricle | 4 Participants | 5 Participants | 9 Participants |
| Congenital Heart Disease Double outlet right ventricle | 1 Participants | 1 Participants | 2 Participants |
| Congenital Heart Disease Hypoplastic left heart syndrome | 5 Participants | 5 Participants | 10 Participants |
| Congenital Heart Disease L-transposition of the great arteries + pulmonary atresia | 1 Participants | 0 Participants | 1 Participants |
| Congenital Heart Disease Pulmonary atresia with intact ventricular septum | 2 Participants | 2 Participants | 4 Participants |
| Congenital Heart Disease Tricuspid atresia | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 7 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 9 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 14 Participants | 15 Participants | 29 Participants |
| Region of Enrollment United States | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 13 Participants | 11 Participants | 24 Participants |
| Systemic atrioventricular valve function Mild-Moderate regurgitation | 2 Participants | 1 Participants | 3 Participants |
| Systemic atrioventricular valve function Mild regurgitation | 6 Participants | 2 Participants | 8 Participants |
| Systemic atrioventricular valve function Moderate regurgitation | 2 Participants | 0 Participants | 2 Participants |
| Systemic atrioventricular valve function No regurgitation | 3 Participants | 1 Participants | 4 Participants |
| Systemic atrioventricular valve function Trace regurgitation | 5 Participants | 12 Participants | 17 Participants |
| Ventricular morphology Left ventricle | 10 Participants | 11 Participants | 21 Participants |
| Ventricular morphology Right ventricle | 8 Participants | 5 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 18 |
| other Total, other adverse events | 7 / 16 | 0 / 18 |
| serious Total, serious adverse events | 0 / 16 | 0 / 18 |
Outcome results
Primary
Chest Tube Duration
This outcome measures the number of days that chest tubes were in place postoperatively.
Time frame: 2-3 wks
Population: Intention to treat analysis based on study group assignment at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil | Chest Tube Duration | 8.0 days |
| Saline | Chest Tube Duration | 7.0 days |
p-value: 0.0395% CI: [1.02, 1.64]Poisson regression
Secondary
Length of Hospital Stay
This outcome measures the hospital length of stays in days.
Time frame: 2-3 wks
Population: Intention to treat analysis based on group assignment at randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil | Length of Hospital Stay | 11.0 days |
| Saline | Length of Hospital Stay | 9.0 days |
p-value: 0.049895% CI: [1, 1.51]Poisson regression
Secondary
Postoperative Atrial Pressure
Patient hemodynamics as measured by invasive postoperative lines were recorded and compared between groups
Time frame: postoperative hour 0, 12 and 24
Population: Participants with available data at the respective time points are included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil | Postoperative Atrial Pressure | Postoperative hour 0 | 7.0 mmHg |
| Treprostinil | Postoperative Atrial Pressure | Postoperative hour 12 | 6.0 mmHg |
| Treprostinil | Postoperative Atrial Pressure | Postoperative hour 24 | 6.0 mmHg |
| Saline | Postoperative Atrial Pressure | Postoperative hour 0 | 5.0 mmHg |
| Saline | Postoperative Atrial Pressure | Postoperative hour 12 | 6.0 mmHg |
| Saline | Postoperative Atrial Pressure | Postoperative hour 24 | 7.0 mmHg |
Comparison: Between-group comparison at postoperative hour 0p-value: 0.23Unadjusted repeated measure analysis
Comparison: Between-group comparison at postoperative hour 12p-value: 0.27Unadjusted repeated measure analysis
Comparison: Between-group comparison at postoperative hour 24p-value: 0.65Unadjusted repeated measure analysis
Secondary
Postoperative Fontan Pressure
Patient hemodynamics as measured by invasive postoperative lines were recorded and compared between groups
Time frame: postoperative hour 0, 12 and 24
Population: Participants with available data at the respective time points are included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil | Postoperative Fontan Pressure | Fontan pressure- postoperative hour 0 | 13.0 mmHg |
| Treprostinil | Postoperative Fontan Pressure | Fontan pressure- postoperative hour 12 | 13.0 mmHg |
| Treprostinil | Postoperative Fontan Pressure | Fontan pressure- postoperative hour 24 | 13.0 mmHg |
| Saline | Postoperative Fontan Pressure | Fontan pressure- postoperative hour 0 | 12.5 mmHg |
| Saline | Postoperative Fontan Pressure | Fontan pressure- postoperative hour 12 | 10.5 mmHg |
| Saline | Postoperative Fontan Pressure | Fontan pressure- postoperative hour 24 | 9.0 mmHg |
Comparison: Between-group comparison at postoperative hour 0p-value: 0.05Unadjusted repeated measure analysis
Comparison: Between-group comparison at postoperative hour 12p-value: <0.01Unadjusted repeated measure analysis
Comparison: Between-group comparison at postoperative hour 24p-value: 0.14Unadjusted repeated measure analysis
Secondary
Postoperative Transpulmonary Gradient
Patient hemodynamics as measured by invasive postoperative lines were recorded and compared between groups. Transpulmonary pressure gradient is defined as the difference between mean pulmonary artery pressure and left atrial pressure (commonly estimated by a pulmonary artery wedge pressure).
Time frame: postoperative hour 0, 12 and 24
Population: Participants with available data at the respective time points are included in the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil | Postoperative Transpulmonary Gradient | Postoperative hour 24 | 6.0 mmHg |
| Treprostinil | Postoperative Transpulmonary Gradient | Postoperative hour 0 | 7.0 mmHg |
| Treprostinil | Postoperative Transpulmonary Gradient | Postoperative hour 12 | 7.0 mmHg |
| Saline | Postoperative Transpulmonary Gradient | Postoperative hour 0 | 7.0 mmHg |
| Saline | Postoperative Transpulmonary Gradient | Postoperative hour 12 | 4.0 mmHg |
| Saline | Postoperative Transpulmonary Gradient | Postoperative hour 24 | 6.0 mmHg |
Comparison: Between-group comparison at postoperative hour 0p-value: 0.37Unadjusted repeated measure analysis
Comparison: Between-group comparison at postoperative hour 12p-value: <0.01Unadjusted repeated measure analysis
Comparison: Between-group comparison at postoperative hour 24p-value: 0.3Unadjusted repeated measure analysis