Congenital Diaphragmatic Hernia, Hypoxemic Respiratory Failure, Persistent Pulmonary Hypertension of the Newborn, Pulmonary Hypoplasia
Conditions
Keywords
CDH, PPHN, HRF
Brief summary
Infants with congenital diaphragmatic hernia (CDH) usually have pulmonary hypoplasia and persistent pulmonary hypertension of the newborn (PPHN) leading to hypoxemic respiratory failure (HRF). Pulmonary hypertension associated with CDH is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO). Increased pulmonary vascular resistance (PVR) can lead to right ventricular overload and dysfunction. In patients with CDH, left ventricular dysfunction, either caused by right ventricular overload or a relative underdevelopment of the left ventricle, is associated with poor prognosis. Milrinone is an intravenous inotrope and lusitrope (enhances cardiac systolic contraction and diastolic relaxation respectively) with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PPHN. Milrinone is commonly used during the management of CDH although no randomized trials have been performed to test its efficacy. Thirty percent of infants with CDH in the Children's Hospital Neonatal Database (CHND) and 22% of late-preterm and term infants with CDH in the Pediatrix database received milrinone. In the recently published VICI trial, 84% of patients with CDH received a vasoactive medication. In the current pilot trial, neonates with an antenatal or postnatal diagnosis of CDH will be randomized to receive milrinone or placebo to establish safety of this medication in CDH and test its efficacy in improving oxygenation.
Detailed description
This is a pilot trial to determine if milrinone infusion in neonates ≥ 36 weeks' postmenstrual age (PMA) at birth with CDH would lead to an increase in PaO2 with a corresponding decrease in OI by itself or in conjunction with other pulmonary vasodilators such as iNO at 24 h post-infusion.
Interventions
DRUGMilrinone
The study intervention is an intravenous infusion of milrinone or placebo
DRUGPlacebo (5% Dextrose)
The study intervention is an intravenous infusion of milrinone or placebo
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD Neonatal Research Network
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
0 Hours to 168 Hours
Healthy volunteers
No
Inclusion criteria
Eligibility criteria: Infants are eligible if they meet all of the following criteria: * ≥ 36 0/7 weeks PMA by best obstetric estimate AND birth weight of ≥ 2000g * postnatal age ≤7 days (168 hours of age) * invasive mechanical ventilation (defined as ventilation with an endotracheal tube) and * one arterial blood gas with an OI ≥ 10 (after tracheal tube obstruction and other easily resolvable mechanical causes for increased OI are ruled out) on the most recent arterial blood gas within 12 hours prior to the time of randomization. * if an arterial blood gas is not available at the time of randomization, a preductal OSI of ≥ 5 can be used as an inclusion criterion instead of OI ≥ 10; (the OSI should be based on the most recent preductal pulse oximetry recording and must be within 12 hours of randomization) * postnatal blood gas with PCO2 ≤ 80 mmHg (arterial, capillary or venous blood gas) on the most recent blood gas sample obtained within 12 hours prior to randomization Note: Criteria (iv) to (vi) must be met at the most recent analysis within 12 hours prior to randomization.
Exclusion criteria
Infants are ineligible if they meet any of the following criteria: * known hypertrophic cardiomyopathy * Note 1: infants of diabetic mothers with asymmetric septal hypertrophy can be included as long as there is no evidence of obstruction to left ventricular outflow tract on echocardiogram, * Note 2: infants with other acyanotic congenital heart disease (CHD) and CDH may be included in the study and will be a predetermined subgroup for analysis) * cyanotic CHD - transposition of great arteries (TGA), total anomalous pulmonary venous return (TAPVR), partial anomalous pulmonary venous return (PAPVR), truncus arteriosus (TA), tetralogy of Fallot (TOF), single ventricle physiology - hypoplastic left heart syndrome (HLHS), tricuspid atresia, critical pulmonic stenosis or atresia etc., * enrolled in conflicting clinical trials (such as a randomized controlled blinded trial of another pulmonary vasodilator therapy); Note: mothers enrolled in fetal tracheal occlusion studies such as FETO may be enrolled if permitted by investigators of the fetal tracheal occlusion study; \[FETO refers to fetoscopic endoluminal tracheal occlusion and involves occlusion of fetal trachea with a balloon device at mid-gestation and subsequent removal in later gestation\] * infants with bilateral CDH o Note 3: infants with anterior and central defects are included in the study * associated abnormalities of the trachea or esophagus (trachea-esophageal fistula, esophageal atresia, laryngeal web, tracheal agenesis) * renal dysfunction (with serum creatinine \> 2 mg/dL not due to maternal factors) or severe oligohydramnios associated with renal dysfunction at randomization; renal dysfunction may be secondary to renal anomalies or medical conditions such as acute tubular necrosis * severe systemic hypotension (mean blood pressure \< 35 mm Hg for at least 2 h with a vasoactive inotrope score of \> 30) * decision is made to provide comfort/ palliative care and not full treatment * Intracranial bleed (including the following findings on the cranial ultrasound) * Cerebral parenchymal hemorrhage * Blood/echodensity in the ventricle with distension of the ventricle * Periventricular hemorrhagic infarction * Posterior fossa hemorrhage * Cerebellar hemorrhage * persistent thrombocytopenia (platelet count \< 80,000/mm3) despite blood product administration on the most recent blood draw prior to randomization * coagulopathy (PT INR \> 1.7) despite blood product administration on the most recent blood draw (if checked - there is no reason to check PT for the purpose of this study) * aneuploidy associated with short life span (such as trisomy 13 or 18) will not be included in the study (infants with trisomy 21 can be included in the study) * elevated arterial, venous or capillary PCO2 \> 80 mmHg in spite of maximal ventilator support (including high frequency ventilation) on the most recent blood gas obtained within 12 hours prior to randomization * use of milrinone infusion prior to randomization (the use of other inhaled pulmonary vasodilators such as iNO, inhaled epoprosternol, inhaled PGE1 and oral such as endothelin receptor antagonists is permitted - Note: it is unlikely to be on oral pulmonary vasodilators early in the course of CDH) * ongoing therapy with parenteral (intravenous or subcutaneous) pulmonary vasodilators such as IV/SQ prostacyclin analogs (Epoprostenol - Flolan or Treprostinil - Remodulin or PGE1 - Alprostadil) or IV phosphodiesterase 5 inhibitors (sildenafil - Revatio) at the time of randomization. In addition, initiation of therapy with these two classes of parenteral medications during the first 24 hours of study drug initiation is not permitted and will be considered a protocol deviation. The risk of systemic hypotension is high during the first 24 hours of study-drug (milrinone) infusion and hence parenteral administration of other pulmonary vasodilators is avoided to minimize risk of hypotension. * Subjects already on ECMO or patients who are being actively considered for ECMO by the neonatal or surgical team * attending (neonatal, critical care or surgical) refusal for participation in the trial (including concern about presence of hemodynamic instability)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Oxygenation Response | 24 h after initiation of study drug | The primary outcome of this study is change in oxygenation from baseline (prior to study drug infusion) to 24 hours after initiation of study drug infusion. Oxygenation is assessed by oxygenation index (OI = mean airway pressure x oxygen concentration in % / PaO2 in mmHg). Oxygen saturation index (OSI = mean airway pressure x oxygen concentration in % / oxygen saturation in %) values were converted to OI values for this measure. Data are presented as OI at 24 hours minus OI at baseline. A negative value indicates improvement in oxygenation. A positive value indicates deterioration in oxygenation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Estimated Systolic Pulmonary Arterial Pressure on Echocardiogram | Prior to initiation of study drug to between 24 and 72 hours after initiation of study drug | Changes in echocardiogram to assess pulmonary arterial pressure (as defined by protocol) between pre-study drug echocardiogram and echocardiogram obtained between 24 and 72 h after starting the study drug. The outcome will be available only for those infants who have a pre-study drug echocardiogram and a second echocardiogram between 24 and 72 hours after initiation of study drug performed for clinical reasons. |
| Vasoactive Inotrope Score and Systemic Blood Pressure | 72 hours after initiation of study drug | Vasoactive Inotrope Score is a quantitative assessment of the degree of therapeutic support required by the patient to maintain adequate perfusion and/or blood pressure. |
| Area Under the Curve for Inspired Oxygen | After initiation of the study drug at 4 time points per day - every 6 hours x 72 hours or discontinuation of study drug (whichever comes first) | Area under the curve for inspired oxygen after initiation of the study drug (inspired oxygen and ventilator data from 4 time points per day - every 6 hours will be recorded to calculate area under the curve) |
| Oxygenation Response to Additional Inotropes or Pulmonary Vasodilators | Through 24 h post study drug initiation | If subsequent to the study drug, any additional inotrope or pulmonary vasodilator is used (such as iNO), we will evaluate the oxygenation response to these agents. If inotropes or vasodilators were used prior to the initiation of study drug, similar values will be recorded. The OI and PaO2/ FiO2 ratio prior to at least 30 min after initiation of the inotrope / vasodilator are recorded. The change in OI and PaO2/ FiO2 ratio in response to these agents is evaluated as a continuous variable and arbitrarily classified into responders, partial responders and non-responders |
| Supplemental Continuous Oxygen | 28 days and 56 days postnatal age (or discharge whichever comes first) | The use of supplemental oxygen at 28 d will be used to calculate the incidence of chronic lung disease. Chronic lung disease severity will be classified similar to the BPD classification in preterm infants at \> 32 week gestation. |
| Survival to Discharge Without ECMO | Measured by no ECMO at time of hospital discharge or at the time the infant reaches 120 days of life and remains in the hospital, whichever comes earlier | — |
| Oxygenation Response at 48 and 72 h | 48 and 72 h after initiation of study drug | Oxygenation index at 48 and 72 h (or OI at the time of initiation of ECMO or immediately prior to death, for infants placed on ECMO or died before these time points) |
| Feasibility and Sample Size Calculation to Perform a Definitive Trial (Primary Outcome - Improvement in Survival Without ECMO | From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years | — |
| Feasibility to Perform a Definitive Trial (Incidence of Systemic Hypotension) | From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years | — |
| Feasibility to Perform a Definitive Trial (Incidence of Intracranial Bleeding) | From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years | — |
| Feasibility to Perform a Definitive Trial (Incidence of Arrhythmias) | From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years | — |
| Adjusted Oxygen Response | 24 h after initiation of study drug | — |
| Clinical Status (Pulmonary and Nutritional) | All clinical status measures (as defined by protocol) will be obtained just prior to the infants discharge from the hospital and again at 12 months of age. | Clinical status - pulmonary (use of supplemental oxygen or respiratory medications - diuretics, methylxanthines, steroids, inhaled or nebulized steroids or bronchodilators) and nutritional (weight, length, head circumference, use of anti-reflux medications) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Milrinone Milrinone infusion at 0.33µg/kg/min. The dose of the study drug will be increased to 0.66 µg/kg/min if oxygenation index (OI) remains ≥ 10 without any evidence of hypotension (as defined by the protocol) two hours after initiation of study drug. Infusion will be continued until the OI decreases to \< 7. The maximum duration of study drug infusion is 72 hours. | 33 |
| 5% dextrose (D5W) An equivalent volume of 5% dextrose (D5W) will be used for infants randomized to the placebo arm. | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | 5% dextrose (D5W) | Total | Milrinone |
|---|---|---|---|
| Age, Customized | 19.6 hours | 16.9 hours | 14.4 hours |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 12 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 52 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) White | 25 Participants | 55 Participants | 30 Participants |
| Sex: Female, Male Female | 13 Participants | 30 Participants | 17 Participants |
| Sex: Female, Male Male | 20 Participants | 36 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 33 | 2 / 33 |
| other Total, other adverse events | 5 / 33 | 2 / 33 |
| serious Total, serious adverse events | 5 / 33 | 3 / 33 |
Outcome results
Primary
Oxygenation Response
The primary outcome of this study is change in oxygenation from baseline (prior to study drug infusion) to 24 hours after initiation of study drug infusion. Oxygenation is assessed by oxygenation index (OI = mean airway pressure x oxygen concentration in % / PaO2 in mmHg). Oxygen saturation index (OSI = mean airway pressure x oxygen concentration in % / oxygen saturation in %) values were converted to OI values for this measure. Data are presented as OI at 24 hours minus OI at baseline. A negative value indicates improvement in oxygenation. A positive value indicates deterioration in oxygenation.
Time frame: 24 h after initiation of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Milrinone | Oxygenation Response | 4.2 Change in Oxygenation Index |
| 5% dextrose (D5W) | Oxygenation Response | 2.6 Change in Oxygenation Index |
Secondary
Adjusted Oxygen Response
Time frame: 24 h after initiation of study drug
Secondary
Area Under the Curve for Inspired Oxygen
Area under the curve for inspired oxygen after initiation of the study drug (inspired oxygen and ventilator data from 4 time points per day - every 6 hours will be recorded to calculate area under the curve)
Time frame: After initiation of the study drug at 4 time points per day - every 6 hours x 72 hours or discontinuation of study drug (whichever comes first)
Secondary
Changes in Estimated Systolic Pulmonary Arterial Pressure on Echocardiogram
Changes in echocardiogram to assess pulmonary arterial pressure (as defined by protocol) between pre-study drug echocardiogram and echocardiogram obtained between 24 and 72 h after starting the study drug. The outcome will be available only for those infants who have a pre-study drug echocardiogram and a second echocardiogram between 24 and 72 hours after initiation of study drug performed for clinical reasons.
Time frame: Prior to initiation of study drug to between 24 and 72 hours after initiation of study drug
Secondary
Clinical Status (Pulmonary and Nutritional)
Clinical status - pulmonary (use of supplemental oxygen or respiratory medications - diuretics, methylxanthines, steroids, inhaled or nebulized steroids or bronchodilators) and nutritional (weight, length, head circumference, use of anti-reflux medications)
Time frame: All clinical status measures (as defined by protocol) will be obtained just prior to the infants discharge from the hospital and again at 12 months of age.
Secondary
Feasibility and Sample Size Calculation to Perform a Definitive Trial (Primary Outcome - Improvement in Survival Without ECMO
Time frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
Secondary
Feasibility to Perform a Definitive Trial (Incidence of Arrhythmias)
Time frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
Secondary
Feasibility to Perform a Definitive Trial (Incidence of Intracranial Bleeding)
Time frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
Secondary
Feasibility to Perform a Definitive Trial (Incidence of Systemic Hypotension)
Time frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years
Secondary
Oxygenation Response at 48 and 72 h
Oxygenation index at 48 and 72 h (or OI at the time of initiation of ECMO or immediately prior to death, for infants placed on ECMO or died before these time points)
Time frame: 48 and 72 h after initiation of study drug
Secondary
Oxygenation Response to Additional Inotropes or Pulmonary Vasodilators
If subsequent to the study drug, any additional inotrope or pulmonary vasodilator is used (such as iNO), we will evaluate the oxygenation response to these agents. If inotropes or vasodilators were used prior to the initiation of study drug, similar values will be recorded. The OI and PaO2/ FiO2 ratio prior to at least 30 min after initiation of the inotrope / vasodilator are recorded. The change in OI and PaO2/ FiO2 ratio in response to these agents is evaluated as a continuous variable and arbitrarily classified into responders, partial responders and non-responders
Time frame: Through 24 h post study drug initiation
Secondary
Supplemental Continuous Oxygen
The use of supplemental oxygen at 28 d will be used to calculate the incidence of chronic lung disease. Chronic lung disease severity will be classified similar to the BPD classification in preterm infants at \> 32 week gestation.
Time frame: 28 days and 56 days postnatal age (or discharge whichever comes first)
Secondary
Survival to Discharge Without ECMO
Time frame: Measured by no ECMO at time of hospital discharge or at the time the infant reaches 120 days of life and remains in the hospital, whichever comes earlier
Secondary
Vasoactive Inotrope Score and Systemic Blood Pressure
Vasoactive Inotrope Score is a quantitative assessment of the degree of therapeutic support required by the patient to maintain adequate perfusion and/or blood pressure.
Time frame: 72 hours after initiation of study drug