Milrinone in Congenital Diaphragmatic Hernia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 66
- 试验地点
- 19
- 主要终点
- Oxygenation Response
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 0 Hours 至 168 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •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)
研究组 & 干预措施
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.
干预措施: Milrinone (Drug)
5% dextrose (D5W)
An equivalent volume of 5% dextrose (D5W) will be used for infants randomized to the placebo arm.
干预措施: Placebo (5% Dextrose) (Drug)
结局指标
主要结局
Oxygenation Response
时间窗: 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.
次要结局
- Oxygenation Response at 48 and 72 h(48 and 72 h after initiation of study drug)
- 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)
- Vasoactive Inotrope Score and Systemic Blood Pressure(72 hours after initiation of study drug)
- 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))
- Oxygenation Response to Additional Inotropes or Pulmonary Vasodilators(Through 24 h post study drug initiation)
- Supplemental Continuous Oxygen(28 days and 56 days postnatal age (or discharge whichever comes first))
- 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)
- 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.)
- 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)