The objective of this study is to analyse the hypothesis that intravenous milrinone used in conjunction with iNO results in the reduction in the time on iNO therapy and the time spent on invasive ventilation in infants * 34 weeks gestation and *…
ID
Source
Brief title
Condition
- Other condition
- Heart failures
- Neonatal respiratory disorders
Synonym
Health condition
Persisterende pulmonale hypertensie van de pasgeborene
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome of this study is the time on iNO in hours and the time on
invasive ventilation.
Secondary outcome
The incidence of the use of other inotropes; critically low LV and RV function
and output measured by echocardiography and a non-invasive cardiac output
monitor (NICOM); the rate of adverse effects associated with milrinone
including the incidence of hypotension; and the pre-discharge outcomes in the
two groups.
We will collect the following demographic characteristics and relevant
short-term secondary outcomes: duration of hospital stay; time to extubation;
duration of oxygen therapy, and survival.
Details of cardiorespiratory stability (blood pressure, heart rate, oxygen
saturation), ventilation support (FiO2, mean airway pressure (MAP), oxygenation
index [MAP × F FiO2/PaO2]), efficacy of oxygenation [PaO2], plasma lactate, pH,
PCO2, HCO3-, Base excess; and relevant co- treatments (i.e., sedation,
analgesics, muscle relaxants, inotropes, fluid administration) at the following
time points:
1) Prior to treatment; 2) Following the loading dose; 3) 12 hours after
initiation of therapy; 4) 24 hours after initiation of therapy; 5) Two hours
after discontinuation of therapy
Monitoring of blood parameters will be carried out as follows during the study
period and 24 hours after drug discontinuation:
* Daily full blood count (including platelets):
* Daily electrolytes, Urea and Creatinine:
* Daily liver function tests (ALT, AST, GGT):
* Twelve hourly blood gas analysis:
Echocardiography will be performed according to the following schedule: a
timing window of ± 3 hours will be applied. 1) Prior to the Commencement of
Study Drug: Diagnose PPHN and rule out CHD; 2) 12 hours following the
administration of Study Drug; 3) 24 hours following the administration of the
study drug; 4) 8 hours following the discontinuation of the study drug.
Non-invasive Cardiac output Monitoring (NICOM) will be commenced prior to the
commencement of the study drug and continued until the last echocardiogram, 8
hours after the discontinuation of the study medication.
Cranial ultrasound will performed prior to treatment commencement and after the
discontinuation of the infusion.
Background summary
Persistent pulmonary hypertension of the newborn is common and leads to a major
burden of neonatal illness, carries a significant mortality, need for ECMO, and
adverse neurodevelopmental outcome. There is poor appreciation of the
physiologic determinants of PPHN and predictors of iNO (nitric oxide
inhalation) response at presentation; up to 40% of infants do not respond to
iNO treatment. The increasing cost of iNO may preclude its use in both the
developed and developing countries. The use of milrinone in infants with PPHN
as an adjunct to iNO is worth further exploration with preliminary evidence
suggesting an improvement in both oxygenation and myocardial performance in
this group of infants. It*s inotropic, lusitropic and pulmonary vasodilator
properties make it an ideal agent to use in this setting and may improve
response to therapy and reduce mortality associated with the disease.
Study objective
The objective of this study is to analyse the hypothesis that intravenous
milrinone used in conjunction with iNO results in the reduction in the time on
iNO therapy and the time spent on invasive ventilation in infants * 34 weeks
gestation and * 2000 grams with a clinical and echocardiography diagnosis of
PPHN.
Study design
This is a multicentre, randomized, double-blind, two arm pilot study, with a
balanced (1:1) allocation that will be carried out in level III neonatal
intensive care units in Ireland and The Netherlands
Intervention
Infants in the intervention arm will receive an intravenous loading dose of
milrinone lactate injection (10 mg/10 mL) at a dose of 50*g/kg administered
over 60 minutes followed by a maintenance infusion, beginning at 0.375*g/
kg/min to a maximum 0.750*g/ kg/min. The duration of therapy is until
discontinuation of iNO or a maximum of 35 hours in adherence with the SmPC
recommendation. A 10 mL/ kg bolus of normal saline will be administered with
the milrinone bolus over the same 1 hour period. Dose increase will be
performed in response to parameters reflecting oxygenation.
Infants in the control arm will receive an intravenous loading dose of placebo
(normal saline) at a rate equivalent to the infusion rate of the milrinone
bolus, administered over 60 minutes. A bolus of normal saline of 10 ml/kg will
accompany the placebo infusion, as per the intervention arm. Following the
loading protocol, a saline infusion running at a rate similar to the milrinone
infusion will be commenced for a maximum period of 35 hours or until
discontinuation of iNO if it occurs sooner. The saline infusion will be
titrated up in increments similar to the milrinone infusion.
Study burden and risks
The patients in this study are admitted to the neonatal intensive care unit,
given their critical condition. The administration of milrinone in adjunct to
nitric oxide inhalation is a strategy that is already in use on this department
outside this trial.
Cardiac output will non-invasively be monitored using a thoracic bioreactance
technology (NICOM, Cheetah Medical), which needs the application of 4 sensors
on the newborn. These electrodes will not interfere with regular monitoring and
nursing. This type of cardiac output monitoring is already in use on our
department.
Echocardiography and echoencephalography is already part of standard neonatal
intensive care in these patients with PPHN and will not have influence on the
condition of the newborn.
The necessary monitoring of blood parameters is in accordance with the standard
protocol of the NICU, so no extra blood is withdrawn solely for the purpose of
this study.
Given the fact that these patients will have both an arterial and a central
venous catheter, there will be no need for extra blood punctures.
All patients in this study are managed according current (inter)national
guidelines and protocols.
A risk classification has been performed according the "NFU document
'Kwaliteitsborging mensgebonden onderzoek 2.0' ", that resulted in a
neglectable risk associated with participation with this study.
The study is group related because persistent pulmonary hypertension is a
condition that specifically concerns newborn infants without any known
variability related to sex or ethnicity.
123 St Stephen's Green 123
Dublin 2 0000
IE
123 St Stephen's Green 123
Dublin 2 0000
IE
Listed location countries
Age
Inclusion criteria
1) Gestational age *34 weeks and birth weight *2000 grams
2) * 10 postnatal days of life and within 4 days of admission
3) Echocardiographic diagnosis of PPHN
4) Absence of significant congenital heart defect excluding a small atrial
septal defect or ventricular septal defect (measuring< 3mm)
5) Oxygenation index of * 10
Exclusion criteria
1) Lethal congenital anomalies or obvious syndrome
2) Bleeding diathesis (abnormal coagulation screen/platelet <100,000/ mm3)
3) The presence of Intraventricular haemorrhage.
4) Diastolic Hypotension (defined as a diastolic blood pressure less than the
3rd centile for any given gestation) unresponsive to medical treatment (*30
mL/kg fluid bolus and * 2 inotropes of at least 10 *g/ kg/min)
5) Hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia
6) Evidence of renal impairment (Creatinine > 100micromol/l)
7) Severe Hypovolaemia: Heart rate > 180, capillary refill > 5 seconds, urine
output < 0.5ml/kg/hour, in addition to diastolic hypotension mentioned above.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-002988-16-NL |
| ISRCTN | ISRCTN12949496 |
| CCMO | NL64885.091.18 |