Management of Hypotension In the Preterm Infant
Information source: University College Cork
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypotension; Low Blood Pressure; Intraventricular Hemorrhage of Prematurity
Intervention: Dopamine hydrochloride (Drug); Dextrose 5% (Drug)
Phase: Phase 3
Status: Recruiting
Sponsored by: University College Cork Official(s) and/or principal investigator(s): Eugene Dempsey, Study Director, Affiliation: University College Cork Peter Filan, Principal Investigator, Affiliation: Cork University Maternity Hospital Gunnar Naulaers, Principal Investigator, Affiliation: Katholieke Universiteit Leuven Zybnek Stranak, Principal Investigator, Affiliation: Univerzita Karlova v Praze Keith Barrington, Principal Investigator, Affiliation: St. Justine's Hospital Colm O Donnell, Principal Investigator, Affiliation: University College Dublin Jan Miletin, Principal Investigator, Affiliation: Coombe Women and Infants University Hospital Po-Yin Cheung, Principal Investigator, Affiliation: University of Alberta David Corcoran, Principal Investigator, Affiliation: Royal College of Surgeons in Ireland Neil Marlow, Principal Investigator, Affiliation: University College, London Gerard Pons, Principal Investigator, Affiliation: Institut National de la Santé Et de la Recherche Médicale, France David Van Laere, Principal Investigator, Affiliation: Neonatale Intensieve Zorgen David Millar, Principal Investigator, Affiliation: Royal Maternity Hospital
Overall contact: Eugene Dempsey, Phone: 00 353 21 4920525, Email: Gene.Dempsey@hse.ie
Summary
The HIP trial is a large pragmatic, multinational, randomised trial of two different
strategies for the management of hypotension in extremely low gestational age newborns
(Standard with dopamine versus a restricted with placebo approach).
HYPOTHESIS: A restricted approach to the management of hypotension in extremely low
gestational age newborns will result in improved neonatal and long-term developmental
outcomes.
PRIMARY OBJECTIVE: To determine whether a restricted approach to the management of
hypotension compared to using dopamine as first line pressor agent in infants born less than
28 weeks of gestation within the first 72 hrs after birth (transitional period), improves
survival without significant brain injury at 36 weeks postmenstrual age (PMA) and improves
survival without moderate or severe neurodevelopmental disability at 2 years corrected age.
Clinical Details
Official title: Management of Hypotension In Preterm Infants: The HIP Trial Protocol for a Randomized Controlled Trial of Hypotension Management in the Extremely Low Gestational Age Newborn
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: First Co-Primary Outcome Measure: Survival to 36 weeks postmenstrual age free of severe brain injurySecond Co-Primary Outcome Measure: Survival without moderate or serious disability as defined using consensus criteria for neurodevelopmental impairment.
Secondary outcome: All cause mortality at 36 weeks gestational age
Detailed description:
While hypotension - low blood pressure (BP) - is commonly diagnosed and treated in the very
preterm infant there is enormous variation in clinical practice. Hypotension is statistically
associated with adverse short-term and long-term outcomes however a systematic review of the
literature was unable to find clear criteria to define hypotension. In addition the evidence
to support current management strategies is minimal and mostly dependent on small studies
that have measured short-term physiologic endpoints. Preterm infants who are diagnosed with
and treated for low BP often have no biochemical or clinical signs of shock, they may have
normal systemic blood flow, low systemic vascular resistance, and adequate tissue oxygen
delivery and probably do not require treatment. Careful observation of such infants without
intervention approach previously coined "permissive hypotension" may well be appropriate.
Excessive intervention in preterm infants may be unnecessary or even harmful. Analysis of a
large neonatal database (Canadian Neonatal Network, CNN) demonstrated that treatment of
hypotension was associated with an increase in serious brain injury. This remained true even
after mean BP was included in the regression model suggesting that it may be the treatment
of hypotension rather than the presence of hypotension which is harmful. The most common
approach to treatment is to give one or more fluid boluses followed by dopamine. However,
observational data have shown an association of fluid bolus administration with intracranial
bleeding and in animal models correction of hypotension by rapid volume infusion can result
in intraventricular haemorrhage; a complication which is associated with increased rates of
death and neurosensory impairment in preterm human infants. Fluctuations in BP following
commencement of inotropes are well recognised and could also trigger intraventricular
haemorrhage. Furthermore dopamine the most commonly used inotrope has effects on many
physiologic functions including pituitary effects which lead to secondary hypothyroidism a
known risk factor for poor long-term neurodevelopmental outcome in the preterm infant. In
addition dopamine elevates BP in the newborn predominantly due to vasoconstriction, which
may be associated with a reduction in systemic perfusion.
There is no consensus on definitions of hypotension in the preterm infant. Many clinicians
rely on absolute BP values alone to guide intervention. BP reference ranges are often based
on birth weight, gestational age and postnatal age criteria. These statistically determined
values vary considerably being based on observations of BP made in small cohorts of infants
the majority of whom were born before the widespread implementation of important perinatal
interventions (e. g antenatal glucocorticoid therapy) which are known to improve outcome and
reduce the incidence of intraventricular haemorrhage in preterm infants. The Joint Working
Group of the British Association of Perinatal Medicine has recommended that the mean
arterial BP in mmHg should be maintained above the gestational age in weeks (e. g. an infant
born at 25 weeks gestation should have a mean BP > 25mmHg). Despite little published
evidence to support this 'rule', it remains the most common criterion used to define
hypotension and it has been used in a number of recent randomised therapeutic intervention
trials where it was the sole entry criteria. However, Cunningham et al have shown a poor
relationship between this criterion and the incidence of intraventricular haemorrhage in
preterm infants. In a separate study, the CNN report that 52% of preterm infants with birth
weight < 1500g have a mean arterial BP less than their gestational age on the first day of
life and thus may be diagnosed with and treated for hypotension.
It is uncertain whether hypotension (however defined) results in adverse clinical outcomes
including adverse short-term outcomes (increased incidence of intraventricular haemorrhage)
and adverse long-term neurodevelopmental outcome. Furthermore it is unclear whether
intervention to treat hypotension results in improved outcomes. Dopamine is the most
commonly used agent, an endogenous catecholamine that causes vasoconstriction and elevates
BP, but has not been shown to improve clinical outcomes. Epinephrine is another endogenous
catecholamine, which at low to moderate doses causes vasodilatation and stimulates cardiac
function. It may increase perfusion when used in hypotensive neonates but the data are
limited.
Current standard approaches to evaluation and treatment of transitional circulatory problems
in the preterm infant are not evidence based. It is essential that these approaches be
adequately investigated in this at risk group of infants.
Eligibility
Minimum age: 23 Weeks.
Maximum age: 27 Weeks.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Gestational age at birth less than 28 completed weeks, i. e. up to and including 27
weeks and 6 days.
2. Within 72 hours of birth
3. An indwelling arterial line, either umbilical or peripheral (e. g. radial, posterior
tibial), suitably calibrated and zeroed, to monitor BP with the measuring dome at the
level of the infant's mid-axillary line when supine
4. A pre-trial cerebral ultrasound scan demonstrating no evidence of grade 3 or 4
haemorrhage intraventricular haemorrhage (IVH)(i. e. intraparenchymal echodensity or
echolucency, with or without acquired cerebral ventriculomegaly)
5. A mean blood pressure 1 mmHg or more below a mean BP value equivalent to the
gestational age in completed weeks, which persists over a 15 minute period (mean BP <
gestational age)
Exclusion Criteria:
1. Considered non-viable by attending clinicians.
2. Life-threatening congenital abnormalities including congenital heart disease
(excluding patent ductus arteriosus, small atrial and/or ventricular septal defect).
Infants known to require surgical treatment e. g. congenital diaphragmatic hernia,
trache-oesophageal fistula, omphalocele, gastroschisis. Neuromuscular disorders.
Frank hypovolaemia. Hydrops Fetalis.
3. Cranial ultrasound abnormality grade 3 IVH or more prior to enrolment
Locations and Contacts
Eugene Dempsey, Phone: 00 353 21 4920525, Email: Gene.Dempsey@hse.ie
Cork University Maternity Hospital, Cork, Ireland; Recruiting Eugene Dempsey, Phone: 00 353 21 4920525, Email: gene.dempsey@hse.ie Niamh O Shea, Phone: 00 353 879696229, Email: n.oshea@ucc.ie Peter Filan, Principal Investigator
Royal College of Surgeons in Ireland, Dublin, Ireland; Not yet recruiting David Corcoran, Phone: 0035314022100, Email: dcorcoran@rotunda.ie David Corcoran, Principal Investigator
Royal Maternity Hospital, Belfast BT12 6BA, United Kingdom; Not yet recruiting David Millar, Email: david.millar@belfasttrust.hscni.net David Millar, Principal Investigator
University of Alberta, Edmonton, Alberta T6G 2R3, Canada; Not yet recruiting Po-Yin Cheung, Phone: 0017804923111, Email: poyin@ualberta.ca Po-Yin Cheung, Principal Investigator
Coombe Women and Infants University Hospital, Dublin 8, Dublin 8, Ireland; Recruiting Jan Miletin, Phone: 0035314085200, Email: miletinj@yahoo.com Jan Miletin, Principal Investigator
University College Dublin, Dun Laoghaire, Rathdown, Dublin, Ireland; Not yet recruiting Colm O Donnell, Phone: 0035317167777, Email: codonnell@nmh.ie Colm O Donnell, Principal Investigator
University Hospital Antwerp, Wilrijkstraat 10, Edegem B-2650, Belgium; Not yet recruiting David Van Laere, Phone: 00 32 3 821 58 07, Email: David.VanLaere@uza.be David Van Laere, Principal Investigator
Katholieke Universiteit Leuven, Oude God, Leuven 3000, Belgium; Not yet recruiting Gunnar Naulaers, Phone: 003216324010, Email: gunnar.naulaers@uzleuven.be Gunnar Naulaers, Principal Investigator
Univerzita Karlova v Praze, Ovocný trh 5, Prague 11636, Czech Republic; Recruiting Zbyněk Straňák, Phone: 00420224491111, Email: z.stranak@seznam.cz Zbyněk Straňák, Principal Investigator
Centre hospitalier universitaire Sainte-Justine, Montreal, Quebec H1T 1C9, Canada; Not yet recruiting Keith Barrington, Phone: 0015143454931, Email: keith.barrington@umontreal.ca Keith Barrington, Principal Investigator
Additional Information
Starting date: January 2015
Last updated: January 27, 2015
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