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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 injury

Second 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

Page last updated: August 23, 2015

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