Management of Hypotension In the Preterm Infant (HIP)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified June 2013 by University College Cork
Sponsor:
Collaborators:
BrePco Biopharma Limited
Cork University Hospital
Katholieke Universiteit Leuven
Univerzita Karlova v Praze
St. Justine's Hospital
University College Dublin
Coombe Women and Infants University Hospital
University of Alberta
Royal College of Surgeons, Ireland
GABO:milliarium mbH & Co. KG
Institut National de la Santé Et de la Recherche Médicale, France
Neonatale Intensieve Zorgen
Royal Maternity Hospital
University College, London
Clininfo S.A.
Information provided by (Responsible Party):
Dr. Gene Dempsey, University College Cork
ClinicalTrials.gov Identifier:
NCT01482559
First received: November 27, 2011
Last updated: June 26, 2013
Last verified: June 2013

November 27, 2011
June 26, 2013
August 2013
September 2017   (final data collection date for primary outcome measure)
  • First Co-Primary Outcome Measure: Survival to 36 weeks postmenstrual age free of severe brain injury [ Time Frame: 36 weeks ] [ Designated as safety issue: Yes ]
    Survival to 36 weeks postmenstrual age free of severe brain injury (moderate or severe ventricular dilatation, intracerebral echodense lesions, and cystic periventricular leukomalacia) on cranial ultrasound at 36 weeks or discharge home which ever is the earlier.
  • Second Co-Primary Outcome Measure: Survival without moderate or serious disability as defined using consensus criteria for neurodevelopmental impairment. [ Time Frame: 2 years of age ] [ Designated as safety issue: Yes ]
    Families will be offered routine appointments as per the local follow-up system. At 12-months, the physician will complete a simple disability assessment and all surviving infants will have a locally performed formal neurodisability assessment at 24 months age corrected for weeks of prematurity defined using criteria set out in the consensus statement "Health status...." (ww bapm.org/publications).
Survival to 36 weeks gestational age free of severe brain injury on cranial ultrasound at or nearest 36 weeks [ Time Frame: 2 years corrected gestational age ] [ Designated as safety issue: Yes ]
A composite primary outcome, of survival to 36 weeks gestational age free of severe brain injury (moderate or severe ventricular dilatation, intracerebral echodense lesions, and cystic periventricular leukomalacia) on cranial ultrasound at or nearest 36 weeks. It is important to combine these two outcome components because early death may preclude the formal diagnosis of IVH. It is a standard composite, dichotomous outcome.
Complete list of historical versions of study NCT01482559 on ClinicalTrials.gov Archive Site
All cause mortality at 36 weeks gestational age [ Time Frame: 36 weeks gestational age ] [ Designated as safety issue: Yes ]
Same as current
Not Provided
Not Provided
 
Management of Hypotension In the Preterm Infant
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

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Hypotension
  • Low Blood Pressure
  • Intraventricular Hemorrhage of Prematurity
  • Drug: Dopamine hydrochloride
    Active drug substance 1.5 mg in 1 mL IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min
    Other Name: ATC Code: C01CA04
  • Drug: Dextrose 5%
    IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min
    Other Name: Placebo
  • Placebo Comparator: dextrose 5%
    IV Infusion
    Intervention: Drug: Dextrose 5%
  • Experimental: Dopamine Hydrochloride
    IV Infusion
    Intervention: Drug: Dopamine hydrochloride
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Not yet recruiting
830
September 2017
September 2017   (final data collection date for primary outcome measure)

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
Both
23 Weeks to 27 Weeks
No
Contact: Eugene Dempsey 00 353 21 4920525 Gene.Dempsey@hse.ie
Contact: Niamh O Shea 00 353 87 9696229 N.oshea@ucc.ie
Canada,   Ireland,   Belgium,   United Kingdom,   Czech Republic
 
NCT01482559
HIP-FP7-BrePco, 2010-023988-17
Yes
Dr. Gene Dempsey, University College Cork
University College Cork
  • BrePco Biopharma Limited
  • Cork University Hospital
  • Katholieke Universiteit Leuven
  • Univerzita Karlova v Praze
  • St. Justine's Hospital
  • University College Dublin
  • Coombe Women and Infants University Hospital
  • University of Alberta
  • Royal College of Surgeons, Ireland
  • GABO:milliarium mbH & Co. KG
  • Institut National de la Santé Et de la Recherche Médicale, France
  • Neonatale Intensieve Zorgen
  • Royal Maternity Hospital
  • University College, London
  • Clininfo S.A.
Study Director: Eugene Dempsey University College Cork
Principal Investigator: Peter Filan Cork University Maternity Hospital
Principal Investigator: Gunnar Naulaers Katholieke Universiteit Leuven
Principal Investigator: Zybnek Stranak Univerzita Karlova v Praze
Principal Investigator: Keith Barrington St. Justine's Hospital
Principal Investigator: Colm O Donnell University College Dublin
Principal Investigator: Jan Miletin Coombe Women and Infants University Hospital
Principal Investigator: Po-Yin Cheung University of Alberta
Principal Investigator: David Corcoran Royal College of Surgeons in Ireland
Principal Investigator: Neil Marlow University College, London
Principal Investigator: Gerard Pons Institut National de la Santé Et de la Recherche Médicale, France
Principal Investigator: David Van Laere Neonatale Intensieve Zorgen
Principal Investigator: David Millar Royal Maternity Hospital
University College Cork
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP