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Management of Hypotension In the Preterm Infant (HIP)

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ClinicalTrials.gov Identifier: NCT01482559
Recruitment Status : Terminated (Study ceased enrolling due to poor overall recruitment. Long-term follow up of enrolled participants ongoing.)
First Posted : November 30, 2011
Last Update Posted : October 2, 2019
Sponsor:
Collaborators:
Cork University Hospital
Coombe Women and Infants University Hospital
Royal College of Surgeons, Ireland
National Maternity Hospital, Ireland
University Hospital, Antwerp
KU Leuven
University of Alberta
St. Justine's Hospital
Institute for the Care of Mother and Child, Prague, Czech Republic
GABO:mi
BrePco Biopharma Limited
University College, London
Institut National de la Santé Et de la Recherche Médicale, France
Clininfo S.A.
Information provided by (Responsible Party):
Dr. Gene Dempsey, University College Cork

Tracking Information
First Submitted Date  ICMJE November 27, 2011
First Posted Date  ICMJE November 30, 2011
Last Update Posted Date October 2, 2019
Actual Study Start Date  ICMJE February 2015
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 26, 2013)
  • First Co-Primary Outcome Measure: Survival to 36 weeks postmenstrual age free of severe brain injury [ Time Frame: 36 weeks ]
    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 ]
    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).
Original Primary Outcome Measures  ICMJE
 (submitted: November 29, 2011)
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 ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2011)
All cause mortality at 36 weeks gestational age [ Time Frame: 36 weeks gestational age ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Management of Hypotension In the Preterm Infant
Official Title  ICMJE 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
Brief 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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Hypotension
  • Low Blood Pressure
  • Intraventricular Hemorrhage of Prematurity
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Placebo Comparator: dextrose 5%
    IV Infusion
    Intervention: Drug: Dextrose 5%
  • Experimental: Dopamine Hydrochloride
    IV Infusion
    Intervention: Drug: Dopamine hydrochloride
Publications * Dempsey EM, Barrington KJ, Marlow N, O'Donnell CPF, Miletin J, Naulaers G, Cheung PY, Corcoran JD, El-Khuffash AF, Boylan GB, Livingstone V, Pons G, Macko J, Van Laere D, Wiedermannova H, Straňák Z; HIP consortium. Hypotension in Preterm Infants (HIP) randomised trial. Arch Dis Child Fetal Neonatal Ed. 2021 Jul;106(4):398-403. doi: 10.1136/archdischild-2020-320241. Epub 2021 Feb 24.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 30, 2019)
58
Original Estimated Enrollment  ICMJE
 (submitted: November 29, 2011)
756
Actual Study Completion Date  ICMJE October 2019
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 23 Weeks to 27 Weeks   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   Czechia,   Ireland,   United Kingdom
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01482559
Other Study ID Numbers  ICMJE HIP-FP7-BrePco
2010-023988-17 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dr. Gene Dempsey, University College Cork
Study Sponsor  ICMJE University College Cork
Collaborators  ICMJE
  • Cork University Hospital
  • Coombe Women and Infants University Hospital
  • Royal College of Surgeons, Ireland
  • National Maternity Hospital, Ireland
  • University Hospital, Antwerp
  • KU Leuven
  • University of Alberta
  • St. Justine's Hospital
  • Institute for the Care of Mother and Child, Prague, Czech Republic
  • GABO:mi
  • BrePco Biopharma Limited
  • University College, London
  • Institut National de la Santé Et de la Recherche Médicale, France
  • Clininfo S.A.
Investigators  ICMJE
Study Director: Eugene Dempsey University College Cork
Principal Investigator: Peter Filan Cork University Maternity Hospital
Principal Investigator: Gunnar Naulaers KU 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
PRS Account University College Cork
Verification Date September 2019

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