Management of Hypotension In the Preterm Infant

NCT ID: NCT01482559

Last Updated: 2019-10-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 58 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-28
• Study Completion Date: 2019-10-31

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.

Conditions

Hypotension; Low Blood Pressure; Intraventricular Hemorrhage of Prematurity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

dextrose 5%

IV Infusion

Group Type: PLACEBO_COMPARATOR

Dextrose 5%

Intervention Type: DRUG

IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min

Dopamine Hydrochloride

IV Infusion

Group Type: EXPERIMENTAL

Dopamine hydrochloride

Intervention Type: DRUG

Active drug substance 1.5 mg in 1 mL IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min

Interventions

Dopamine hydrochloride

Active drug substance 1.5 mg in 1 mL IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min

Intervention Type: DRUG

Dextrose 5%

IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min

Intervention Type: DRUG

Other Intervention Names

ATC Code: C01CA04; Placebo

Eligibility 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

• Minimum Eligible Age: 23 Weeks
• Maximum Eligible Age: 27 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cork University Hospital

OTHER

Sponsor Role: collaborator

Coombe Women and Infants University Hospital

OTHER

Sponsor Role: collaborator

Royal College of Surgeons, Ireland

OTHER

Sponsor Role: collaborator

National Maternity Hospital, Ireland

OTHER

Sponsor Role: collaborator

University Hospital, Antwerp

OTHER

Sponsor Role: collaborator

KU Leuven

OTHER

Sponsor Role: collaborator

University of Alberta

OTHER

Sponsor Role: collaborator

St. Justine's Hospital

OTHER

Sponsor Role: collaborator

Institute for the Care of Mother and Child, Prague, Czech Republic

OTHER

Sponsor Role: collaborator

GABO:mi

INDUSTRY

Sponsor Role: collaborator

BrePco Biopharma Limited

OTHER

Sponsor Role: collaborator

University College, London

OTHER

Sponsor Role: collaborator

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: collaborator

Clininfo S.A.

INDUSTRY

Sponsor Role: collaborator

University College Cork

OTHER

Sponsor Role: lead

Responsible Party

Dr. Gene Dempsey

Professor Eugene Dempsey, Consultant Neonatologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Eugene Dempsey

Role: STUDY_DIRECTOR

University College Cork

Peter Filan

Role: PRINCIPAL_INVESTIGATOR

Cork University Maternity Hospital

Gunnar Naulaers

Role: PRINCIPAL_INVESTIGATOR

KU Leuven

Zybnek Stranak

Role: PRINCIPAL_INVESTIGATOR

Univerzita Karlova v Praze

Keith Barrington

Role: PRINCIPAL_INVESTIGATOR

St. Justine's Hospital

Colm O Donnell

Role: PRINCIPAL_INVESTIGATOR

University College Dublin

Jan Miletin

Role: PRINCIPAL_INVESTIGATOR

Coombe Women and Infants University Hospital

Po-Yin Cheung

Role: PRINCIPAL_INVESTIGATOR

University of Alberta

David Corcoran

Role: PRINCIPAL_INVESTIGATOR

Royal College of Surgeons in Ireland

Neil Marlow

Role: PRINCIPAL_INVESTIGATOR

University College, London

Gerard Pons

Role: PRINCIPAL_INVESTIGATOR

Institut National de la Santé Et de la Recherche Médicale, France

David Van Laere

Role: PRINCIPAL_INVESTIGATOR

Neonatale Intensieve Zorgen

David Millar

Role: PRINCIPAL_INVESTIGATOR

Royal Maternity Hospital

Locations

University Hospital Antwerp

Antwerp, Edegem, Belgium

Katholieke Universiteit Leuven

Oude God, Leuven, Belgium

University of Alberta

Edmonton, Alberta, Canada

Centre hospitalier universitaire Sainte-Justine

Montreal, Quebec, Canada

Univerzita Karlova v Praze

Prague, , Czechia

Coombe Women and Infants University Hospital

Dublin, Dublin, Ireland

Cork University Maternity Hospital

Cork, , Ireland

Royal College of Surgeons in Ireland

Dublin, , Ireland

University College Dublin

Dublin, , Ireland

Royal Maternity Hospital

Belfast, , United Kingdom

Countries

Belgium; Canada; Czechia; Ireland; United Kingdom

References

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, Stranak 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.

Reference Type: DERIVED

PMID: 33627329 (View on PubMed)

Other Identifiers

2010-023988-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

HIP-FP7-BrePco

Identifier Type: -

Identifier Source: org_study_id