Management of Hypotension In the Preterm Infant

Hypotension Clinical Trial

— HIP  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01482559
• Other study ID #: HIP-FP7-BrePco
• Secondary ID: 2010-023988-17
• Status: Terminated
• Phase: Phase 3
• Start date: February 2015
• Est. completion date: October 2019

Study information

• Verified date: September 2019
• Source: University College Cork
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 58
• Est. completion date: October 2019
• Est. primary completion date: September 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 23 Weeks to 27 Weeks

Eligibility

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

Related Conditions & MeSH terms

• Hemorrhage
• Hypotension
• Intraventricular Hemorrhage of Prematurity
• Low Blood Pressure

Intervention

Drug:
• Dopamine hydrochloride
Active drug substance 1.5 mg in 1 mL IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min
• Dextrose 5%
IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min

Locations

Country	Name	City	State
Belgium	University Hospital Antwerp	Antwerp	Edegem
Belgium	Katholieke Universiteit Leuven	Oude God	Leuven
Canada	University of Alberta	Edmonton	Alberta
Canada	Centre hospitalier universitaire Sainte-Justine	Montreal	Quebec
Czechia	Univerzita Karlova v Praze	Prague
Ireland	Cork University Maternity Hospital	Cork
Ireland	Royal College of Surgeons in Ireland	Dublin
Ireland	University College Dublin	Dublin
Ireland	Coombe Women and Infants University Hospital	Dublin 8	Dublin
United Kingdom	Royal Maternity Hospital	Belfast

Sponsors (15)

Lead Sponsor

Collaborator

University College Cork

BrePco Biopharma Limited, Clininfo S.A., Coombe Women and Infants University Hospital, Cork University Hospital, GABO:mi, Institut National de la Santé Et de la Recherche Médicale, France, Institute for the Care of Mother and Child, Prague, Czech Republic, KU Leuven, National Maternity Hospital, Ireland, Royal College of Surgeons, Ireland, St. Justine's Hospital, University College, London, University Hospital, Antwerp, University of Alberta

Countries where clinical trial is conducted

Belgium,  Canada,  Czechia,  Ireland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	First Co-Primary Outcome Measure: Survival to 36 weeks postmenstrual age free of severe brain injury	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.	36 weeks
Primary	Second Co-Primary Outcome Measure: Survival without moderate or serious disability as defined using consensus criteria for neurodevelopmental impairment.	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).	2 years of age
Secondary	All cause mortality at 36 weeks gestational age		36 weeks gestational age