Management of Hypotension In the Preterm Infant (HIP)
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.
|Hypotension Low Blood Pressure Intraventricular Hemorrhage of Prematurity||Drug: Dopamine hydrochloride Drug: Dextrose 5%||Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|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|
- 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).
- All cause mortality at 36 weeks gestational age [ Time Frame: 36 weeks gestational age ]
|Study Start Date:||January 2015|
|Estimated Study Completion Date:||January 2018|
|Estimated Primary Completion Date:||January 2018 (Final data collection date for primary outcome measure)|
Placebo Comparator: dextrose 5%
Drug: Dextrose 5%
IV Infusion Minimum dose = 5mcg/kg/min Maximum dose = 20mcg/kg/min
Other Name: Placebo
Experimental: Dopamine Hydrochloride
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
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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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01482559
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01482559
|Contact: Eugene Dempsey||00 353 21 4920525||Gene.Dempsey@hse.ie|
|Contact: Niamh O Shea||00 353 87 9696229||N.email@example.com|
|University Hospital Antwerp||Not yet recruiting|
|Wilrijkstraat 10, Edegem, Belgium, B-2650|
|Contact: David Van Laere 00 32 3 821 58 07 David.VanLaere@uza.be|
|Principal Investigator: David Van Laere|
|Katholieke Universiteit Leuven||Not yet recruiting|
|Oude God, Leuven, Belgium, 3000|
|Contact: Gunnar Naulaers 003216324010 firstname.lastname@example.org|
|Principal Investigator: Gunnar Naulaers|
|University of Alberta||Not yet recruiting|
|Edmonton, Alberta, Canada, T6G 2R3|
|Contact: Po-Yin Cheung 0017804923111 email@example.com|
|Principal Investigator: Po-Yin Cheung|
|Centre hospitalier universitaire Sainte-Justine||Not yet recruiting|
|Montreal, Quebec, Canada, H1T 1C9|
|Contact: Keith Barrington 0015143454931 firstname.lastname@example.org|
|Principal Investigator: Keith Barrington|
|Univerzita Karlova v Praze||Recruiting|
|Ovocný trh 5, Prague, Czech Republic, 11636|
|Contact: Zbyněk Straňák 00420224491111 email@example.com|
|Principal Investigator: Zbyněk Straňák|
|Coombe Women and Infants University Hospital||Recruiting|
|Dublin 8, Dublin, Ireland, 8|
|Contact: Jan Miletin 0035314085200 firstname.lastname@example.org|
|Principal Investigator: Jan Miletin|
|University College Dublin||Not yet recruiting|
|Dun Laoghaire, Rathdown, Dublin, Ireland|
|Contact: Colm O Donnell 0035317167777 email@example.com|
|Principal Investigator: Colm O Donnell|
|Cork University Maternity Hospital||Recruiting|
|Contact: Eugene Dempsey 00 353 21 4920525 firstname.lastname@example.org|
|Contact: Niamh O Shea 00 353 879696229 email@example.com|
|Principal Investigator: Peter Filan|
|Royal College of Surgeons in Ireland||Not yet recruiting|
|Contact: David Corcoran 0035314022100 firstname.lastname@example.org|
|Principal Investigator: David Corcoran|
|Royal Maternity Hospital||Not yet recruiting|
|Belfast, United Kingdom, BT12 6BA|
|Contact: David Millar email@example.com|
|Principal Investigator: David Millar|
|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|