Management of Hypotension In the Preterm Infant
Management of Hypotension In the Preterm Infant
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.
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